WO2024055042A1 - Methods for treating agitation in community settings - Google Patents

Methods for treating agitation in community settings Download PDF

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Publication number
WO2024055042A1
WO2024055042A1 PCT/US2023/073874 US2023073874W WO2024055042A1 WO 2024055042 A1 WO2024055042 A1 WO 2024055042A1 US 2023073874 W US2023073874 W US 2023073874W WO 2024055042 A1 WO2024055042 A1 WO 2024055042A1
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Prior art keywords
patient
dexmedetomidine
micrograms
agitation
pharmaceutically acceptable
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PCT/US2023/073874
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French (fr)
Inventor
Michael De Vivo
Lavanya Rajachandran
Rob RISINGER
Hajira KOELLER
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Bioxcel Therapeutics, Inc.
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Publication of WO2024055042A1 publication Critical patent/WO2024055042A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays

Definitions

  • the present disclosure relates to method of treating agitation in schizophrenia or bipolar disorder patients in a non-clinical setting, comprising administering oromucosally an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant or self-administration by the patient.
  • the agitation may be mild to moderate.
  • BACKGROUND [0003] Agitation, represented by a state of motor restlessness and accompanying mental tension, is a serious medical problem that can be present in some psychiatric disorders and may escalate quickly to aggressive behaviour. Patients with neuropsychiatric disorders like schizophrenia and bipolar disorder are particularly vulnerable to acute episodes of agitation, especially during exacerbation of the disease.
  • the present methods as described herein improve the health care service in non-clinical settings such as at home, group home, assisted living facility, correctional facility, hospice or long-term care facility, by allowing for a greater proportion of patients to be treated at a much lower cost than if they were still receiving inpatient services.
  • the technical effect of the methods of the present disclosure is to enable caregivers or informants and individuals to collect objective data with minimal patient inconvenience; to correlate patterns and changes in the data to an individual's state of mental health; and to regulate and, if necessary, change the individual's medication or other therapy regime based on patterns in the data and changes in the individual's types, responses, and level of activities.
  • the overall result lessens the burden on the healthcare system and provides a more positive outcome for the patient.
  • the present disclosure provides methods of treating agitation in schizophrenia or bipolar disorder patients in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 60 micrograms to the patient wherein the patient is 18 years or older.
  • the present disclosure provides methods of treating agitation in schizophrenia or bipolar disorder patients in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 80 micrograms to the patient wherein the patient is 18 years or older.
  • the present disclosure provides methods of treating acute agitation in schizophrenia or bipolar disorder patients in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a total daily dose of about 60 micrograms to about 360 micrograms to the patient, wherein the patient is 18 years or older.
  • the present disclosure provides methods of treating acute agitation in a schizophrenia or bipolar disorder patient in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a total daily dose of about 60 micrograms to about 180 micrograms to the patient, wherein the patient is 18 years or older.
  • the schizophrenia includes schizoaffective or schizophreniform disorder.
  • the bipolar disorder includes bipolar disorder I or bipolar disorder II.
  • dexmedetomidine or a pharmaceutically acceptable salt thereof is administered by the caregiver or informant of the patient.
  • the caregiver or informant is a family member or a family friend.
  • the caregiver or informant is a person employed by or for the patient.
  • the caregiver or informant maintains close physical proximity to the patient for at least 8 hours after the administration of 2 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 dexmedetomidine or a pharmaceutically acceptable salt thereof.
  • dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.
  • the non-clinical setting is at home. In embodiments, the non-clinical setting is at group home, assisted living facility, correctional facility, hospice or long-term care facility. [0013] In embodiments, the patient experiences not more than 2 episodes of agitation per week.
  • the patient may have at least 1 episode per month, at least 2 episodes per month, or at least 3 episodes of agitation per month.
  • the non-clinical setting may have an upper limit on episodes in a given time period; for example, the patient may have up to 1, up to 2, up to 3, up to 4, up to 5, or up to 6 episodes of agitation per month.
  • the agitation is mild or moderate.
  • the agitation is acute.
  • the agitation is not severe.
  • the route of administration is oromucosal (e.g., sublingual, buccal or gingival).
  • dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in an oromucosal dosage form selected from the group consisting of a film, wafer, patch, lozenge, gel, spray, tablet and liquid drops.
  • the dosage form is a thin film.
  • the dosage form is a sublingual film.
  • the dosage form is a buccal film.
  • the dosage form is a gingival film.
  • dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as a single dose per day.
  • the total daily dose may be administered oromucosally multiple times (e.g., one to four times) as a single unit dose, as multiple unit doses, or as a fraction of one or more unit doses (e.g., half of a unit dose), or a combination thereof at an appropriate dosing interval (e.g., at least after 0.5 hours) to produce a desired effect.
  • the total daily dose of dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as a first and optional second dose.
  • the first dose is about 60 micrograms, about 70 micrograms, about 80 micrograms, about 90 micrograms, about 100 micrograms, about 110 micrograms, about 120 micrograms or about 180 micrograms of dexmedetomidine hydrochloride.
  • 3 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 the first dose is 60 micrograms of dexmedetomidine hydrochloride.
  • the first dose is 80 micrograms of dexmedetomidine hydrochloride.
  • the second dose is administered at least about 2 hours after administration of the first dose if there is no improvement in PEC score by more than 2 points.
  • the patient is hemodynamically stable.
  • the second dose is administered at least about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours, about 8 hours, about 8.5 hours, about 9 hours, about 9.5 hours, about 10 hours, about 10.5 hours, about 11 hours, about 11.5 hours, about 12 hours, about 12.5 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours or about 24 hours after administration of the first dose.
  • the optional second dose is about 60 micrograms, about 70 micrograms, about 80 micrograms, about 90 micrograms, about 100 micrograms, about 110 micrograms, about 120 micrograms or about 180 micrograms of dexmedetomidine hydrochloride. In embodiments, the optional second dose is about 60 micrograms of dexmedetomidine hydrochloride. In embodiments, the optional second dose is 80 micrograms of dexmedetomidine hydrochloride.
  • the present disclosure provides methods of treating acute agitation in a schizophrenia patient with in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a total daily dose of about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant.
  • oromucosally e.g., sublingually, buccally, or gingivally
  • the present disclosure provides methods of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant.
  • oromucosally e.g., sublingually, buccally, or gingivally
  • the present disclosure provides methods of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a dose of about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant.
  • oromucosally e.g., sublingually, buccally, or gingivally
  • the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a total daily dose of about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant.
  • a bipolar disorder e.g., bipolar disorder I or bipolar disorder II
  • oromucosally e.g., sublingually, buccally, or gingivally
  • the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g. bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a total daily dose of about 60 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant.
  • a bipolar disorder e.g. bipolar disorder I or bipolar disorder II
  • oromucosally e.g., sublingually, buccally, or gingivally
  • the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant.
  • a bipolar disorder e.g., bipolar disorder I or bipolar disorder II
  • oromucosally e.g., sublingually, buccally, or gingivally
  • the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a dose of about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant.
  • a bipolar disorder e.g., bipolar disorder I or bipolar disorder II
  • oromucosally e.g., sublingually, buccally, or gingivally
  • the present disclosure provides methods of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising self-administering, by the patient, an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides methods of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising an oromucosal dosage form comprising administering about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.
  • the present disclosure provides methods of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising self-administering, by the patient, 5 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 an oromucosal dosage form comprising about 60 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides methods of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising administrating an oromucosal dosage form comprising about 60 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.
  • the present disclosure provides methods of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising self-administering, by the patient, an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides methods of treating acute agitation in a schizophrenia patient in a non-clinical setting, administering an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self- administered by the patient.
  • the present disclosure provides methods of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising self-administering, by the patient, an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides methods of treating acute agitation in a schizophrenia patient in a non-clinical setting, administering an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self- administered by the patient.
  • the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising self-administering, by the patient, an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.
  • a bipolar disorder e.g., bipolar disorder I or bipolar disorder II
  • an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 60 micrograms to 6 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self- administered by the patient.
  • a bipolar disorder e.g., bipolar disorder I or bipolar disorder II
  • the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising self-administering, by the patient, an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.
  • a bipolar disorder e.g., bipolar disorder I or bipolar disorder II
  • an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting comprising administering an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.
  • a bipolar disorder e.g., bipolar disorder I or bipolar disorder II
  • the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising self-administering, by the patient, an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.
  • a bipolar disorder e.g., bipolar disorder I or bipolar disorder II
  • an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.
  • the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in two phases.
  • phase 1 comprises administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof under medical supervision, wherein the duration of phase 1 is at least 8 hours.
  • phase 2 comprises administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof under non-medical supervision (non-clinical setting), wherein the duration of phase 2 is up to 12 weeks.
  • the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient, the method comprising: 7 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 (a) administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof under medical supervision for at least 8 hours; and (b) administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof under non-medical supervision (non-clinical setting) for up to 12 weeks.
  • a bipolar disorder e.g., bipolar disorder I or bipolar disorder II
  • phase 1 comprises oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof under medical supervision, wherein the duration of phase 1 is at least 8 hours.
  • phase 2 comprises administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof under non-medical supervision (non-clinical setting), wherein the duration of phase 2 is up to 12 weeks.
  • oromucosally e.g., sublingually, buccally, or gingivally
  • non-medical supervision non-medical setting
  • the present disclosure provides methods of treating acute agitation in a schizophrenia patient, the method comprising: (a) administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof under medical supervision for at least 8 hours; and (b) administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof under non-medical supervision (non-clinical setting) for up to 12 weeks.
  • oromucosally e.g., sublingually, buccally, or gingivally
  • non-medical supervision non-medical setting
  • the oromucosal dosage form is selected from the group consisting of a film, wafer, patch, lozenge, gel, spray, tablet and liquid drops. In embodiments, the dosage form is a sublingual or buccal or gingival film. [0053] In embodiments, the administration of dexmedetomidine or the oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof produces anti- agitation effect within about 30 minutes after administration.
  • the administration of dexmedetomidine or the oromucosal dosage form comprising 8 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 dexmedetomidine or a pharmaceutically acceptable salt thereof produces anti-agitation effect within about 20 minutes after administration.
  • the administration of dexmedetomidine or the oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof produces anti-agitation effect within about 15 minutes after administration.
  • the agitation is treated without also inducing significant sedation.
  • the treatment is effective with reduced or no side effects (e.g., cardiac or respiratory side effects).
  • the patient achieves a mean change in PEC score of greater than -7 relative to baseline within 30 minutes of administration.
  • the patient achieves a CGI-I score improvement to about a 1 (very much improved) or about a 2 (much improved).
  • the agitation is reduced to a 2 (moderate agitation), 3 (mild agitation) or 4 (normal behavior) 30 minutes after administration as measured by the Agitation-Calmness Evaluation Scale (ACES).
  • ACS Agitation-Calmness Evaluation Scale
  • a caregiver or informant is altered to a patient’s impending episode of agitation via Ecological Momentary Assessment (EMA) device or other remote compatible device.
  • the EMA device is monitored by the caregiver or informant.
  • the EMA device comprises a caregiver’s or informant’s smart phone or a tablet with an application installed to report the patient’s observations.
  • a caregiver or an information is altered to a reduction in a patient’s agitation via Ecological Momentary Assessment (EMA) device or other remote compatible device.
  • the alerts are received in the form of a text message, a call, a sound or a window flashing/display on the device of the caregiver or informant.
  • the patient’s observations are recorded from one or more wearable devices (or wearable sensors) worn/placed/mounted on the body of the patient.
  • the wearable device (or a wearable sensor) is in contact with the patient and may be selected from iPhone (BYOD or provisioned), accelerometers, gyroscopes, portable devices, digital devices, smart fabrics, bands and actuators like an Apple watch or iWatch, patch such as MC10 Patch, sensors like Microsoft Kinect and the like.
  • the wearable device is a bracelet, anklet, shoe, armband, thigh band or a mitten.
  • the wearable device is smartwatch, ring, patch, conductive tattoo, head wearable.
  • the wearable device is wrist worn multi-sensor device with networking capability (e.g., wearable watch such as Apple watch).
  • the patient, the caregiver, or informant records observations in an agitation episode diary for each episode of agitation.
  • the agitation episode diary comprises questions based on safety information, use of emergency services, use of other concomitant medications and sleepiness.
  • the agitation episode diary comprises questions based on efficacy information after taking study medication (Yes/No), mCGI-S, CGI-C, the agitation behaviors scale (Informant only), use of study medication or use of rescue medication.
  • the present disclosure provides an individual unit oromucosal film dosage form provided as a kit comprising: (i) about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; and (ii) instructions for the administration of (i) to schizophrenia or bipolar disorder patients in need thereof, wherein the dosage form is administered for treating acute agitation in the patient in a non- clinical setting.
  • the present disclosure provides an individual unit oromucosal film dosage form provided as a kit comprising: (iii) about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; and (iv) instructions for the administration of (i) to schizophrenia or bipolar disorder patients in need thereof, wherein the dosage form is administered for treating acute agitation in the patient in a non- clinical setting.
  • the present disclosure provides an individual unit oromucosal film dosage form provided as a kit comprising: (i) about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; and (ii) instructions for the administration of (i) to schizophrenia or bipolar disorder patients in need thereof, wherein the dosage form is administered for treating mild to moderate agitation in the patient in a non-clinical setting.
  • 10 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1 depicts the mean change from baseline in PEC total score over time in schizophrenic and/or bipolar patients treated with a sublingual film containing dexmedetomidine hydrochloride (60 ⁇ g) versus a placebo group.
  • FIG. 2 depicts the percentage of responders in the PEC total Score over time in schizophrenic and/or bipolar patients treated with a sublingual film containing dexmedetomidine hydrochloride (60 ⁇ g) versus a placebo group.
  • FIG.3 depicts change in CGI- score over time in schizophrenic and/or bipolar patients treated with a sublingual film containing dexmedetomidine hydrochloride (60 ⁇ g) versus a placebo group.
  • FIG.4 depicts percent of responders in CGI-I Score over time in schizophrenic and/or bipolar patients treated with a sublingual film containing dexmedetomidine hydrochloride (60 ⁇ g) versus a placebo group.
  • FIG.4 depicts percent of responders in CGI-I Score over time in schizophrenic and/or bipolar patients treated with a sublingual film containing dexmedetomidine hydrochloride (60 ⁇ g) versus a placebo group.
  • ranges comprise all subranges therein.
  • the range “from 50 to 80” includes all possible ranges therein (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.).
  • all values within a given range may be an endpoint for the range encompassed thereby (e.g., the range 50-80 includes the ranges with endpoints such as 55-80, 50-75, etc.).
  • the term “a” or “an” refers to one or more of that entity. As such, the terms “a” (or “an”), “one or more” and “at least one” are used interchangeably herein.
  • an agent by the indefinite article “a” or “an” does not exclude the possibility that more 12 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 than one of the agents are present, unless the context clearly requires that there is one and only one of the agents.
  • “about” means plus or minus 10% of the indicated numerical value.
  • the present disclosure may suitably “comprise”, “consist of”, or “consist essentially of”, the steps, elements, and/or reagents described in the claims.
  • pharmaceutically acceptable salt refers to a salt known to be non-toxic and commonly used in the pharmaceutical literature. Typical inorganic acids used to form such salt include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, and the like.
  • an effective amount is interchangeable with "therapeutically effective dose,” or “therapeutically effective amount,” and refers to an amount sufficient to produce the desired effect.
  • An effective amount is sufficient to cause an improvement in a condition (e.g., agitation) of the patient.
  • An effective amount can be administered in one or more administrations, applications, or dosages.
  • the terms “formulation” and “composition” are used interchangeably, except where otherwise clearly intended to have different meanings.
  • the term “unit dose,” “unit dosage,” or “unit dosage form” means a physically discrete unit that contains a predetermined quantity of dexmedetomidine or a pharmaceutically acceptable salt thereof.
  • pharmaceutically acceptable carrier refers to a pharmacologically inert substance to be used as a carrier.
  • carrier and “excipients” are used interchangeably, except where otherwise clearly intended to have different meanings.
  • film herein includes thin films, in any shape, including rectangular, square, or other desired shape.
  • the film may be of any desired thickness and size, such that it can be conveniently placed oromucosally (i.e., sublingually or buccally or gingivally) in the patient.
  • the film may be a relatively thin film having a thickness of from about 20 micrometers to about 200 micrometers or may be a somewhat thicker film having a thickness of from about 20 13 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 micrometers to about 1000 micrometers.
  • the film may be even thicker, e.g., having a thickness greater than about 30 millimeters (mm).
  • the term “self-supporting” means the films herein maintain structural integrity upon handling without the need for a backing layer. Some flexibility in the film is contemplated and may be desirable.
  • the term “therapeutic” as used herein refers to treatment and/or prophylaxis, depending on context.
  • the terms “treat”, “treating,” and “treatment,” as used herein refer to a particular disease or disorder includes lessening, improving, ameliorating or abrogating the symptoms and/or pathology of the disease or disorder. Treatment may be measured as a reduction level by at least 10% or higher, preferably 20% or higher, more preferably 40% or higher, even more preferably 60%.
  • agitation means a disorder characterized by signs and symptoms of irritability, emotional outburst, impaired thinking, or excess motor and verbal activity that may occur due to either dysfunction of specific brain regions such as frontal lobes or due to dysfunction of neurotransmitter systems such as the noradrenergic system.
  • the agitation may be caused by noradrenergic hyperarousal.
  • the “signs and/or symptoms of agitation” non-limitedly as used herein includes excessive motor activity (examples include: pacing, rocking, gesturing, pointing fingers, restlessness, performing repetitious mannerisms), verbal aggression (e.g., yelling, speaking in an excessively loud voice, using profanity, screaming, shouting, threatening other people), physical aggression (e.g., grabbing, shoving, pushing, clenching hands into fists, resisting, hitting others, kicking objects or people, scratching, biting, throwing objects, hitting self, slamming doors, tearing things, and destroying property).
  • an agitated patient may also exhibit aggression.
  • the agitation may be acute.
  • the agitation may be mild to moderate.
  • An occurrence of “agitation” is referred to herein as an “agitation episode” or an “agitation event”.
  • the term "acute agitation” means agitation that occurs rapidly and sudden in onset. Acute agitation may be associated with, for example, neurodegenerative disorders and neuropsychiatric disorders, although it may particularly exist in neuropsychiatric conditions. Acute agitation may lead to chronic agitation if it remains untreated.
  • agitation includes low level of symptoms and little interference in functioning; “moderate agitation” includes some prominent symptoms with some interference 14 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 in functioning and “severe agitation” includes agitation symptoms that interfere with all functioning.
  • schizoaffective disorder refers to chronic mental health condition characterized primarily by symptoms of schizophrenia, such as hallucinations or delusions, and symptoms of a mood disorder, such as mania and depression.
  • schizophreniform disorder refers to a type of psychotic illness with symptoms similar to those of schizophrenia, but lasting for less than 6 months. The symptoms of both disorders can include delusions, hallucinations, disorganized speech, disorganized or catatonic behavior, and social withdrawal.
  • mania refers to a psychological condition that causes a person to experience unreasonable euphoria, very intense moods, hyperactivity, and delusions. Mania (or manic episodes) is a common symptom of bipolar disorder. A milder or less severe form of mania is called hypomania that lasts for a short period (usually a few days).
  • the term “without significant sedation”, “without inducing significant sedation,” or “without causing significant sedation” and the like means that the patient experiences a level of sedation not greater than Level 3 on the Ramsay Sedation Scale. Level 3 means sedated but responds to commands. In embodiments, the dexmedetomidine may be dosed to achieve a Richmond Agitation Sedation Scale (RASS) of -1 (“light sedation”).
  • RASS Richmond Agitation Sedation Scale
  • the term “significantly reduced” refers to a reduction level by at least 10% or higher, preferably 20% or higher, more preferably 40% or higher, even more preferably 60% or higher, still more preferably 80% or higher, and 90% or higher, as compared to a control.
  • oromucosal delivery or “oromucosal administration” and the like means administration to the oral mucosa. It includes delivery across any tissue of the mouth, pharynx, larynx, trachea, or upper gastrointestinal tract, particularly including the sublingual, buccal, gingival and palatal mucosal tissues.
  • sublingual literally means “under the tongue” and refers to a method of administering substances via the mouth in such a way that the substances are rapidly absorbed via the blood vessels under the tongue rather than via the digestive tract.
  • Sublingual absorption occurs through the highly vascularized sublingual mucosa, which allows a substance direct access to the blood circulation, thereby providing for direct systemic administration independent of gastrointestinal influences and avoiding undesirable first-pass hepatic metabolism.
  • the term “buccal” means administration of the dosage form against the gum and the inner lip or cheek.
  • the term “gingival” means administration of the dosage form to the gingiva (gums) found in the oral cavity of humans surrounding part of their teeth.
  • the term “clinical setting,” as used herein, refers to any service or treatment that must be administered by a medical professional or diagnosed by a medical professional.
  • the term “non-clinical setting” is interchangeable with “home-care setting” or “home setting,” “community setting,” “ambulatory care,” or “outpatient” and refers to any service or treatment that does not require medical professional for diagnosis or administration.
  • a non-clinical setting is outside of a hospital, for example, at home, a group home, an assisted living facility, a correctional facility, hospice, or long-term care facility.
  • the term “caregiver” as used herein refers to a person who cares for the patient affected by bipolar I disorder, bipolar II disorder, schizophrenia, schizoaffective disorder, or schizophreniform disorder. Caregivers can be, for example, family members, friends, or social workers, or a paid person depending on the patient’s circumstances.
  • EDA electrodermal activity/response, which is also known as skin conductance response (and in older terminology as "galvanic skin response").
  • baseline in medicine is information found at the beginning of a study or other initial known value which is used for comparison with later data.
  • a baseline is essential to the daily practice of medicine in order to establish a relative rather than absolute meaning to data.
  • PANSS-EC aka PEC for patients affected with schizophrenia.
  • the term “heart rate variability” refers to the variability of the time interval between heartbeats and is a reflection of an individual's current health status.
  • the term “EMA” or “Ecological momentary assessment” as used herein refers to repeated sampling of patients' current behaviors and experiences in real time, in patients' natural environments. The repeated measurements of data are for analyzing important characteristics of the dynamics of phenomena.
  • the term “wearable device” or “wearable sensor” as used herein refers to any device that could be worn/placed/mounted on the body of the patient and that is able to detect, and process signals related to sympathetic nervous system activity and/or motor activity.
  • the device may interact (e.g., remotely or otherwise) with any suitable compatible device, such as an end-user display terminal, and will normally include transducers, a transducer control module, a communications device, and a monitoring system or a computer database etc.
  • Physiological measures can also be measured using both standard technology and miniaturized wearable devices such as sensor devices (e.g., waist worn, wrist worn, finger worn, etc.) with networking capacity (e.g., an iPhone).
  • sensor devices e.g., waist worn, wrist worn, finger worn, etc.
  • networking capacity e.g., an iPhone.
  • the term “informant” as used herein refers to is a person who is present most (but not all) the time, to assist in recording the data and prompting the patient to consider taking mediation. The informant simply informs, meaning the informant just reports on the condition of the patient but does not give care.
  • EEG electroencephalography
  • EEG is an electrophysiological monitoring method to record electrical activity of the brain. EEG reflects the electrical activity of the underlying neurons, and provides information regarding neuronal population oscillations, the information flow pathway, and neural activity networks.
  • ACTIVE AGENT [0105] Dexmedetomidine has the IUPAC name (+) 4-(S)-[1-(2,3-dimethylphenyl)ethyl]-1H- imidazole. As the monohydrochloride salt, it is predominantly used as a medication for the sedation of patients during treatment in an intensive care setting or to sedate patients prior to and/or during surgical and other procedures.
  • compositions of dexmedetomidine that may be included herein generally include any suitable salt that has been or may be approved by the U.S. FDA or other appropriate foreign or domestic agency for administration to a human.
  • suitable pharmaceutically acceptable salts include salts of inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrocarbonic, phosphoric, monohydrogen phosphoric, dihydrogen phosphoric, sulfuric, hydrogen sulfuric, and hydroiodic acid.
  • salts derived from non-toxic organic acids including acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acids, or combinations of these acid salts.
  • Exemplary salts include dexmedetomidine hydrochloride, dexmedetomidine hydrobromide, dexmedetomidine sulfate, dexmedetomidine sulfonate, dexmedetomidine phosphate, dexmedetomidine nitrate, dexmedetomidine formate, dexmedetomidine citrate, dexmedetomidine tartrate, dexmedetomidine malate, dexmedetomidine benzoate, dexmedetomidine salicylate, dexmedetomidine ascorbate or the like.
  • 17 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 deuterated forms of dexmedetomidine or a pharmaceutically acceptable salt thereof may be included.
  • suitable dosages include: about 5 micrograms to about 340 micrograms, about 5 micrograms to about 320 micrograms, about 5 micrograms to about 300 micrograms, about 5 micrograms to about 280 micrograms, about 5 micrograms to about 270 micrograms, about 5 micrograms to about 260 micrograms, about 5 micrograms to about 250 micrograms, about 5 micrograms to about 240 micrograms, about 5 micrograms to about 230 micrograms, about 5 micrograms to about 220 micrograms, about 5 micrograms to about 210 micrograms, about 5 micrograms to about 200 micrograms, about 5 micrograms to about 190 micrograms, about 5 micrograms to about 180 micrograms, about 5 micrograms to about 170 micrograms, about 5 micrograms to about 160 micrograms, about 5 micrograms to about 150 micrograms, about 5 micrograms to about 140 micrograms, about 5 micrograms to about 130 micrograms, about 5 micrograms to about 120 microgram
  • the dose may be administered one or more times a day including twice, three times, four times, five times or six times per day.
  • the dosage of dexmedetomidine or a pharmaceutically acceptable salt thereof may be administered twice a day.
  • the dose may be administered on an “as needed basis” in one, two or more doses per day to the patient.
  • dexmedetomidine or a pharmaceutically acceptable salt thereof may be administered oromucosally (e.g., sublingually or buccally or gingivally).
  • the per unit dose of dexmedetomidine or a pharmaceutically acceptable salt thereof is about 10 micrograms, about 15 micrograms, about 20 micrograms, about 25 micrograms, about 30 micrograms, about 35 micrograms, about 40 micrograms, about 45 micrograms, about 50 micrograms, about 55 micrograms, about 60 micrograms, about 65 micrograms, about 70 18 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 micrograms, about 75 micrograms, about 80 micrograms, about 85 micrograms, about 90 micrograms, about 95 micrograms, about 100 micrograms, about 110 micrograms, about 120 micrograms, about 130 micrograms, about 140 micrograms, about 150 micrograms, about 160 micrograms, about 170 micrograms, or about 180 micrograms.
  • dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in an amount of about 30 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 40 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 50 micrograms.
  • dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in an amount of about 60 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 70 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 80 micrograms.
  • dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in an amount of about 90 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 100 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 110 micrograms.
  • dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in an amount of about 120 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 130 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 140 micrograms.
  • dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in an amount of about 150 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 160 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., 19 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 dexmedetomidine hydrochloride) is administered in an amount of about 170 micrograms.
  • dexmedetomidine or a pharmaceutically acceptable salt thereof e.g., 19 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 dexmedetomidine hydrochloride
  • dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in an amount of about 180 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 190 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 200 micrograms.
  • dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in an amount of about 210 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 220 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 230 micrograms.
  • dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in an amount of about 240 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 260 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 280 micrograms.
  • dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in an amount of about 300 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 320 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 340 micrograms.
  • dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in an amount of about 360 micrograms.
  • the dosages of dexmedetomidine or a pharmaceutically acceptable salt thereof may depend on a variety of factors such as the type and extent of the condition, the overall health status of the particular patient, the particular form of dexmedetomidine and the particular formulation used to treat the patient.
  • the present disclosure provides methods of treating agitation in schizophrenia or bipolar disorder patients in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 60 micrograms to the patients.
  • the present disclosure provides methods of treating agitation in schizophrenia or bipolar disorder patients in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 80 micrograms to the patients.
  • the present disclosure provides methods of treating agitation in schizophrenia or bipolar disorder patients in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 60 micrograms to the patients, wherein the patients are 18 years or older.
  • the present disclosure provides methods of treating agitation in a schizophrenia or bipolar disorder patients in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 80 micrograms to the patients, wherein the patients are 18 years or older.
  • the present disclosure provides methods of treating agitation in schizophrenia or bipolar disorder patients in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a total daily dose of about 60 micrograms to about 360 micrograms to the patients.
  • the present disclosure provides methods of treating agitation in schizophrenia or bipolar disorder patients in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a total daily dose of about 60 micrograms to about 360 micrograms to the patients, wherein the patients are 18 years or older.
  • the present disclosure provides methods of treating agitation in schizophrenia or bipolar disorder patients in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a total daily dose of about 60 micrograms to about 180 micrograms to the patient.
  • the present disclosure provides methods of treating agitation in schizophrenia or bipolar disorder patients in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a total daily dose of about 21 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 60 micrograms to about 180 micrograms to the patients, wherein the patients are 18 years or older.
  • the present disclosure provides methods of treating agitation in schizophrenia or bipolar disorder patients in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a total daily dose of about 80 micrograms to about 360 micrograms to the patients, wherein the patients are 18 years or older.
  • the present disclosure provides methods of treating acute agitation in schizophrenia or bipolar disorder patients in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a total daily dose of about 60 micrograms to about 360 micrograms to the patients.
  • the present disclosure provides methods of treating acute agitation in schizophrenia or bipolar disorder patients in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a total daily dose of about 60 micrograms to about 360 micrograms to the patients, wherein the patients are 18 years or older.
  • the present disclosure provides methods of treating acute agitation in schizophrenia or bipolar disorder patients in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a total daily dose of about 60 micrograms to about 180 micrograms to the patients.
  • the present disclosure provides methods of treating acute agitation in schizophrenia or bipolar disorder patients in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a total daily dose of about 60 micrograms to about 180 micrograms to the patients, wherein the patients are 18 years or older.
  • dexmedetomidine or a pharmaceutically acceptable salt thereof is administered by the caregiver or informant of the patient.
  • the caregiver or informant is a family member or a family friend.
  • the caregiver or informant is dedicated for the patient.
  • the caregiver or informant is a social worker.
  • the caregiver or informant is a person employed by or for the patient.
  • the caregiver or informant maintains close physical proximity to the patient for at least 8 hours after the administration of dexmedetomidine or a pharmaceutically acceptable salt thereof. 22 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 [0125]
  • dexmedetomidine or a pharmaceutically acceptable salt thereof is self- administered by the patient.
  • the bipolar disorder includes bipolar I disorder, bipolar II disorder, and bipolar mania.
  • bipolar disorder is bipolar disorder I.
  • bipolar disorder is bipolar mania.
  • the schizophrenia includes schizoaffective and schizophreniform disorder. In embodiments, the schizophrenia is schizoaffective disorder. In embodiments, the schizophrenia is schizophreniform disorder.
  • the route of administration is oromucosal (e.g., sublingual, buccal or gingival).
  • dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in an oromucosal dosage form selected from the group consisting of a film, wafer, patch, lozenge, gel, spray, tablet and liquid drops.
  • the dosage form is a thin film.
  • the dosage form is a sublingual film.
  • the dosage form is a buccal film.
  • the dosage form is a gingival film. Suitable films are described in US Patent No.10,792,246, which is hereby incorporated by reference in its entirety for all purposes.
  • dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as a single dose per day.
  • the total daily dose may be administered oromucosally multiple times (e.g., one to four times) as a single unit dose, as multiple unit doses, or as a fraction of one or more unit doses (e.g., half of a unit dose), or a combination thereof at an appropriate dosing interval (e.g., at least after 0.5 hours) to produce a desired effect.
  • the dosage of dexmedetomidine or a pharmaceutically acceptable salt thereof may be administered twice a day, for example, a 60 micrograms unit dose is administered two times at a dosing interval of about 2 hours to produce the effect of a 120 micrograms dose.
  • 23 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 [0132]
  • the total daily dose of dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as a first and optional second dose.
  • the first dose is about 60 micrograms, about 70 micrograms, about 80 micrograms, about 90 micrograms, about 100 micrograms, about 110 micrograms, about 120 micrograms, or about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof. In embodiments, the first dose is about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof. [0134] In embodiments, the first dose is about 60 micrograms, about 70 micrograms, about 80 micrograms, about 90 micrograms, about 100 micrograms, about 110 micrograms, about 120 micrograms, or about 180 micrograms of dexmedetomidine hydrochloride.
  • the first dose is about 60 micrograms of dexmedetomidine hydrochloride.
  • the second dose is administered at least 2 hours after administration of the first dose if there is no improvement in PEC score by more than 2 points.
  • the patient is hemodynamically stable.
  • the optional second dose is about 60 micrograms, about 70 micrograms, about 80 micrograms, about 90 micrograms, about 100 micrograms, about 110 micrograms, about 120 micrograms, or about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.
  • the optional second dose is about 60 micrograms, about 70 micrograms, about 80 micrograms, about 90 micrograms, about 100 micrograms, about 110 micrograms, about 120 micrograms or about 180 micrograms of dexmedetomidine hydrochloride. In embodiments, the optional second dose is about 60 micrograms of dexmedetomidine hydrochloride. In embodiments, the optional second dose is 80 micrograms of dexmedetomidine hydrochloride.
  • the second dose is administered at least about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours, about 8 hours, about 8.5 hours, about 9 hours, about 9.5 hours, about 10 hours, about 10.5 hours, about 11 hours, about 11.5 hours, about 12 hours, about 12.5 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours or about 24 hours after administration of the first dose.
  • a rescue medication is optionally administered to the patient after the second dose of dexmedetomidine in case of persistent or uncontrolled agitation.
  • the rescue medication is selected from benzodiazepines (such as alprazolam, clonazepam, lorazepam, oxazepam, midazolam, triazolam, chlordiazepoxide, clorazepate, diazepam, estazolam, flurazepam, temazepam, quazepam) or antipsychotics selected from the group consisting of but not limited to aripiprazole, olanzapine, quetiapine, chlorpromazine, cariprazine, asenapine, clozapine, lurasidone, risperidone
  • the rescue medicine is lorazepam at a dose of about 4 mg. In embodiments, the rescue medicine is oxazepam at a dose of about 60 mg. In embodiments, the rescue medicine is chlorpromazine at a dose of about 300 mg.
  • the agitation is acute. [0140] In embodiments, the patient experiences not more than 5 episodes of agitation in a week. In embodiments, the patient experiences not more than 3 episodes of agitation in a week. In embodiments, the patient experiences not more than 2 episodes of agitation in a week. In embodiments, the patient experiences at least 1 episode of agitation in the past month.
  • the patient experiences not more than 5 episodes of agitation in a month. In embodiments, the patient experiences not more than 3 episodes of agitation in a month. In embodiments, the patient experiences not more than 2 episodes of agitation in a month.
  • the present disclosure provides methods of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a total daily dose of about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant.
  • oromucosally e.g., sublingually, buccally, or gingivally
  • the present disclosure provides methods of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a total daily dose of about 60 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant.
  • oromucosally e.g., sublingually, buccally, or gingivally
  • the present disclosure provides methods of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally) to the patient about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant.
  • oromucosally e.g., sublingually, buccally, or gingivally
  • the present disclosure provides a method of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising administering oromucosally (e.g., 25 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 sublingually, buccally, or gingivally) to the patient about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant.
  • oromucosally e.g., 25 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 sublingually, buccally, or gingivally
  • the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a total daily dose of about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant.
  • a bipolar disorder e.g., bipolar disorder I or bipolar disorder II
  • oromucosally e.g., sublingually, buccally, or gingivally
  • the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a total daily dose of about 60 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant.
  • a bipolar disorder e.g., bipolar disorder I or bipolar disorder II
  • oromucosally e.g., sublingually, buccally, or gingivally
  • the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally) to the patient about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant.
  • a bipolar disorder e.g., bipolar disorder I or bipolar disorder II
  • oromucosally e.g., sublingually, buccally, or gingivally
  • the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally) to the patient about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant.
  • a bipolar disorder e.g., bipolar disorder I or bipolar disorder II
  • oromucosally e.g., sublingually, buccally, or gingivally
  • the present disclosure provides methods of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising self-administering by the patient an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides methods of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.
  • the present disclosure provides methods of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising self-administering by the patient 26 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides methods of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self- administered by the patient.
  • the present disclosure provides a method of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising self-administering by the patient an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising adminsitering an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.
  • the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising self-administering by the patient an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.
  • a bipolar disorder e.g., bipolar disorder I or bipolar disorder II
  • an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self- administered by the patient.
  • a bipolar disorder e.g., bipolar disorder I or bipolar disorder II
  • the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising self-administering by the patient an oromucosal dosage form comprising about 60 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.
  • a bipolar disorder e.g., bipolar disorder I or bipolar disorder II
  • an oromucosal dosage form comprising about 60 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising adminsitering an oromucosal dosage form comprising about 60 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self- administered by the patient.
  • a bipolar disorder e.g., bipolar disorder I or bipolar disorder II
  • an oromucosal dosage form comprising about 60 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self- administered by the patient.
  • the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising self-administering by the patient an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.
  • a bipolar disorder e.g., bipolar disorder I or bipolar disorder II
  • an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising adminstering an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.
  • a bipolar disorder e.g., bipolar disorder I or bipolar disorder II
  • the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising self-administering by the patient an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.
  • a bipolar disorder e.g., bipolar disorder I or bipolar disorder II
  • an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising adninstering an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.
  • the present disclosure provides a method of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in two phases.
  • phase 1 comprises administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof under medical supervision, wherein the duration of phase 1 is at least 8 hours.
  • oromucosally e.g., sublingually, buccally, or gingivally
  • the duration of phase 1 is at least about 8 hours, at least about 8.5 hours, at least about 9 hours, at least about 9.5 hours, at least about 10 hours, at least about 10.5 hours, at least about 11 hours, at least about 11.5 hours, at least about 12 28 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 hours, at least about 12.5 hours, at least about 13 hours, at least about 13.5 hours, at least about 14 hours, at least about 14.5 hours, at least about 15 hours, at least about 20 hours, at least about 22 hours, or at least about 24 hours.
  • phase 2 comprises administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof under non- medical supervision (non -clinical setting), wherein the duration of phase 2 is up to 12 weeks.
  • oromucosally e.g., sublingually, buccally, or gingivally
  • non- medical supervision non -clinical setting
  • the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient, the method comprising: (a) administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof under medical supervision for at least 8 hours; and (b) administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof under non-medical supervision (non-clinical setting) for up to 12 weeks.
  • oromucosally e.g., sublingually, buccally, or gingivally
  • non-medical supervision non-medical setting
  • phase 1 comprises administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof under medical supervision, wherein the duration of phase 1 is at least 8 hours.
  • oromucosally e.g., sublingually, buccally, or gingivally
  • the duration of phase 1 is at least about 8 hours, at least about 8.5 hours, at least about 9 hours, at least about 9.5 hours, at least about 10 hours, at least about 10.5 hours, at least about 11 hours, at least about 11.5 hours, at least about 12 hours, at least about 12.5 hours, at least about 13 hours, at least about 13.5 hours, at least about 14 hours, at least about 14.5 hours, at least about 15 hours, at least about 20 hours, at least about 22 hours, or at least about 24 hours.
  • phase 2 comprises administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof under non- medical supervision (non -clinical setting), wherein the duration of phase 2 is up to 12 weeks.
  • oromucosally e.g., sublingually, buccally, or gingivally
  • non- medical supervision non -clinical setting
  • the present disclosure provides methods of treating mild to moderate agitation in a schizophrenia or bipolar disorder patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally) to the patient a dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant.
  • oromucosally e.g., sublingually, buccally, or gingivally
  • the present disclosure provides methods of treating mild to moderate agitation in a schizophrenia or bipolar disorder patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally) to the patient a dosage form comprising about 60 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant.
  • oromucosally e.g., sublingually, buccally, or gingivally
  • the present disclosure provides methods of treating mild to moderate agitation in a schizophrenia or bipolar disorder patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally) to the patient a dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant.
  • oromucosally e.g., sublingually, buccally, or gingivally
  • the present disclosure provides methods of treating mild to moderate agitation in a schizophrenia or bipolar disorder patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally) to the patient a dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant.
  • oromucosally e.g., sublingually, buccally, or gingivally
  • the present disclosure provides methods of treating mild to moderate agitation in a schizophrenia or bipolar disorder patient in a non-clinical setting, comprising self-administering by the patient an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides methods of treating mild to moderate agitation in a schizophrenia or bipolar disorder patient in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.
  • the present disclosure provides methods of treating mild to moderate agitation in a schizophrenia or bipolar disorder patient in a non-clinical setting, comprising 30 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 self-administering by the patient an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides methods of treating mild to moderate agitation in a schizophrenia or bipolar disorder patient in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.
  • the present disclosure provides methods of treating mild to moderate agitation in a schizophrenia or bipolar disorder patient in a non-clinical setting, comprising self-administering by the patient an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides methods of treating mild to moderate agitation in a schizophrenia or bipolar disorder patient in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.
  • the diagnosis of schizophrenia or bipolar disorder is performed as per DSM-IV criteria.
  • the Diagnostic and Statistical Manual of Mental Disorders (DSM) is the handbook widely used by clinicians and psychiatrists to diagnose psychiatric illnesses. It contains descriptions, symptoms, and other criteria necessary for diagnosing mental health disorders.
  • the DSM-IV was originally published in 1994 and listed more than 250 mental disorders.
  • An updated version, called the DSM-IV-TR was published in 2000. (TR stands for "text revision.") This version utilized a multiaxial or multidimensional approach for diagnosing mental disorders.
  • the patient experienced at least one clinical presentation of agitation requiring intervention in the previous month (i.e., the month prior to starting treatment).
  • the patient experienced two or three (or more) episodes of agitation in the previous month (i.e., the month prior to starting treatment).
  • the patient was clinically administered a medication for agitation.
  • the patient experienced at least one episode of agitation in a previous month (i.e., the month prior to starting treatment) requiring emergency visit or medical service.
  • the patient is suffering from one or more psychiatric comorbidities.
  • the patient is not suffering from other psychiatric comorbidities .
  • the patient is not concurrently taking other medications (e.g., alpha-1 noradrenergic blockers and alpha-2 adrenergic agonists).
  • the patient is about 18 years old to about 75 years old, e.g., about 18 years old, about 19 years old, about 20 years old, about 21 years old, about 22 years old, about 23 years old, about 24 years old, about 25 years old, about 26 years old, about 27 years old, about 28 years old, about 29 years old, about 30 years old, about 31 years old, about 32 years old, about 33 years old, about 34 years old, about 35 years old, about 36 years old, about 37 years old, about 38 years old, about 39 years old, about 40 years old, about 41 years old, about 42 years old, about 43 years old, about 44 years old, about 45 years old, about 46 years old, about 47 years old, about 48 years old, about 49 years old, about 50 years old, about 51 years old, about 52 years old, about 53 years old, about 54 years old, about 55 years old, about 56 years old, about 57 years old, about 58 years old, about 59 years old, about 60 years old, about 61 years old, about 62 years
  • the patient is older than 75 years old. In embodiments, the patient is about 65 years old to about 80 years old, e.g., about 76 years old, about 77 years old, about 78 years old, about 79 years old, about 80 years old, including all values and ranges in between. In embodiments, the patient is about 75 years old to about 80 years old, e.g., about 75 years old, about 76 years old, about 77 years old, about 78 years old, about 79 years old, or about 80 years old, including all values and ranges in between.
  • the patient is older than 80 years old, e.g., about 81 years old, about 82 years old, about 83 years old, about 84 years old, about 85 years old, about 86 years old, about 87 years old, about 88 years old, about 89 years old, about 90 years old, about 91 years old, about 92 years old, about 93 years old, about 94 years old, about 95 years old, about 96 years old, about 97 years old, about 98 years old, about 99 years old, or about 100 years old, including all values and ranges in between.
  • the oromucosal dosage form is selected from the group consisting of a film, wafer, patch, lozenge, gel, spray, tablet and liquid drops.
  • the dosage form is a sublingual or buccal or gingival film.
  • the administration of dexmedetomidine, a pharmaceutically acceptable salt thereof, or an oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof produces anti-agitation effect within about 120 32 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 minutes after administration without causing significant sedation.
  • the administration of dexmedetomidine, a pharmaceutically acceptable salt thereof, or an oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof form produces anti-agitation effect within about 60 minutes after administration without causing significant sedation. In embodiments, the administration of dexmedetomidine, a pharmaceutically acceptable salt thereof, or an oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof produces anti-agitation effect within about 30 minutes after administration without causing significant sedation.
  • the administration of dexmedetomidine, a pharmaceutically acceptable salt thereof, or an oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof produces anti-agitation effect within about 20 minutes after administration without causing significant sedation. In embodiments, the administration of dexmedetomidine, a pharmaceutically acceptable salt thereof, or an oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof produces anti- agitation effect within about 15 minutes after administration without causing significant sedation. [0191] In embodiments, the treatment is effective without causing clinically significant cardiovascular effects. In embodiments, the treatment is effective with reduced or no side effects (e.g., respiratory side effects).
  • side effects e.g., respiratory side effects
  • PCT Publication No. 2018/126182 discloses the treatment of agitation in a patient by administering dexmedetomidine or a pharmaceutically acceptable salt thereof where agitation is effectively treated without also causing significant sedation.
  • the clinical improvement in agitation is measured using PANSS, ACES, and/or CGI-I scales.
  • the reduction in agitation is assessed by relative change in PEC score after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.
  • the reduction in agitation is assessed by relative change in modified CGI-S 4-point (0-3) scale after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.
  • the reduction in agitation is assessed after a suitable period of time such as 0.5 hours, 1 hour, 2 hours, 4 hours or 6 hours after administration of the first dose of dexmedetomidine or a pharmaceutically acceptable salt thereof administration. In embodiments, the reduction in agitation is assessed before the administration of rescue medication in the patient.
  • the patient achieves a mean change in PEC score of greater than -2, -3, -4, -5, -6, -7, -8, -9, or -10 relative to baseline within 30 minutes of administering the composition.
  • the patient achieves a mean change in PEC score of greater than -7 relative to baseline within 2 hours of administering dexmedetomidine or a pharmaceutically acceptable salt thereof. In embodiments, the decrease in PEC score is maintained for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, hours following administration of dexmedetomidine or a pharmaceutically acceptable salt thereof. In embodiments, the agitated patient has a baseline score in PEC scale of about 14 or higher. [0195] In embodiments, the patient achieves a CGI-I score improvement to about a 1 (very much improved) or about a 2 (much improved).
  • the agitation is reduced to a 2 (moderate agitation), 3 (mild agitation) or 4 (normal behavior) 30 minutes after administration, as measured by the Agitation-Calmness Evaluation Scale (ACES).
  • the score improvement is sustained for a period of about 2 hours to about 6 hours.
  • the agitated patient has a baseline score in CGI-I of about 3 or higher.
  • the agitation is reduced to 2 (moderate agitation), 3 (mild agitation) or 4 (normal behavior) 30 minutes after administering the composition, as measured by the Agitation-Calmness Evaluation Scale (ACES).
  • the agitation is reduced to a 3 (mild agitation).
  • the improved ACES score may be obtained within about 5 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 70 minutes, about 80 minutes, about 90 minutes, about 100 minutes, about 110 minutes, or about 120 minutes.
  • the agitated patient has a baseline score in ACES score of about 3 or below.
  • the ACES score improvement is sustained for about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours following administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.
  • the decrease in the PEC, CGI-S and ACES scores is maintained for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, hours following administration.
  • the single administration of dexmedetomidine or a pharmaceutically acceptable salt thereof treats agitation and maintains calming effect for at least 12 hours.
  • the methods describe herein provides improvement in the residual signs and symptoms of schizophrenia following administration of dexmedetomidine or a pharmaceutically acceptable salt thereof as measured by reduction in PEC score of greater than -7 relative to baseline.
  • the methods describe herein provides improvement in duration of calming as measured using reduction in ACES score of 2 or more following administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.
  • Wearable devices/EMA devices [0201] Agitation in patients with neuro-psychiatric or neuro-degenerative disorders results in patients that are uncooperative to treatment, and are also potentially violent and aggressive, making them a danger to themselves and to caregivers or informants. By detecting a signal that indicates a patient is about to become agitated, the present disclosure pairs a diagnostic with a treatment component using dexmedetomidine, to prevent the manifestation of an agitation episode. Thus, according to the present disclosure, dexmedetomidine can be used as a prophylactic or preventive therapeutic agent. [0202] In embodiments, the impending episode of agitation is alerted to the caregiver or informant via Ecological Momentary Assessment (EMA) device or other remote compatible device.
  • EMA Ecological Momentary Assessment
  • the EMA device is monitored by the caregiver or informant.
  • the EMA device comprises a caregiver’s or informant’s smart phone or a tablet with an application installed to report the patient’s observations.
  • the application on the caregiver’s or informant’s device provides prompt to report on adverse effects after dexmedetomidine administration.
  • the application on the caregiver’s or informant’s device provides prompt to report on absence or presence of episode of agitation.
  • the caregiver or informant reports information on frequency or number of episodes of agitation on the application installed on EMA device.
  • the EMA device may be an end user terminal capable of alerting the caregiver or informant by means of the sound/alarm and/or display.
  • the alerts are received in the form of a text message, a call, a sound or a window flashing/display on the caregiver’s or informant’s device. Suitable examples of such devices are described in PCT Publication Nos.2021/055595, 2021/163482 and 2021/163482, the contents of which are herein incorporated by reference.
  • the prediction of the agitation episode (or event) includes determining a time period within which the agitation episode of the patient will occur and also includes 35 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 determining a degree of the agitation episode of the patient.
  • the prediction involves comparing the physiological data with the baseline value of at least one physiological parameter.
  • the signal/alert is generated when physiological data exceeds threshold of baseline value.
  • the impending episode of agitation is diagnosed by the steps comprising: monitoring one or more physiological signals of sympathetic nervous system activity in the patient using a wearable device (or sensor) placed or mounted on the patient’s skin surface; identifying, via the processing of incoming data in the wearable device, when the patient is about to have an agitation episode; sending a signal from the wearable device to an EMA device or a remote compatible device monitored by a caregiver or informant alerting the caregiver or informant to an impending agitation episode in the patient.
  • the reduction in agitation is alerted to the caregiver or informant via Ecological Momentary Assessment (EMA) device or other remote compatible device.
  • EMA Ecological Momentary Assessment
  • the alerts are sent to the patient for self-administration of oral mucosal dosage form comprising dexmedetomidine or a salt thereof.
  • the caregiver or informant determines that the patient would benefit from administration of dexmedetomidine, and the caregiver or informant alerts the patient to administer the oral mucosal dosage form comprising dexmedetomidine or a salt thereof.
  • patient’s observations are recorded from one or more wearable devices (or wearable sensors) worn/placed/mounted on the body of the patient.
  • the wearable device (or a wearable sensor) is in contact with the patient and may be selected from iPhone (BYOD or provisioned), accelerometers, gyroscopes, portable devices, digital devices, smart fabrics, bands and actuators like an Apple watch or iWatch, patch such as MC10 Patch, sensors like Microsoft Kinect, wireless communication networks and power supplies, and data capture technology for processing and decision support or any conventional or non-conventional device/sensor performing similar functions.
  • the wearable device is a bracelet, anklet, shoe, armband, thigh band or a mitten.
  • the wearable device is smartwatch, ring, patch, conductive tattoo, head wearable.
  • the wearable device is wrist worn multi-sensor device with networking capability (e.g., wearable watch such as Apple watch).
  • the wearable device monitors the change in sympathetic nervous system activity in the patient by measuring EDA over time. 36 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377
  • EDA is the phenomenon where the skin momentarily becomes a better conductor of electricity when either external or internal stimuli occur that are physiologically arousing. EDA is considered one of the fastest-responding physiological measures of stress response and arousal. The study of EDA has led to important tools such as EEG.
  • a wearable device placed on the skin of the patient monitors the EDA by recording the changes in the patient’s skin’s electrical resistance. Any change in sympathetic nervous system activity results in a slight increase in perspiration, which lowers skin resistance (because perspiration contains water and electrolytes). Such changes in the skin’s electrical resistance are recorded by the wearable or sensoring device.
  • the measurement of electrodermal activity is done by clipping the monitoring device to the finger of a patient with attaching electrodes to the middle phalanges of adjacent fingers of a hand and measuring/analyzing EDA waveforms. The data obtained by the clipped device is then transferred to the computer database, connected the monitoring device, wherein the computer database includes one or more of early warning algorithms.
  • early warning algorithms operates to predict the early signs of the emergence of agitation of a patient and generates patient alerts/warnings based upon the operation of the early warning algorithm to the caregiver or informant that an anti-agitation agent should be administered.
  • the wearable device may also monitor other physiological signals, including heart rate variability such as resting EEG, cognitive assessments such as pupil size, secretion of salivary amylase, blood pressure; pulse; respiratory rate, level of oxygen in the blood and other signals related to increased sympathetic nervous system activity.
  • the wearable device records and collect objective data on integrated physiological parameters (such as EDA, resting EEG, blood pressure, mobility/ motor, memory/processing, speech/sleep patterns, social engagement, etc.)
  • the baseline value is calculated for a patient to statistically classify any change in the physiological parameters such as EDA and/or resting EEG levels etc. on a defined scale (from 0 to 5).
  • the wearable device signals information related to increases in sympathetic nervous system activity and motor activity to an EMA device (such as smartphone or tablet) or an apparatus (for example, a computer database) that is monitored by a caregiver or informant.
  • an EMA device such as smartphone or tablet
  • an apparatus for example, a computer database
  • the wearable device comprises one or more early warning algorithm, alerting unit and a storage unit for storing data regarding one or more alerts provided by the alerting unit, i.e., previous detections increase in the sympathetic nervous activities, data 37 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 about the patient, predetermined acceptable ranges and thresholds etc.
  • the wearable device comprises a display unit for displaying the stored data or measured values of one or more parameters.
  • the wearable device also detects the severity of the agitation (e.g., mild, moderate or elevated).
  • the wearable device predicts the probability of specific patient to move from mild to moderate to elevated agitation and the wearable devices can also predict a severity change probability.
  • the severity change probability can be measured using at least one machine learning model’s (e.g., an agitation state detection model’s) predictions to create and/or define a chain of events.
  • the severity change probability involves the estimation of the conditional probabilities of changing state using conditional random fields or a similar approach.
  • the patient, the caregiver or informant records the observations in an agitation episode diary for each episode of agitation.
  • the agitation episode diary comprises questions based on safety information, use of emergency services, use of other concomitant medications and sleepiness.
  • the agitation episode diary comprises questions based on efficacy information after taking study medication (Yes/No), mCGI-S, CGI-C, the agitation behaviors scale (Informant only), use of study medication or use of rescue medication.
  • the composition may conveniently be presented in a unit dosage form and may be prepared by any of the methods well known in the art. Typically, these methods include the step of bringing into association the active ingredient (e.g., dexmedetomidine or a pharmaceutically acceptable salt thereof) with the carrier which constitutes one or more accessory ingredients.
  • the dosage form is an oromucosal dosage form comprising: (i) about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) one or more mucoadhesive agents; and (iii) one or more pharmaceutically acceptable excipients or carriers, wherein the dosage form disintegrates within about 5 seconds to about 10 minutes upon contact with an oral mucosa and wherein the dosage form is administered for the treatment of acutely agitated schizophrenia or bipolar disorder patients in a non-clinical setting.
  • the non-clinical setting is at home. In embodiments, the non-clinical setting is at group home, assisted living facility, correctional facility, hospice or long-term care facility. In embodiments, the dosage form is self-administered by the patient or is administered by the caregiver or informant.
  • the dosage form is an oromucosal dosage form comprising: (i) about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) one or more mucoadhesive agents; and (iii) one or more pharmaceutically acceptable excipients or carriers, wherein the dosage form disintegrates within about 5 seconds to about 10 minutes upon contact with an oral mucosa and wherein the dosage form is administered for the treatment of acutely agitated schizophrenia or bipolar disorder patients in a non-clinical setting.
  • the dosage form is an oromucosal dosage form comprising: (i) about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) one or more mucoadhesive agents; and (iii) one or more pharmaceutically acceptable excipients or carriers, wherein the dosage form disintegrates within about 5 seconds to about 10 minutes upon contact with an oral mucosa and wherein the dosage form is administered for the treatment of acutely agitated schizophrenia or bipolar disorder patients in a non-clinical setting.
  • the non-clinical setting is at home. In embodiments, the non-clinical setting is at group home, assisted living facility, correctional facility, hospice or long-term care facility.
  • the dosage form is self-administered by the patient or is administered by the caregiver or informant.
  • the oromucosal dosage form is a tablet, capsules, patch, film, sachet, wafer, powder, minitablet, pellet, paste, gel, ointment, cream, drops, liquid (e.g., solution, suspension or emulsion), spray, microspheres or nanospheres which can be formulated in accordance with methods that are standard in the art.
  • the composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof is administered oromucosally (sublingually/buccally or gingivally) in the form of a tablet, film, spray, gel or drops.
  • the composition is in the form of a tablet or packed powder.
  • the composition is in the form of a film.
  • the composition is a thin film.
  • the film is placed under the 39 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 tongue, close to the base of the tongue, on the left or right side.
  • dexmedetomidine or a pharmaceutically acceptable salt thereof is administered buccally in the form of a film, patch or tablet, particularly a film.
  • the film is placed against the inner lip or check, close to the jaw line.
  • the dosage form is an oromucosal tablet for sublingual or buccal, or gingival administration.
  • the dosage form is lyophilized (or freeze-dried). Examples of oromucosal dosage forms includes orally disintegrating tablets disclosed in US Patent No. 6,509,040, US Patent No. 7,972,621, US Patent No. 10,548,839, US Patent No. 9,775,819, US Patent No. 5,188,825, US Patent No.
  • dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to the patient intranasally or by inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
  • dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to the patient in a single dosage form.
  • dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to the patient in a single dosage form multiple times a day (e.g., two, three, four, five, etc. times a day).
  • the composition is an intra-nasal spray, particularly a spray comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, for example, as described in PCT Publication No. 2013/090278, the contents of which are herein incorporated by reference.
  • dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to the patient by oral route.
  • dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally in the form of tablets, orally 40 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 disintegrating tablets (ODTs), effervescent tablets, capsules, pellets, pills, lozenges or troches, powders, dispersible granules, catchets, aqueous solutions, syrups, emulsions, suspensions, solutions, soft gels, dispersions and the like.
  • ODTs disintegrating tablets
  • dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally to the patient in the form of an orally disintegrating tablet.
  • the composition or the dosage form is conveniently delivered on an "as needed basis" in one, two or more doses per day to the patient.
  • the dosage form effectively treats agitation in a patient without causing significant sedation.
  • Oromucosal formulations (Sublingual and/or buccal or gingival formulations)
  • Formulations suitable for use according to the present disclosure are described in US Appl. Publication No.2020/0000717, which is hereby incorporated by reference in its entirety for all purposes.
  • Dexmedetomidine or a pharmaceutically acceptable salt thereof can be formulated, according to the present disclosure, into dosage forms suitable for oromucosal (e.g., sublingual or buccal or gingival) administration.
  • Such dosage forms include tablets, powders, pills, films, capsules, liquids, gels, syrups, slurries, suspensions, and the like.
  • dexmedetomidine or a pharmaceutically acceptable salt thereof is formulated as a film product.
  • Carriers suitable for inclusion in oromucosal (e.g., sublingual or buccal or gingival) formulations include, but are not limited to, sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulphate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffered solutions, emulsifiers, isotonic saline, pyrogen - free water and combinations thereof.
  • Oromucosal (e.g., sublingual or buccal or gingival) formulations may also include other pharmaceutically acceptable carriers and/or excipients such as binders, lubricants, diluents, coatings, disintegrants, barrier layer components, glidants, coloring agents, solubility enhancers, gelling agents, fillers, proteins, co-factors, emulsifiers, solubilizing agents, suspending agents and mixtures thereof.
  • Particular excipients which may be used according to this disclosure, are known in the art, for example as described in Handbook of Pharmaceutical Excipients, fifth edition, 2005 edited by Rowe et al., Mcgraw Hill.
  • Suitable films for sublingual or buccal or gingival administration i.e. oromucosal administration
  • Suitable films for sublingual or buccal or gingival administration comprise dexmedetomidine or a pharmaceutically acceptable salt thereof either (i) disposed within a polymer matrix or (ii) deposited on the surface of a polymer matrix, e.g., on the surface of a “placebo” film.
  • the polymer component consists of one or more water-soluble polymers within the film matrix and/or as part of the drug-containing deposit (e.g., one or more droplets) on the surface of the polymer.
  • the polymer component consists of a single water-soluble polymer.
  • the polymer component consists of two or more water-soluble polymers, including two or more of the same water-soluble polymers having different molecular weights.
  • the polymer component in the film matrix is of a suitable composition and present in a sufficient amount to ensure rapid disintegration of the film matrix in the oral mucosa.
  • the presence of the polymer component may allow the film matrix to disintegrate completely oromucosally in about 15 seconds to about 180 seconds, for example, about 30 seconds to about 180 seconds, including about 120 seconds.
  • the polymer component in the film matrix also provides the film with sufficient strength (i.e., the film is self-supporting).
  • the polymer component may, for example, consist of the water-soluble polymer hydroxypropyl cellulose, although different water-soluble polymers are also contemplated as described hereinafter under the definition “first water- soluble polymer” and “second water soluble polymer”.
  • the polymer component may consist of one, two or three hydroxypropyl celluloses having different molecular weights.
  • the molecular weights of the different hydroxypropyl celluloses may conveniently range from (i) less than about 60,000 Daltons (e.g., about 5,000 Daltons to about 49,000 Daltons) (ii) about 90,000 Daltons to about 200,000 Daltons and (iii) about 200,000 Daltons to about 500,000 Daltons.
  • the two or more hydroxypropyl celluloses may be mixed in any suitable ratio to achieve the desired droplet viscosity.
  • the viscosity of the dexmedetomidine composition solution or suspension can be measured using a Brookfield viscometer with a small sample adapter at a temperature of 25 ⁇ C and may range from about 5 cps to about 3700 cps. For example, it may range from about 5 cps to about 500 cps, about 6 cps to about 200 cps, about 42 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 6 cps to about 100 cps or about 6 cps to about 50 cps.
  • the viscosity of the dexmedetomidine composition solution or suspension is from about 6 cps to about 20 cps at 25 ⁇ C and a shear rate of about 7 (1/s).
  • a self-supporting, dissolvable, film comprising: (i) about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt); (ii) one or more water-soluble polymers; (iii) a polyethylene oxide; and (iv) optionally, one or more pharmaceutically acceptable carriers, wherein the film is to be administered in a non-clinical setting by a caregiver or informant to acutely agitated schizophrenia or bipolar disorder patients.
  • the agitation is mild to moderate. In embodiments, the agitation is not severe.
  • a self-supporting, dissolvable, film comprising: (i) about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt); (ii) one or more water-soluble polymers; (iii) a polyethylene oxide; and (iv) optionally, one or more pharmaceutically acceptable carriers, wherein the film is self-administered in a non-clinical setting by an acutely agitated schizophrenia or bipolar disorder patients.
  • the agitation is mild to moderate. In embodiments, the agitation is not severe.
  • a self-supporting, dissolvable, film comprising: (i) about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt); (ii) one or more water-soluble polymers; (iii) a polyethylene oxide; and (iv) optionally, one or more pharmaceutically acceptable carriers, wherein the film is self-administered in a non-clinical setting by an acutely agitated schizophrenia or bipolar disorder patients.
  • the agitation is mild to moderate. In embodiments, the agitation is not severe.
  • a self-supporting, dissolvable, film comprising: (i) about 90 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt); 43 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 (ii) one or more water-soluble polymers; (iii) a polyethylene oxide; and (iv) optionally, one or more pharmaceutically acceptable carriers, wherein the film is to be administered in a non-clinical-setting by a caregiver or informant to acutely agitated schizophrenia or bipolar disorder patients.
  • a pharmaceutically acceptable salt thereof e.g., the hydrochloride salt
  • 43 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 ii) one or more water-soluble polymers; (iii) a polyethylene oxide;
  • the agitation is mild to moderate. In embodiments, the agitation is not severe.
  • a self-supporting, dissolvable, film comprising: (i) about 90 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt); (ii) one or more water-soluble polymers; (iii) a polyethylene oxide; and (iv) optionally, one or more pharmaceutically acceptable carriers, wherein the film is self-administered in a non-clinical-setting by an acutely agitated schizophrenia or bipolar disorder patients.
  • the agitation is mild to moderate. In embodiments, the agitation is not severe.
  • a self-supporting, dissolvable, film comprising: (i) about 120 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt); (ii) one or more water-soluble polymers; (iii) a polyethylene oxide; and (iv) optionally, one or more pharmaceutically acceptable carriers, wherein the film is to be administered in a non-clinical-setting by a caregiver or informant to acutely agitated schizophrenia or bipolar disorder patients.
  • the film is self-administered in a non-clinical-setting by an acutely agitated patient.
  • the agitation is mild to moderate.
  • a self-supporting, dissolvable, film comprising: (i) about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt); (ii) one or more water-soluble polymers; (iii) a polyethylene oxide; and (iv) optionally, one or more pharmaceutically acceptable carriers, 44 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 wherein the film is to be administered in a non-clinical setting by a caregiver or informant to acutely agitated schizophrenia or bipolar disorder patients.
  • a pharmaceutically acceptable salt thereof e.g., the hydrochloride salt
  • the film is self- administered in a non-clinical setting by the patient.
  • the agitation is mild to moderate. In embodiments, the agitation is not severe.
  • Medical kits [0248] The present disclosure provides an individual unit dosage form provided as a kit comprising the compositions as described herein in a container with or without instructions for administration to a patient in need thereof.
  • the composition is a film for oromucosal administration. to a patient in non-clinical settings.
  • the present disclosure provides an individual unit oromucosal film dosage form provided as a kit comprising: (i) about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; and (ii) instructions for the administration of (i) to schizophrenia or bipolar disorder patients in need thereof, wherein the dosage form is administered for treating acute agitation in the patients in a non- clinical setting.
  • the present disclosure provides an individual unit oromucosal film dosage form provided as a kit comprising: (i) about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; and (ii) instructions for the administration of (i) to schizophrenia or bipolar disorder patients in need thereof, wherein the dosage form is administered for treating mild to moderate agitation in the patients in a non-clinical setting.
  • the present disclosure provides an individual unit oromucosal film dosage form provided as a kit comprising: (i) about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; and (ii) instructions for the administration of (i) to schizophrenia or bipolar disorder patients in need thereof, 45 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 wherein the dosage form is administered for treating mild to moderate agitation in the patients in a non-clinical setting.
  • the present disclosure provides an individual unit oromucosal film dosage form provided as a kit comprising: (i) about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; and (ii) instructions for the administration of (i) to schizophrenia or bipolar disorder patients in need thereof, wherein the dosage form is administered for treating mild to moderate agitation in the patients in a non-clinical setting.
  • the agitation is not severe.
  • the dosage form is administered through a caregiver or informant to the patient.
  • the dosage form is self-administered by the patient.
  • the film dosage form comprises about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt). In embodiments, the film dosage form comprises about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt). In embodiments, the film dosage form comprises about 90 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt). In embodiments, the film dosage form comprises about 120 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt).
  • the film dosage form comprises about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt).
  • the dosage form is administered sublingually.
  • the dosage form is administered buccally.
  • the dosage form is administered gingivally.
  • the kit comprises a package insert comprising instructions for using the compositions described herein for treatment of agitation in a patient.
  • the agitation is acute.
  • the agitation is mild to moderate.
  • the total daily dose of dexmedetomidine is administered as a first dose and optional second dose.
  • the kit comprising dexmedetomidine or pharmaceutically acceptable salt thereof is provided as two dosage forms for administration of one dosage form after the other dosage form separated by a suitable period of time (e.g., 2 hours or more).
  • a suitable period of time e.g. 2 hours or more.
  • the two film dosage forms may be packaged separately and provided in same or different containers.
  • one or both dosage forms contain about 60 micrograms of dexmedetomidine hydrochloride.
  • the dosage forms contain about 120 micrograms of dexmedetomidine hydrochloride.
  • the dosage forms contain about 180 micrograms of dexmedetomidine hydrochloride.
  • the kit comprises a container that includes, but is not limited to bottles, vials (e.g., dual chamber vials), syringes (such as single or dual chamber syringes) and test tubes.
  • the container may be formed from a variety of materials such as glass or plastic.
  • the kit may comprise a label (e.g., on or associated with the container) or a package insert.
  • the label or the package insert may indicate that the compound contained therein may be useful or intended for treating acute agitation in a schizophrenia or bipolar disorder patients.
  • Embodiment 1 A method of treating agitation in a schizophrenia or bipolar disorder patient in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 60 micrograms to the patient, wherein the patient is 18 years or older.
  • Embodiment 2. A method of treating agitation in a schizophrenia or bipolar disorder patient in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 80 micrograms to the patient, wherein the patient is 18 years or older.
  • a method of treating acute agitation in a schizophrenia patient in a non- clinical setting comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a total daily dose of about 60 micrograms to about 360 micrograms to the patient, wherein the patient is 18 years or older.
  • Embodiment 4. A method of treating acute agitation in a bipolar disorder patient in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a total daily dose of about 60 micrograms to about 360 micrograms to the patient, wherein the patient is 18 years or older.
  • a method of treating acute agitation in a schizophrenia patient in a non- clinical setting comprising administering dexmedetomidine or a pharmaceutically acceptable 47 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 salt thereof at a total daily dose of about 60 micrograms to about 180 micrograms to the patient, wherein the patient is 18 years or older.
  • a method of treating acute agitation in a bipolar disorder patient in a non-clinical setting comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a total daily dose of about 60 micrograms to about 180 micrograms to the patient, wherein the patient is 18 years or older.
  • Embodiment 7. The method of any one of embodiments 1 to 6, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered by the caregiver or informant of the patient.
  • Embodiment 8 The method of embodiment 7, wherein the caregiver or informant is a family member, a family friend, social worker or any person employed by or for the patient.
  • Embodiment 10 The method of any one of embodiments 1 to 6, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.
  • Embodiment 10. The method of embodiments 1, 2, or 4, wherein the bipolar disorder includes bipolar I disorder, bipolar II disorder and bipolar mania.
  • Embodiment 11. The method of any one of embodiments 1 to 3, wherein the schizophrenia includes schizoaffective and schizophreniform disorder.
  • Embodiment 12 The method of any one of embodiments 1 to 11, wherein the agitation is mild or moderate.
  • Embodiment 13 The method of any one of embodiments 1 to 11, wherein the agitation is not severe.
  • a method of treating acute agitation in a schizophrenia patient in a non-clinical setting comprising administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a total daily dose of about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant.
  • oromucosally e.g., sublingually, buccally, or gingivally
  • a method of treating acute agitation in a schizophrenia patient in a non-clinical setting comprising administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient at a dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant.
  • oromucosally e.g., sublingually, buccally, or gingivally
  • a method of treating acute agitation in a schizophrenia patient in a non-clinical setting comprising administering oromucosally (e.g., sublingually, buccally, or 48 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 gingivally), to the patient at a dose of about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant.
  • oromucosally e.g., sublingually, buccally, or 48 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 gingivally
  • a method of treating acute agitation in a bipolar disorder patient in a non-clinical setting comprising administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a total daily dose of about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant.
  • oromucosally e.g., sublingually, buccally, or gingivally
  • a method of treating acute agitation in a bipolar disorder patient in a non-clinical setting comprising administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient at a dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant.
  • Embodiment 19 A method of treating acute agitation in a bipolar disorder patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient at a dose of about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant.
  • Embodiment 20 A method of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self- administered by the patient.
  • an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self- administered by the patient.
  • a method of treating acute agitation in a bipolar disorder patient in a non-clinical setting comprising administering an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self- administered by the patient.
  • an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self- administered by the patient.
  • a method of treating acute agitation in a bipolar disorder patient in a non-clinical setting comprising administering an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.
  • a method of treating acute agitation in a bipolar disorder patient in a non-clinical setting comprising administering an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the 49 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.
  • a method of treating mild to moderate agitation in a schizophrenia or bipolar disorder patient in a non-clinical setting comprising administering oromucosally (e.g., sublingually, buccally, or gingivally) to the patient a dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant.
  • oromucosally e.g., sublingually, buccally, or gingivally
  • a dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant.
  • a method of treating mild to moderate agitation in a schizophrenia or bipolar disorder patient in a non-clinical setting comprising administering oromucosally (e.g., sublingually, buccally, or gingivally) to the patient a dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant.
  • oromucosally e.g., sublingually, buccally, or gingivally
  • a method of treating mild to moderate agitation in a schizophrenia or bipolar disorder patient in a non-clinical setting comprising administering oromucosally (e.g., sublingually, buccally, or gingivally) to the patient a dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant.
  • oromucosally e.g., sublingually, buccally, or gingivally
  • a method of treating mild to moderate agitation in schizophrenia patient in a non-clinical setting comprising adminstering an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.
  • an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.
  • a method of treating mild to moderate agitation in a schizophrenia patient with in a non-clinical setting comprising administering an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self- administered by the patient.
  • Embodiment 29 A method of treating mild to moderate agitation in a schizophrenia patient with in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self- administered by the patient.
  • Embodiment 30 A method of treating mild to moderate agitation in a bipolar disorder (bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.
  • Embodiment 31 A method of treating mild to moderate agitation in a bipolar disorder (bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.
  • a method of treating mild to moderate agitation in a bipolar disorder patient in a non-clinical setting comprising adminsitering an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self- administered by the patient.
  • Embodiment 32 A method of treating mild to moderate agitation in a bipolar disorder patient in a non-clinical setting, comprising adminsitering an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self- administered by the patient.
  • Embodiment 33 A method of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient, comprising: (a) administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof under medical supervision for at least 8 hours (“phase 1”); and (b) administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a unit dose of about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof under non- medical supervision (non -clinical setting) for up to 12 weeks (“phase 2”).
  • phase 1 administering oromucosally
  • phase 2 administering oromucosally (e.g., sublingually, buccally, or gingivally)
  • phase 2 administering oromucos
  • Embodiment 34 A method of treating acute agitation in a schizophrenia patient, comprising: (a) administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof under medical supervision for at least 8 hours (“phase 1”).
  • oromucosally e.g., sublingually, buccally, or gingivally
  • Embodiment 35 The method of any one of embodiments 1 to 34, wherein the patient experiences periodic episodes of agitation.
  • Embodiment 37 The method of any one of embodiments 1 to 34, wherein the patient has a score of ⁇ 4 on at least 1 of the 5 items on the PEC at baseline.
  • Embodiment 38 The method of any one of embodiments 1 to 34, wherein the patient has a total score of ⁇ 14 on 5 items on PEC.
  • Embodiment 38 The method of any one of embodiments 1 to 34, wherein the patient has a score ⁇ 4 on C-SSRS.
  • Embodiment 39 The method of any one of embodiments 1 to 34, wherein the patient experiences not more than 2 episodes of agitation in a week [0299] Embodiment 40.
  • Embodiment 41 The method of any one of embodiments 1 to 34, wherein the patient is suffering from one or more psychiatric comorbidities.
  • Embodiment 42 The method of any one of embodiments 1 to 34, wherein the patient is not concurrently taking other medications.
  • Embodiment 43 The method of any one of embodiments 1 to 34, wherein the patient is about 18 years to about 75 years old.
  • Embodiment 44 The method of any one of embodiments 1 to 34, wherein the patient is about 75 years or older.
  • Embodiment 45 Embodiment 45.
  • Embodiment 46 The method of embodiment 45, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in an oromucosal dosage form selected from the group consisting of a film, wafer, patch, lozenge, gel, spray, tablet and liquid drops
  • Embodiment 47 The method of embodiment 45, wherein the dosage form is a thin film.
  • Embodiment 48 The method of embodiment 46 or 47, wherein the dosage form is a sublingual film.
  • Embodiment 49 Embodiment 49.
  • Embodiment 50 The method of embodiment 46 or 47, wherein the dosage form is a gingival film.
  • Embodiment 51 The method of any one of the preceding embodiments, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as a single dose per day.
  • Embodiment 52 The method of any one of the preceding embodiments, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as a single dose per day.
  • Embodiment 53 The method of embodiment 52, wherein the first dose is about 30 micrograms, about 40 micrograms, about 50 micrograms, about 60 micrograms, about 70 micrograms, about 80 micrograms, about 90 micrograms, about 100 micrograms, about 110 micrograms, about 120 micrograms or about 180 micrograms of dexmedetomidine hydrochloride.
  • Embodiment 54 Embodiment 54.
  • Embodiment 55 The method of embodiment 52 or 53, wherein the first dose is about 80 micrograms of dexmedetomidine hydrochloride.
  • Embodiment 56 The method of embodiment 52, wherein the second dose is administered at least about 2 hours after administration of the first dose if there is no improvement in PEC score by more than 2 points.
  • Embodiment 57 The method of embodiment 52 or 53, wherein the second dose is administered at least about 2 hours after administration of the first dose if there is no improvement in PEC score by more than 2 points.
  • Embodiment 58 The method of embodiment 52, 56, or 57, wherein the optional second dose is about 30 micrograms, about 40 micrograms, about 50 micrograms, about 60 micrograms, about 70 micrograms, about 80 micrograms, about 90 micrograms, about 100 micrograms, about 110 micrograms, about 120 micrograms, or about 180 micrograms of dexmedetomidine hydrochloride. 53 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 [0318] Embodiment 59. The method of embodiment 52 or 58, wherein the optional second dose is about 60 micrograms. [0319] Embodiment 60.
  • Embodiment 61 The method of any one of the preceding embodiments, wherein the administration of dexmedetomidine, a pharmaceutically acceptable salt thereof, or the oromucosal dosage comprising dexmedetomidine or a pharmaceutically acceptable salt thereof form produces anti-agitation effect within about 30 minutes after administration.
  • Embodiment 62 The method of any one of the preceding embodiments, wherein the administration of dexmedetomidine, a pharmaceutically acceptable salt thereof, or the oromucosal dosage comprising dexmedetomidine or a pharmaceutically acceptable salt thereof form produces anti-agitation effect within about 90 minutes after administration.
  • Embodiment 63 The method of any one of the preceding embodiments, wherein the administration of dexmedetomidine, a pharmaceutically acceptable salt thereof, or the oromucosal dosage comprising dexmedetomidine or a pharmaceutically acceptable salt thereof produces anti-agitation effect within about 120 minutes after administration.
  • Embodiment 64 The method of any one of the preceding embodiments, wherein the agitation is treated without also inducing significant sedation.
  • Embodiment 65 The method of any one of the preceding embodiments, wherein the treatment is effective with reduced or no side effects (e. g. cardiac or respiratory side effects).
  • Embodiment 66 The method of any one of the preceding embodiments, wherein the treatment is effective with reduced or no side effects (e. g. cardiac or respiratory side effects).
  • Embodiment 67 The method of any one of the preceding embodiments, wherein the reduction in agitation is assessed by relative change in PEC score after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.
  • Embodiment 68 The method of any one of the preceding embodiments, wherein the reduction in agitation is assessed by relative change in modified CGI-S 4-point (0-3) scale after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.
  • Embodiment 69 Embodiment 69.
  • Embodiment 70 The method of any one of the preceding embodiments, wherein the patient achieves a mean change in PEC score of greater than -7 relative to baseline within 30 minutes of administration. 54 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 [0329] Embodiment 70. The method of any one of the preceding embodiments, wherein the patient achieves a CGI-I score improvement to about a 1 (very much improved) or about a 2 (much improved). [0330] Embodiment 71.
  • Embodiment 72 The method of any one of the preceding embodiments, wherein the decrease in the PEC, CGI-S and ACES scores is maintained for at least about 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, hours following administration.
  • Embodiment 73 The method of any one of the preceding embodiments, wherein the single administration of dexmedetomidine treats agitation and maintains calming effect for at least 12 hours.
  • Embodiment 74 The method of any one of the preceding embodiments, wherein the administration of dexmedetomidine provides improvement in duration of calming as measured using reduction in ACES score to 2 or more following administration of dexmedetomidine or a pharmaceutically acceptable salt thereof.
  • Embodiment 75 The method of any one of the preceding embodiments, wherein the administration of dexmedetomidine provides improvement in the residual signs and symptoms of schizophrenia following administration of dexmedetomidine or a pharmaceutically acceptable salt thereof as measured by reduction in PEC score of greater than -2 relative to baseline.
  • Embodiment 76 Embodiment 76.
  • Embodiment 77 The method of any one of the preceding embodiments, wherein the reduction in agitation is alerted to the caregiver or informant via Ecological Momentary Assessment (EMA) device or other remote compatible device.
  • Embodiment 78 Embodiment 78.
  • Embodiment 79 The method of any one of the preceding embodiments, wherein a rescue medication is optionally administered to the patient after the second dose of dexmedetomidine.
  • Embodiment 80 The method of any one of the preceding embodiments, wherein the reduction in agitation is assessed before the administration of rescue medication in the patient.
  • Embodiment 81 The method of embodiment 76 or 77, wherein the method comprises a wearable device (or a wearable sensor) in contact with the patient.
  • Embodiment 82 The method of embodiment 81, wherein the wearable device (or a wearable sensor) is selected from iPhone (BYOD or provisioned), accelerometers, gyroscopes, portable devices, digital devices, smart fabrics, bands and actuators like an Apple watch or iWatch, patch such as MC10 Patch, sensors like Microsoft Kinect and the like.
  • Embodiment 83 Embodiment 83.
  • Embodiment 84 The method of embodiment 81 or 82, wherein the wearable device is wrist worn multi-sensor device with networking capability (e.g., wearable watch such as Apple watch).
  • Embodiment 85 The method of embodiment 76 or 77, wherein the EMA device comprises a smartphone or a tablet with an application installed to report the patient’s observations.
  • Embodiment 86 The method of embodiment 86 or 77, wherein the EMA device comprises a smartphone or a tablet with an application installed to report the patient’s observations.
  • Embodiment 85 wherein the application on the caregiver’s or informant’s EMA device provides prompt to report on absence or presence of episode of agitation
  • Embodiment 87 The method of embodiment 85, wherein the caregiver or informant reports information on frequency or number of episodes of agitation on the application installed on EMA device.
  • Embodiment 88 The method of embodiment 81, wherein the wearable device detects the severity of the agitation (e.g., mild, moderate or elevated).
  • Embodiment 89 The method of embodiment 81, wherein the wearable device predicts the probability of specific patient to move from mild to moderate to elevated agitation.
  • Embodiment 90 Embodiment 90.
  • Embodiment 91 The method of embodiment 90, wherein the severity change probability can be measured using at least one machine learning model’s (e.g., an agitation state detection model’s) predictions to create and/or define a chain of events.
  • Embodiment 92 The method of any one of the preceding embodiments, wherein the patient, caregiver, or informant records the observations in an agitation episode diary for each episode of agitation.
  • Embodiment 95 The method of any one of the preceding embodiments, wherein the agitation episode diary comprises questions based on safety information, use of emergency services, use of other concomitant medications and sleepiness.
  • Embodiment 94 The method of any one of the preceding embodiments, wherein the agitation episode diary comprises questions based on efficacy information after taking study medication (Yes/No), mCGI-S, CGI-C, the agitation behaviors scale (Informant only), use of study medication or use of rescue medication.
  • Embodiment 95 Embodiment 95.
  • An oromucosal dosage form for the treatment of acutely agitated schizophrenia or bipolar disorder patients in a non-clinical setting comprising: (i) about 5 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) one or more mucoadhesive agents; and (iii) one or more pharmaceutically acceptable excipients or carriers, wherein the dosage form disintegrates within about 5 seconds to about 10 minutes upon contact with an oral mucosa.
  • An oromucosal dosage form for the treatment of acutely agitated schizophrenia or bipolar disorder patients in a non-clinical setting comprising: (i) about 60 micrograms to about 300 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) one or more mucoadhesive agents; and (iii) one or more pharmaceutically acceptable excipients or carriers, wherein the dosage form disintegrates within about 5 seconds to about 10 minutes upon contact with an oral mucosa.
  • An oromucosal dosage form for the treatment of acutely agitated schizophrenia or bipolar disorder patients in a non-clinical setting comprising: (i) about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; 57 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 (ii) one or more mucoadhesive agents; and (iii) one or more pharmaceutically acceptable excipients or carriers, wherein the dosage form disintegrates within about 5 seconds to about 10 minutes upon contact with an oral mucosa. [0357] Embodiment 98.
  • An oromucosal dosage form for the treatment of acutely agitated schizophrenia or bipolar disorder patients in a non-clinical setting comprising: (i) about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) one or more mucoadhesive agents; and (iii) one or more pharmaceutically acceptable excipients or carriers, wherein the dosage form disintegrates within about 5 seconds to about 10 minutes upon contact with an oral mucosa.
  • An oromucosal dosage form for the treatment of acutely agitated schizophrenia or bipolar disorder patients in a non-clinical setting comprising: (i) about 120 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) one or more mucoadhesive agents; and (iii) one or more pharmaceutically acceptable excipients or carriers, wherein the dosage form disintegrates within about 5 seconds to about 10 minutes upon contact with an oral mucosa.
  • An oromucosal dosage form for the treatment of acutely agitated schizophrenia or bipolar disorder patients in a non-clinical setting comprising: (i) about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) one or more mucoadhesive agents; and (iii) one or more pharmaceutically acceptable excipients or carriers, wherein the dosage form disintegrates within about 5 seconds to about 10 minutes upon contact with an oral mucosa.
  • Embodiment 101 The oromucosal dosage form of embodiment 95 to 100, wherein non- clinical setting is at home or group home, assisted living facility, correctional facility, hospice or long-term care facility.
  • Embodiment 103 The oromucosal dosage form of any one of embodiments 95 to 100, wherein the dosage form is administered by the caregiver or informant.
  • Embodiment 104 Embodiment 104.
  • Embodiment 105 The oromucosal dosage form of embodiment 104, wherein the dosage form is an oromucosal film (sublingual or buccal or gingival).
  • Embodiment 106 Embodiment 106.
  • Embodiment 105 The oromucosal dosage form of embodiment 105, wherein the dosage form is an oromucosal tablet.
  • Embodiment 107 The oromucosal dosage form of embodiment 106, wherein the tablet is lyophilized.
  • Embodiment 108 The oromucosal dosage form of any one of embodiments 95 to 107, wherein the dosage form is conveniently delivered on an "as needed basis" in one, two or more doses per day to the patient.
  • Embodiment 109 The oromucosal dosage form of any one of embodiments 95 to 107, wherein the dosage form effectively treats agitation in a patient without causing significant sedation.
  • Embodiment 110 A self-supporting, dissolvable, film, comprising: (i) about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt); (ii) one or more water-soluble polymers; (iii) a polyethylene oxide; and (iv) optionally, one or more pharmaceutically acceptable carriers, wherein the film is to be administered in a non-clinical setting by a caregiver or informant to acutely agitated schizophrenia or bipolar patients.
  • Embodiment 111 Embodiment 111.
  • a self-supporting, dissolvable, film comprising: (i) about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt); (ii) one or more water-soluble polymers; (iii) a polyethylene oxide; (iv) optionally, one or more pharmaceutically acceptable carriers, 59 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 wherein the film is self-administered in a non-clinical setting by acutely agitated schizophrenia or bipolar disorder patients.
  • a pharmaceutically acceptable salt thereof e.g., the hydrochloride salt
  • Embodiment 112 A self-supporting, dissolvable, film, comprising: (i) about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt); (ii) one or more water-soluble polymers; (iii) a polyethylene oxide; (iv) optionally, one or more pharmaceutically acceptable carriers, wherein the film is self-administered in a non-clinical setting by acutely agitated schizophrenia or bipolar disorder patients.
  • Embodiment 113 Embodiment 113.
  • a self-supporting, dissolvable, film comprising: (i) about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt); (ii) one or more water-soluble polymers; (iii) a polyethylene oxide; and (iv) optionally, one or more pharmaceutically acceptable carriers wherein the film is to be administered in a non-clinical setting by a caregiver or informant to acutely agitated schizophrenia or bipolar patients.
  • a pharmaceutically acceptable salt thereof e.g., the hydrochloride salt
  • a self-supporting, dissolvable, film comprising: (i) about 120 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt); (ii) one or more water-soluble polymers; (iii) a polyethylene oxide; and (iv) optionally, one or more pharmaceutically acceptable carriers, wherein the film is to be administered in a non-clinical setting by a caregiver or informant to acutely agitated schizophrenia or bipolar disorder patients.
  • a self-supporting, dissolvable, film comprising: (i) about 120 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt); (ii) one or more water-soluble polymers; (iii) a polyethylene oxide; and (vi) optionally, one or more pharmaceutically acceptable carriers, 60 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 wherein the film is self-administered in a non-clinical setting by acutely agitated schizophrenia or bipolar disorder patients.
  • Embodiment 116 Embodiment 116.
  • An individual unit oromucosal film dosage form provided as a kit comprising: (i) about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; and (ii) instructions for the administration of (i) to schizophrenia or bipolar disorder patients in need thereof, wherein the dosage form is administered for treating acute agitation in the patients in a non- clinical setting.
  • a kit comprising: (i) about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; and (ii) instructions for the administration of (i) to schizophrenia or bipolar disorder patients in need thereof, wherein the dosage form is administered for treating acute agitation in the patients in a non- clinical setting.
  • An individual unit oromucosal film dosage form provided as a kit comprising: (i) about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; and (ii) instructions for the administration of (i) to schizophrenia or bipolar disorder patients in need thereof, wherein the dosage form is administered for treating mild to moderate agitation in the patients in a non-clinical setting.
  • Embodiment 118 The kit of embodiment 116 or 117, wherein the dosage form is administered through a caregiver or informant to the patients.
  • Embodiment 119 The kit of embodiment 116 or 117, wherein the dosage form is self- administered by the patients.
  • Embodiment 120 The kit of embodiment 116 or 117, wherein the dosage form is self- administered by the patients.
  • Embodiment 121 The kit or the oromucosal dosage form of any one of embodiments 97 to 120, wherein the bipolar disorder includes bipolar I disorder, bipolar II disorder and bipolar mania.
  • Embodiment 122 The kit or the oromucosal dosage form of any one of embodiments 97 to 120, wherein the schizophrenia includes schizoaffective and schizophreniform disorder.
  • Embodiment 123 Embodiment 123.
  • kits of any one of embodiments 96 to 122 wherein the kit comprises dexmedetomidine or pharmaceutically acceptable salt thereof provided as two 61 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 dosage forms for administration of one dosage form after the other dosage form separated by a suitable period of time.
  • Embodiment 124 The kit of embodiment 123, wherein the two film dosage forms are packaged separately and provided in same containers.
  • Embodiment 125 The kit of embodiment 123, wherein the two film dosage forms are packaged separately and provided in different containers.
  • Embodiment 126 Embodiment 126.
  • Embodiment 127 The kit of any one of embodiments 116 to 126, wherein dexmedetomidine or pharmaceutically acceptable salt thereof is present in an amount of about 60 micrograms.
  • Embodiment 128 The kit of any one of embodiments 116 to 126, wherein dexmedetomidine or pharmaceutically acceptable salt thereof is present in an amount of about 80 micrograms.
  • Embodiment 129 The kit of any one of embodiments 116 to 128, wherein the film dosage forms are administered sublingually, buccally, or gingivally.
  • Embodiment 130 The method, the oromucosal dosage form or the kit of any one of the preceding embodiments, wherein the agitation is mild to moderate.
  • Embodiment 131 The method, the oromucosal dosage form or the kit of any one of the preceding embodiments, wherein the agitation is not severe.
  • Example 1 To determine the efficacy and safety of Dexmedetomidine hydrochloride sublingual film evaluated for at-home use in a Multisite Double-Blind Placebo Controlled Trial for agitation associated with Schizophrenia and Bipolar Disorder OBJECTIVES: Primary objectives: Part 1: 62 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 [0392] To determine if a 60 micrograms dose of dexmedetomidine hydrochloride sublingual film, effectively reduces symptoms of agitation assessed using the Positive and Negative Syndrome Scale – Excited Component (PEC) change from baseline compared to change from baseline with placebo.
  • PEC Positive and Negative Syndrome Scale – Excited Component
  • Part 2 [0393] To assess the safety of dexmedetomidine hydrochloride sublingual film when used in an at-home environment based on serious adverse events (SAEs), and treatment-emergent adverse events (TEAEs) collected by both the Informant and the clinical Investigator. Secondary objectives: Part 1: • To determine the overall clinical improvement after study treatment administration as measured by the Clinical Global Impression – Improvement Scale (CGI-I). • To determine the overall clinical improvement after drug administration as measured by the modified Clinical Global Impression – Severity Scale (mCGI- S) administered by the investigator. • To describe the duration of calming as measured by PEC and ACES.
  • SAEs serious adverse events
  • TEAEs treatment-emergent adverse events
  • the Treatment Satisfaction Questionnaire for Medication will be administered for this purpose at the end of the treatment period.
  • Primary Endpoints • Part 1: Change in PEC score from Baseline as compared to placebo at 2 hours after drug administration. • Part 2: Comparison of Serious Adverse Events (SAEs) and TEAEs as compared to placebo. Secondary Endpoints Part 1: • The CGI-I will assess overall clinical improvement after drug administration. • The mCGI-S will assess overall clinical improvement after drug administration. • The duration of calming will be measured by the PEC and ACES. • The safety profile of dexmedetomidine hydrochloride sublingual film will be measured by reports of adverse events (AE), vital signs measurements, ECGs and clinical laboratory results.
  • AE adverse events
  • STUDY DESIGN This is a randomized, double-blind, placebo-controlled, 2-part, Phase III study to assess efficacy, safety and tolerability of a 60 micrograms dose of dexmedetomidine hydrochloride sublingual film dosing in adult (18-75 years old) males and females with agitation episodes associated with a primary diagnosis of bipolar I disorder, bipolar II disorder, schizophrenia, schizoaffective disorder, or schizophreniform disorder. Part 1 of the study is a one-day, in- clinic treatment, and post-treatment observation period with patients experiencing an acute episode of agitation.
  • Part 2 of the study is a 12-week study to determine the safety of dexmedetomidine hydrochloride sublingual film when used in an at-home setting when treating episodes of agitation in patients.
  • Each patient may only participate in one part of the study. All patients enrolled will be individuals who have never previously received a dose of dexmedetomidine hydrochloride sublingual film or IGALMI TM.
  • Part 1 In-clinic period Setting Conduct: The in-clinic study period will randomize patients 1:1 to receive 60 mcg of dexmedetomidine hydrochloride sublingual film or a matching placebo.
  • Eligible patients may be identified in outpatient clinics, mental health centers, psychiatric or medical emergency services including medical/psychiatric observation units, or as newly admitted patients to a hospital setting for acute agitation or already hospitalized for their underlying, primary psychiatric disorder. Patients will be domiciled in 65 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 clinical research setting or hospitalized to remain under medical supervision while undergoing screening procedures to assess eligibility, during treatment, and during the post-treatment observation period of at least 8 hours.
  • the randomization scheme will be designed so that no more than 70% of the patients in each arm of the study will have a primary diagnosis of bipolar disorder (bipolar I or bipolar II) or schizophrenia (including schizoaffective and schizophreniform disorder).
  • bipolar disorder bipolar I or bipolar II
  • schizophrenia including schizoaffective and schizophreniform disorder.
  • patients Upon confirmation of eligibility, patients will be randomized to receive either 60 micrograms of dexmedetomidine hydrochloride sublingual film or matching placebo. When dosing, patients will be instructed on how to take the dexmedetomidine hydrochloride film sublingually, and that they should retain it in the sublingual cavity until dissolved. The patient will self-administer under the supervision of a trained staff member.
  • the rescue medication can be either a benzodiazepine (lorazepam maximum dose of 4 milligram (mg) or oxazepam maximum dose of 60 mg) or any antipsychotic except clozapine, pimozide, or prochlorperazine, with a maximum dose approximately equivalent to 300 mg of chlorpromazine as specified by BioXcel and as chosen by the Investigator. [0402] The patient must remain in the clinic for a minimum of 8 hours of observation following administration of study treatment [0403] Efficacy, safety, tolerability, and pharmacokinetics (PK) will be measured throughout the treatment period at various times. (Please refer to the Table 1: Part 1 Schedule of Events for details).
  • PK pharmacokinetics
  • Part 2 Community (At-home) Setting Conduct: The at-home study period will randomize patients 1:1 to receive 60 micrograms of dexmedetomidine hydrochloride sublingual film or matching placebo film when an episode of agitation occurs at home. Eligible patients will be individuals who experience periodic episodes of agitation related to a primary diagnosis of bipolar disorder or schizophrenia. In addition, patients must have a reliable 66 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 informant who can participate in the study conduct at times when an episode of agitation is treated with the study treatment and during monthly clinic visits.
  • the randomization scheme is designed so that no more than 70% of the patients in each arm of the study have a primary diagnosis of bipolar disorder (bipolar I or bipolar II) or schizophrenia (including schizoaffective and schizophreniform disorder).
  • bipolar disorder bipolar I or bipolar II
  • schizophrenia including schizoaffective and schizophreniform disorder.
  • Informants and patients will also be trained at Screening on their responsibilities during the study, rating the severity of agitation using the mCGI-S, and the circumstances in which the Informant can recommend that a patient self-administers a dose of study treatment and rescue medication. Patients are trained as to when they can take study treatment and rescue medication on their recognizance. Ideally, the informant will be present when study treatment is taken, however the patient may self-administer study treatment when the Informant is not present, if the patient feels that they need to do so. [0406]
  • the Informant is responsible for recording the onset time and cessation time of the agitation event time via an ecological momentary assessment (EMA) application, along with the time study treatment and rescue medication (if needed) is taken.
  • EMA ecological momentary assessment
  • the Informant also records all adverse events (AEs) reported by the patient during the 8 hours following study treatment administration or 8 hours following rescue medication administration (whichever comes last) as well as any medications taken by the patient within 4 hours prior to dosing and within 4 hours post-dose.
  • AEs adverse events
  • the Informant also records any interactions with emergency services (specifically, hospitalizations, emergency room visits, urgent care clinic visits, interventions by other emergency services such as ambulance services, and interventions by law enforcement) via the EMA application.
  • the Informant is prompted by the EMA application once daily to ask if an agitation episode occurred that was not reported when it occurred, and to ask if any emergency 67 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 services interventions were required for such an unreported episode.
  • the Informant and patient will be prompted by EMA application twice daily to provide current mCGI-S rating (see Table 3, At Home Patient and Informant Assessments).
  • the rescue medication can be either a benzodiazepine (lorazepam maximum dose of 4 mg or oxazepam maximum dose of 60 mg) or any antipsychotic except clozapine, pimozide, or prochlorperazine, with a maximum dose approximately equivalent to 300 mg of chlorpromazine as specified by BioXcel and as chosen by the Investigator.
  • DIAGNOSIS AND MAIN CRITERIA FOR ELIGIBILITY Stage 1: [0414] Inclusion Criteria (Parts 1 and 2) 1. Male and female patients 18 to 75 years old, inclusive. 2. Patients who can read, understand, and provide written informed consent. 3. Patients who meet DSM-5/5-TR criteria for a primary diagnosis of bipolar I or bipolar II disorder, schizophrenia, schizoaffective or schizophreniform disorder. 4.
  • Medically acceptable methods of contraception that may be used by the participant and/or his/her partner include abstinence, birth control pills or patches, diaphragm with spermicide, intrauterine device (IUD), condom with foam or spermicide, vaginal spermicidal suppository, surgical sterilization and progestin implant or injection.
  • Prohibited methods include: the rhythm method, withdrawal, condoms alone, or diaphragm alone.
  • hepatic moderate-severe hepatic impairment
  • renal gastroenterological, respiratory
  • Psychiatric comorbidities are generally allowed; however, substance use disorders (within part two years) are exclusionary if the substance involved is other than nicotine or caffeine. Mild cannabis use is allowed. Tetrahydrocannabinol (THC) in the urine is not exclusionary if the Investigator judges the severity of the cannabis use disorder as mild. 3.
  • a score (assessed as meeting criteria for Scale items) of ⁇ 4 is exclusionary.
  • Clinically significant risk of risk of suicide based on the investigator’s clinical opinion or a history of an actual suicide attempt in the last year are also exclusionary.
  • mice Female patients who have a positive pregnancy test at screening or are breastfeeding. 8. Patients currently treated with alpha-1 noradrenergic blockers (terazosin, doxazosin, tamsulosin, alfuzosin, or prazosin), alpha-2 adrenergic agonists, or other prohibited medications. 9. Patients who have hydrocephalus, seizure disorder, or history of significant head trauma, stroke, transient ischemic attack, subarachnoid bleeding, brain tumor, encephalopathy, meningitis, Parkinson’s disease, or focal neurological findings. 10.
  • alpha-1 noradrenergic blockers terazosin, doxazosin, tamsulosin, alfuzosin, or prazosin
  • alpha-2 adrenergic agonists or other prohibited medications. 9. Patients who have hydrocephalus, seizure disorder, or history of significant head trauma, stroke, transient ischemic attack, subarachnoid bleeding, brain tumor, encephalopathy, meningit
  • Patients who have previously received dexmedetomidine hydrochloride sublingual film in either a clinical trial or via prescription under the trade name IGALMI). 15. Patients considered by the investigator to be an unsuitable candidate for receiving dexmedetomidine, e.g., patients with a history of allergic reactions to dexmedetomidine or considered to be unsuitable for participating in the study for any reason.
  • Additional Exclusion Criteria for patients to be enrolled into Part 1 16. Patients with agitation caused by acute intoxication, including positive identification of alcohol by breathalyzer or drugs of abuse (with the exception of THC) during urine screening. 17. Use of benzodiazepines or other hypnotics or antipsychotic drugs in the 4 hours before study treatment.
  • the product is a thin film formulation of dexmedetomidine for sublingual (SL) or buccal (BL) administration. Dosing delivers 60 micrograms of dexmedetomidine.
  • the product is a small, solid-dose film formulation, approximately 286 mm2 in area and 0.7 mm thick, designed to completely dissolve in the sublingual space within 1-3 minutes. Patients will receive a single film strip for sublingual placement in the oral cavity.
  • Reference therapy, dosage, and mode of Administration Matching placebo films to be taken sublingually as described above.
  • Efficacy Assessment of efficacy for acute agitation is based primarily on the Positive and Negative Syndrome Scale – Excited Component (PEC).
  • the PEC comprises 5 items associated with agitation: poor impulse control, tension, hostility, uncooperativeness, and excitement; each scored 1 (minimum) to 7 (maximum).
  • the PEC the sum of these 5 subscales, thus ranges from 5 to 35.
  • the overall agitation clinical improvement in response to treatment is also measured with the mCGI-S scale administered by the Investigator.
  • Safety and tolerability assessments AEs, clinical laboratory tests, ECG, percent oxygen saturation measured by pulse oximetry, and vital signs (including under orthostatic stress) will be monitored for tolerability and safety assessment. All observed and volunteered AEs will be recorded. The relationship of AEs to the study treatment will be graded as not related, unlikely/remotely related, possibly related, probably related or definitely related by the investigators. Vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate will be monitored both at rest and under orthostatic stress. The application site will be inspected for any signs of local irritation. Clinical laboratory analytes are assayed, and urinalyses are performed.
  • SBP systolic blood pressure
  • DBP diastolic blood pressure
  • Safety and tolerability assessments AEs, clinical laboratory tests, ECG, pulse oximetry, and vital signs are monitored for tolerability assessment at clinic visits.
  • the Informant collects AEs during the 8 hours following the study treatment or 8 hours after the rescue medication (if taken), whichever comes last. All observed and volunteered AEs are recorded by the Informant via the EMA application during these 8 hours. In addition, the Investigator will assess and record additional AEs at all in-clinic visits.
  • AEs The relationship of AEs to the study treatment is graded as not related, unlikely/remotely related, possibly related, probably related, or definitely related by the Investigator.
  • Vital signs including SBP, DBP, at rest and under orthostatic stress, and heart rate is monitored during the monthly clinic visits. ECGs are obtained at these clinic visits. Blood for clinical laboratory assays is obtained during clinic visits. Finally, the application site is inspected for any signs of local irritation during clinic visits.
  • Efficacy The mCGI-S, as rated by both the Informant and the patient, assesses efficacy in Part 2.
  • the Informant’s ratings are primary. This modified scale is expected to have greater reliability between and within raters without necessary psychiatric training to complete a PEC rating.
  • ⁇ Dexmedetomidine sublingual film_60 ⁇ PBO and HA1: ⁇ Dexmedetomidine sublingual film _60 ⁇ PBO where ⁇ Dexmedetomidine sublingual film _60 denotes the change from baseline in the PEC at 2 hours post-dose in the Dexmedetomidine sublingual film 60 mcg group and ⁇ PBO denotes the change from baseline in the PEC at 2 hours post-dose in the placebo group.
  • MMRM mixed model repeated measures
  • Safety data analysis will be conducted on all subjects receiving at least 1 dose of study treatment. The number and percentage of subjects experiencing 1 or more AEs will be summarized by treatment, relationship to study drug, and severity. AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) terminology. Listings of subjects who experience withdrawal due to an AE, serious adverse event (SAE) and/or death will be presented. Laboratory parameters will be summarized by treatment using descriptive statistics and data listings of clinically significant abnormalities. Vital signs and ECG data will be summarized by changes from baseline values using descriptive statistics.
  • the sample size of 250 patients, 125 per treatment group (1:1 randomization Dexmedetomidine sublingual film: placebo), for the at-home Part 2 is believed to provide enough patients to find the adverse drug reactions that might occur in at-home use, along with their incidences, without false positive findings. Any new adverse drug reactions would be considered additions to those already found and included in the labelling for Dexmedetomidine sublingual film.
  • Non-compliance or refusal of all or any PK draw is not exclusionary and does not result in early termination, nor will this be considered a protocol deviation.
  • the PEC is to be administered within 15 minutes before the administration of study treatment at the pre-dose time point.
  • the ACES is administered within 30 minutes before the administration of the study treatment at the pre-dose time point.
  • the mCGI-S is to be administered immediately prior to dosing at the pre-dose time point 10
  • the window for all assessments at the 30 minute and 1-hour timepoints is +/- 5 minutes 11
  • the window for all assessments at the 2-hour time point is +/- 15 minutes 12
  • the ECG conducted at the 2,4 and 8-hour times are collected before obtaining the PK samples 13
  • the resting vital signs and orthostatic vital signs collected at the 2, 4, 6, and 8-hour times are to be collected before obtaining the PK sample 14
  • the window for all assessments at the 4 hr, 6 hr, and 8 hr times is +/- 30 minutes 15 If the patient is determined to be not ready for discharge at the 8-hour timepoint, the Likability Questions and TSQM should not be completed.
  • Part 1 To determine if a 60-microgram (mcg) dose of dexmedetomidine sublingual film effectively reduces symptoms of agitation, assessed using the Positive and Negative Syndrome Scale – Excited Component (PEC) change from Baseline compared with change from Baseline with placebo.
  • Part 2 To assess the safety of dexmedetomidine sublingual film when used in an at- home environment based on treatment-emergent adverse events (TEAEs) and Serious TEAEs collected by both the Informant and the clinical Investigator. Secondary Objectives Part 1: 1.
  • TEAEs treatment-emergent adverse events
  • CGI-I Clinical Global Impression – Improvement scale
  • mCGI- S modified Clinical Global Impression - Severity scale
  • ECGs Electrocardiograms
  • TQM Treatment Satisfaction Questionnaire for Medication
  • Part 1 Change in PEC score from Baseline as compared with placebo at 2 hours following drug administration.
  • Part 2 Comparison of Serious Adverse Events (SAEs) and TEAEs as compared with placebo.
  • Secondary Endpoints Part 1 1. The number of PEC responders (patients who achieve a ⁇ 40% decrease from Baseline in PEC total score) at or before 2 hours after drug administration. 2. Change in PEC score from Baseline as compared with placebo over time measured from 30 minutes through 8 hours following drug administration. 3. CGI-I scores at 2 hours after drug administration. 4. The number of CGI-I responders (patients who achieve a CGI-I score of 1 or 2) at 2 hours after drug administration. 5. Change in mCGI-S scores from Baseline as assessed at 2 hours after drug administration. 6. The number of mCGI-S responders (patients who achieve a mCGI-S score of 0 or 1) at 2 hours after drug administration. 7.
  • the number of mCGI-S-INF responders (patients who achieve a mCGI-S-INF score of 0 or 1) at 2 hours following drug administration for the first treated episode. 3. Change in ACES scores (as measured by the Informant) from Baseline at 2 hours after drug administration for the first treated episode. 4. CGI-C-INF scores at 2 hours following drug administration for the first treated episode. 5. The number of CGI-C-INF responders (patients who achieve a CGI-C-INF score of 1 or 2) at 2 hours following drug administration for the first treated episode. 6. Change in mCGI-S-INF scores from predose to 2 hours following drug administration for the last treated episode (measures continued efficacy). 7.
  • Part 2 of the study should not have been treated with prescription IGALMI TM and might have participated in Part 1 of the study or other dexmedetomidine sublingual film trial.
  • Part 1 of the study duration was 8 hours, in-clinic treatment, and post-treatment observation period with patients experiencing an acute episode of agitation.
  • the in-clinic study period randomized patients 1:1 to receive 60 mcg of dexmedetomidine sublingual film or a matching placebo.
  • Eligible patients were identified in outpatient clinics, mental health centers, psychiatric or medical emergency services including medical/psychiatric observation units, or as newly admitted patients to a hospital setting for acute agitation or already hospitalized for underlying conditions. Patients were domiciled in clinical research setting or hospitalized to remain under medical supervision while undergoing Screening procedures to assess eligibility and during study participation. [0446] While randomization was not formally stratified, the randomization scheme was designed so that no more than 70% of the patients in each arm of the study had a primary diagnosis of bipolar disorder (bipolar I or bipolar II) or schizophrenia (including schizoaffective and schizophreniform disorder).
  • bipolar disorder bipolar I or bipolar II
  • schizophrenia including schizoaffective and schizophreniform disorder
  • the rescue medication can be either a benzodiazepine (lorazepam maximum dose of 4 mg or oxazepam maximum dose of 60 mg) or any antipsychotic except clozapine, pimozide, or prochlorperazine with a maximum dose approximately equivalent to 300 mg of chlorpromazine as specified by BioXcel and as chosen by the Investigator.
  • the patient must remain in the clinic for a minimum of 8 hours of observation following administration of study treatment; if rescue medication is administered, the patient should remain in the clinic for a minimum of 8 hours following administration.
  • Part 2 of the study was a 12-week study to evaluate the safety of dexmedetomidine sublingual film when used as needed for episodes of agitation at home. The at-home study period randomized patients 1:1 to receive 60 mcg of dexmedetomidine sublingual film or matching placebo film when an episode of agitation occurred at-home.
  • Eligible patients were individuals who experienced periodic episodes of agitation. In addition, patients had a reliable Informant who participated in the study conduct at times when an episode of agitation was treated with the study treatment and who attended the monthly clinic visits. [0453] While randomization was not formally stratified, the randomization scheme was designed so that no more than 70% of the patients in each arm of the study had a primary diagnosis of bipolar disorder (bipolar I or bipolar II) or schizophrenia (including schizoaffective and schizophreniform disorder). [0454] Patients and Informants were trained at Screening on their responsibilities during the study, including how to rate the severity of agitation using the mCGI-S, and how to use the Ecological Momentary Assessment (EMA) application.
  • EMA Ecological Momentary Assessment
  • patients and Informants were trained on the circumstances in which the Informant could recommend that the patient self-administer a dose of study treatment or rescue medication.
  • patients were trained as to when they can take study treatment or rescue medication on their own recognizance.
  • Patients and Informants were also instructed on how the patient was to take the study treatment sublingually, and that they should retain the study treatment in the sublingual cavity until dissolved.
  • patients and Informant dyads were trained on assessment of risk when agitation episode occurs and appropriate response if the risk was elevated.
  • a study reference card was provided to patients and Informants which provided guidance on administration of study medication or rescue medication, safety precautions and management of risks during an agitation episode and self-injurious behaviors, suicide or violence.
  • the Informant was notified via the EMA application to follow up and if readily available, record the data for the episode.
  • the patient and the Informant were also responsible for entering information into the EMA application installed on their devices. Specific information was entered when an agitation episode occurred. On days on which an agitation episode did not occur, other information was collected through the EMA application (the application prompted the patient and Informant to enter this information).
  • the patient and Informant returned to the clinic for follow-up visits one month and two months (28 and 56 days) after the Baseline visit, as well as for a final study visit at the end of the 3-month (84 days) study period (see Table 5: Part 2 Schedule of Events).
  • the patient was dispensed four packages, each containing one 60 mcg strip of dexmedetomidine sublingual film or matching placebo. If all packages were used before the next scheduled clinic visit, the patient or Informant need to return to the clinic to return the used packages and obtain four additional doses of study treatment.
  • Patients were allowed a maximum of 2 doses of study drug within 8 hours.
  • the Investigator provided the patient with a prescription for a rescue medication of the Investigator’s choosing.
  • patients may choose to repeat the study drug administration (re-dose) after at least 30 minutes had passed since the first dose. If re-dose was taken, patients may take rescue medications after an additional 30 minutes had passed.
  • the patients were guided to administer the study drug first for an agitation episode. However, patients may choose to use the rescue medication to treat any episode of agitation at any time after the study medication. If rescue medication was taken, then study drug may not be used to treat that episode of agitation.
  • the rescue medication can be either a benzodiazepine (lorazepam maximum dose of 4 mg or oxazepam maximum dose of 60 mg) or any antipsychotic except clozapine, pimozide, or prochlorperazine, with a maximum dose approximately equivalent to 300 mg of chlorpromazine as specified by BioXcel and as chosen by the Investigator.
  • SUBJECT POPULATION Selection of Study Population [0461] All patients enrolled in Part 1will be individuals who never previously received a dose of dexmedetomidine sublingual film or prescription IGALMI TM .
  • Part 1 Patients in Part 2 of the study 87 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 should not have been treated with prescription IGALMI TM and might have participated in Part 1 of the study or other dexmedetomidine sublingual film trial.
  • Part 1 In Part 1 of the study approximately 200 patients were initially planned to be enrolled at up to 20 study sites in the US. When 40% of the 200 patients (80 patients) completed Part 1 of the study, a blinded analysis of the combined standard deviation of the change in both treatment groups was obtained to compute a final sample size, which might be increased up to a maximum of 266 patients.
  • Part 2 In Part 2 approximately 250 patients were enrolled at up to 30 study sites in the United States. Part 1 and Part 2 were expected to enroll concurrently. Inclusion Criteria [0464] A patient was eligible for inclusion in the study if they met all of the following criteria: Inclusion Criteria (Parts 1 and 2) 1. Male and female patients 18 to 75 years old, inclusive. 2. Patients who could read, understand, and provide written informed consent. 3. Patients who met the Diagnostic and Statistical Manual of Mental Disorders, v5, Text Revision (DSM-5/5-TR) criteria for a primary diagnosis of bipolar I or bipolar II disorder, schizophrenia, schizoaffective or schizophreniform disorder. 4.
  • DSM-5/5-TR Text Revision
  • Medically acceptable methods of contraception that may be used by the patient and their partner include abstinence, birth control pills or patches, diaphragm with spermicide, intrauterine device (IUD), condom with foam or spermicide, vaginal spermicidal suppository, surgical sterilization and 88 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 progestin implant or injection. Prohibited methods included: the rhythm method, withdrawal, condoms alone, or diaphragm alone. Additional Inclusion Criteria for patients to be enrolled into Part 1: 6.
  • PRN as needed
  • Exclusion Criteria A subject was excluded from the study if he or she meets any of the following criteria: Exclusion Criteria (Parts 1 and 2) 1. Patients with serious or unstable medical illnesses.
  • hepatic moderate-severe hepatic impairment
  • renal gastroenterological, respiratory, cardiovascular (including ischemic heart disease, congestive heart failure), endocrinologic, or hematologic disease.
  • cardiovascular including ischemic heart disease, congestive heart failure
  • endocrinologic or hematologic disease.
  • Psychiatric comorbidities were generally allowed; however, substance use disorders (within the past two years) were exclusionary if the substance involved was other than 89 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 nicotine or caffeine.
  • marijuana/cannabis use was not an exclusion based on positive UDS or subject admission of use, provided its use meets the following criteria: a) marijuana is prescribed for medical use (medical marijuana); b) marijuana is not the sole focus of treatment; c) severity of a cannabis-related SUD is not greater than mild (as defined by the DSM-5 Substance Use Disorder criteria); 4) illicit or recreational use is not escalating to recover from the effects of cannabis or withdrawal symptoms related to its use (even agitation). 3. The Investigator believed the patient had a history of agitation episodes due to substance use. 4.
  • alpha-1 noradrenergic blockers terazosin, doxazosin, tamsulosin, alfuzosin, or prazosin
  • alpha-2 adrenergic agonists or other prohibited medications.
  • At least 18 years of age at the time of screening 2. Was a spouse, significant other, family member, friend, or home health aide, residence manager of an adult patient who is determined to be eligible for the study per the patient inclusion/exclusion criteria. 3. Had known the patient for at least 12 months. 4. Currently living with or routinely contacting the patient at least five days a week. 5. Did not plan to discontinue seeing or caring for the patient during the study period. 91 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 6. Willing and able to provide written informed consent. 7. Willing and able to follow the study procedures, including completing the EMA application ratings and other EMA application required procedures during the study 8.
  • Dosing delivers 60 micrograms of dexmedetomidine.
  • the product was a small, solid-dose film formulation, approximately 286 mm2 in area and 0.7 mm thick, designed to completely dissolve in the sublingual space within 1-3 minutes. Patients received a single film strip for sublingual placement in the oral cavity.
  • (a) Study Treatment Administration [0473] Patients were instructed on how to take the study treatment sublingually, and that they should retain the study treatment in the sublingual cavity until dissolved; although the study treatment can be taken sublingually or buccally, all patients in this study will only take the study treatment sublingually.
  • the Informant rated the severity of agitation as 2 (moderate) or 3 (severe), they can recommend to the patient to take study treatment.
  • the patient might refuse to take the study treatment when the Informant recommends it. If refusal occurs, this information was entered into the EMA application by the Informant, along with the reason for refusal. If the patient took the study treatment at a later time, this information was entered into the EMA Application by the Informant. The patient could decide that study treatment is needed and take it irrespective of their rated mCGI-S score or the Informant’s recommendation.
  • Efficacy assessments were completed in Part 2 using the mCGI-S rated by the Informant at each observed agitation episode (primary), rated by the patient at each observed agitation episode (secondary), and rated by the Investigator at each during study clinic visit for the 1-month period overall based on interviews of the patient and the Informant.
  • PEC Positive and Negative Syndrome Scale Excited Component
  • ii Agitation-Calmness Evaluation Scale (ACES)
  • the responses are: 1 – extremely alert, 2 – very alert, 3 – alert, 4 – rather alert, 5 – neither alert nor sleepy, 6 – some signs of sleepiness, 7 – sleepy, but no effort to keep awake, 8 –sleepy, but some effort to keep awake, 9 – very sleepy, great effort to keep awake, fighting sleep and 10 – extremely sleepy, can’t keep awake.
  • the patients rated their sleepiness in the EMA App. iv.
  • Clinical Global Impressions – Improvement Scale CGI-I
  • Clinical Global Impressions – Change Scale CGI-C
  • the CGI-C is scale completed by the Informant (CGI-C-INF) and patient (CGI-C-PAT) to measure the overall change in the patient’s agitation after administration of the study drug.
  • the CGI-C focused on the severity of agitation rather than the severity of the overall illness of bipolar disorder or schizophrenia and related disorders. v.
  • the number of PEC responders (patients who achieve a ⁇ 40% decrease from Baseline in PEC total score) at or before 2 hours after drug administration.
  • the number of CGI-I responders (patients who achieve a CGI-I score of 1 or 2) at 2 hours after drug administration.
  • the secondary efficacy endpoints for Part 2 were: 1. Change in mCGI-S for Informants (mCGI-S-INF) scores from predose to 2 hours following drug administration for the first treated episode. 2. The number of mCGI-S-INF responders (patients who achieve a mCGI-S-INF score of 0 or 1) at 2 hours following drug administration for the first treated episode. 3. Change in ACES scores (as measured by the Informant) from Baseline at 2 hours after drug administration for the first treated episode. 4. CGI-C-INF scores at 2 hours following drug administration for the first treated episode.
  • CGI-C-INF responders patients who achieve a CGI-C-INF score of 1 or 2) at 2 hours following drug administration for the first treated episode. 6. Change in mCGI-S-INF scores from predose to 2 hours following drug administration for the last treated episode (measures continued efficacy). 7. The number of mCGI-S-INF responders at 2 hours following drug administration for the last treated episode (measures continued efficacy). 8. CGI-C-INF scores at 2 hours following drug administration for the last treated episode (measures continued efficacy). 9.
  • the number of CGI-C-INF responders at 2 hours following drug administration for the last treated episode (measures continued efficacy). 10. Percentage of all treated episodes of agitation satisfying the definition of mCGI-S-INF responder (patients who achieve a mCGI-S-INF score of 0 or 1) at 2 hours (measures continued efficacy) 11. Percentage of all treated episodes of agitation satisfying the definition of CGI-C-INF responder (patients who achieve a CGI-C score of 1 or 2 as determined by the Informant) at 2 hours (measures continued efficacy) 12.
  • Part 1 Number and frequency of agitation episodes (measures continued efficacy) Part 1: [0493] Secondary efficacy endpoints for Part 1, including change in agitation in response to treatment as measured by the PEC, CGI-I and the mCGI-S scales and change from baseline in the ACES scores were analyzed using an MMRM model.
  • the MMRM model for the PEC, mCGI-S and ACES scores included the change from baseline through 2 hours post-dose as the outcome and the baseline value of the outcome and treatment group as covariates.
  • the model for the CGI-I scores included scores 30 minutes through 2 hours post-dose as the outcome and the baseline mCGI-S score and treatment group as covariates.
  • the number of PEC responders (patients who achieved a ⁇ 40% decrease from baseline in PEC total score at or before 2 hours after drug administration), the number of CGI-I responders (patients who achieved a mCGI-S score of 0 or 1 at 2 hours after drug administration) and the number of mCGI-S responders (patients who achieved a mCGI-S score of 0 or 1 at 2 hours after drug administration) were analyzed using a Chi-Square test. [0494] All values collected after the use of rescue treatment and withdrawal from study were set to missing.
  • Part 2 97 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377
  • the secondary efficacy endpoints for Part 2 change in agitation in response to treatment as measured by the CGI-C-INF and the mCGI-S-INF scales and change from predose in the ACES scores were analyzed using MMRM models as described above for the analysis of the secondary efficacy endpoints for Part 1.
  • CGI-C-INF responders patients who achieve a CGI-C-INF score of 1 or 2) at 2 hours after drug administration and the number of mCGI-S-INF responders (patients who achieve a mCGI-S-INF score of 0 or 1) at 2 hours after drug administration were analyzed with a Chi-Square test.
  • the frequency of treated agitation episodes was assessed with a Poisson model that includes treatment group as a covariate. This was a single outcome defined as the number of treated episodes of agitation for each subject.
  • a positive tetrahydrocannabinol (THC) in UDS was not exclusionary. If patients were being prescribed benzodiazepines, stimulants or opiates, then a positive UDS was not exclusionary. 4 Resting vital signs and collection: pulse oximetry, temperature, heart rate, and blood pressure after resting 5 minutes in the supine position 5 Orthostatic vital signs collection (systolic and diastolic blood pressure and heart rate) were collected immediately following the collection of resting vital signs; collected at 1 and 3 minutes after standing 6 The PCRS must be performed just before the PEC rating 7 A PK sample may not be collected if the Investigator indicates in source documents that the patient is in a mental state that was not conducive to PK sample collection.
  • Non-compliance or refusal of all or any PK draw was not exclusionary and did not result in early termination, nor will this be considered a protocol deviation. 8
  • the PEC was to be administered within 15 minutes before the administration of study treatment at the pre-dose time point.
  • the ACES was administered within 30 minutes before the administration of the study treatment at the pre-dose time point.
  • the mCGI-S was to be administered immediately prior to dosing at the pre-dose time point 11
  • the window for all assessments at the 30 minute and 1-hour timepoints is +/- 5 minutes 12
  • the window for all assessments at the 2-hour time point was +/- 15 minutes 13
  • the ECG conducted at the 2, 4 and 8-hour times were collected before obtaining the PK samples 14
  • the resting vital signs and orthostatic vital signs collected at the 2, 4, 6, and 8-hour times were to be collected before obtaining the PK sample 15
  • the window for all assessments at the 4 hr, 6 hr, and 8 hr times was +/- 30 minutes 16 If the patient was determined to be not ready for discharge at the 8-hour timepoint, the Likability Questions and TSQM should not be completed.
  • the UDS (on-site dipstick) must be completed with a negative result before randomization and dispensing the study drug.
  • the on-site dipstick UDS result at Visit 1 and Visit 2 must be negative in order for the patient to continue participation in the study.
  • a positive tetrahydrocannabinol (THC) in UDS is not exclusionary. If patients are being prescribed benzodiazepines, stimulants or opiates, then a positive UDS is not exclusionary. 6
  • Investigator will collect and record AEs during the monthly clinic visits and based on review of the side effects recorded in the EMA application.
  • the responder rates at two hours post-administration were 50% and 33% for the treatment cohort and the placebo cohort, respectively.
  • the responder rates were 51% and 39% for the treatment cohort and the placebo cohort, respectively (Refer Table 10 and Fig 2).
  • a secondary endpoint was the score reduction as evaluated by the Clinical Global Impression-improvement scale (CGI-I).
  • the 60-mcg dose exhibited an enhanced safety profile across all monitored adverse event (AE) categories in the current clinical study (Refer Tables 21). For instance, 13% of patients experienced somnolence (defined as feelings of drowsiness, sleepiness, fatigue, or sluggishness), compared to 7% in the placebo group. In comparison, the frequencies for somnolence at dosages of 120 mcg and 180 mcg were 23% and 22%, respectively. Only a single incident (1%) of orthostatic hypotension occurred in the 60-mcg treatment group (none in the placebo group), while incidences were reported at rates of 3% and 5% in the earlier groups with 120 mcg and 180 mcg dosages, respectively (Refer Table 21).
  • AE adverse event
  • Table 9 Demographics and Baseline Characteristics- Safety Population 107 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 108 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 109 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 SD: Standard deviation; BMI: Body mass index Percentages are based on the number of patients in the Safety Population with non-missing data by treatment group and overall.
  • Percentages are based on number of female patients in the Safety Population with non-missing data by treatment group and overall. Patients that selected more than one race are included in the ‘Multiple’ category. BMI (kg/m2) was calculated as 10000*weight(kg)/height(cm) ⁇ 2, rounded to 1 decimal place. 110 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 Table 10. Change from Baseline in the PEC Total Score and percentage of responders in the PEC total score over time-ITT Population 111 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 Table 11.
  • Responders up to 2 hours are patients that satisfy the PEC response criteria at least once up to, and including, the 2 hours timepoint.
  • 6 N 56 at the 6 and 8 Hour Post-Dose timepoints for Placebo 112 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 Table 12. Change from Baseline in PEC total score and percentage of responders in the PEC Total score over time – ITT population of Bipolar population. 1 Estimates were obtained from a MMRM including treatment group, study site, timepoint, timepoint by treatment group interaction, baseline PEC score and baseline PEC score by timepoint interaction. PEC scores collected after the start of rescue medication were not included in the analysis.
  • CGI-I scores collected after the start of rescue medication were not included in the analysis. 2 Patients who achieved a CGI-I score of 1 or 2 (“very much improved” or “much improved”, respectively) after dosing were considered as responders. P-values for the difference between treatments based on Fisher’s exact test. 3 Baseline (Pre-Dose) Mean (SD) mCGI-S. 116 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 Table 16. Exploratory Efficacy Endpoint – Time to Rescue Medication- ITT Population Percentages are based on the number of patients in the ITT Population by treatment group.
  • Treatment-Emergent Adverse Events by System Organ Class and Preferred Term Safety Population 118 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 119 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 E: number of events. Percentages are based on the number of patients in the Safety Population by treatment group and overall. Subjects are counted once within each system organ class and preferred term. Adverse events were coded using MedDRA version 25.1.
  • Part 2 To assess the safety of 80 mcg dexmedetomidine sublingual film when used in an at-home environment based on serious adverse events (SAE) and treatment-emergent adverse events (TEAEs). [0527] Secondary objectives: [0528] Part 1: 1. To determine the overall clinical improvement after study treatment administration as measured by the Clinical Global Impression – Improvement scale (CGI-I). 2. To determine the overall clinical improvement after drug administration as measured by the modified Clinical Global Impression - Severity scale (mCGI-S). 3. To describe the duration of calming as measured by the Agitation-Calmness Evaluation Scale (ACES). 4.
  • CGI-I Clinical Global Impression – Improvement scale
  • mCGI-S modified Clinical Global Impression - Severity scale
  • AVS Agitation-Calmness Evaluation Scale
  • TQM Treatment Satisfaction Questionnaire for Medication
  • CGI-C Clinical Global Impression—Corrections
  • Part 2 The incidence of SAEs and TEAEs compared with placebo.
  • Secondary endpoints 125 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377
  • Part 1 1. The number of PEC responders (patients who achieve a ⁇ 40% decrease from Baseline in PEC total score) at or before 2 hours after drug administration. 2. Change in PEC score from Baseline as compared with placebo over time measured from 30 minutes through 8 hours following drug administration. 3. Change in CGI-I scores from Baseline at 2 hours after drug administration. 4. The number of CGI-I responders (patients who achieve a CGI-I score of 1 or 2) at 2 hours after drug administration 5.
  • Proportion of patients who report somnolence (ACES score ⁇ 8 reported by Informant) pre-dose to post-dose. 4. Proportion of patients who report somnolence (Karolinska Sleepiness Scale [KSS] score ⁇ 7 reported by patient) pre-dose to post-dose. 5. Proportion of patients who report improvement in agitation (Yes/No) post-dose for the first treated episode compared with placebo. 6. Proportion of mCGI-S responders (patients who achieve a mCGI-S score of 0 or 1) following drug administration for the first treated episode. 126 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 7.
  • Proportion of CGI-C responders patients who achieve a CGI-C score of 1 or 2) following drug administration for the first treated episode.
  • Time to end of an agitation episode from dosing for the first treated episode. Proportion of patients who report improvement in agitation (Yes/No) post-dose for all treated episodes compared with placebo.
  • Proportion of mCGI-S responders following drug administration for the last treated episode and all treated episodes. 14.
  • GAS Goal Attainment Scale
  • Study Design This is a randomized, double-blind, placebo-controlled, 2-part, Phase 3 study to assess the efficacy, safety, and tolerability of a 60 mcg or 80 mcg dose of dexmedetomidine sublingual film in adult (18-75 years old) males and females with agitation episodes associated with a primary diagnosis of bipolar I disorder, bipolar II disorder, schizophrenia, schizoaffective disorder, or schizophreniform disorder.
  • Part 1 of the study is an 8-hour, in- clinic treatment, and post-treatment observation period with patients experiencing an acute episode of agitation.
  • Part 2 of the study is a 12-week study to evaluate the safety and efficacy of 80 mcg dexmedetomidine sublingual film when used in an at-home setting when treating episodes of agitation in patients.
  • All patients enrolled in Part 1 will be individuals who have never previously received a dose of dexmedetomidine sublingual film or prescription IGALMITM.
  • Patients in Part 2 of the study should not have been treated with prescription IGALMITM and may have participated in Part 1 of the study or other double-blind dexmedetomidine sublingual film trial.
  • Part 1 In-Clinic Period Setting Conduct: 128 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377
  • the in-clinic study period randomizes patients 1:1 to receive 60 mcg of dexmedetomidine sublingual film or a matching placebo.
  • Eligible patients may be identified in outpatient clinics, mental health centers, psychiatric or medical emergency services, including medical/psychiatric observation units, or as newly admitted patients in a hospital setting for acute agitation or already hospitalized for their underlying, primary psychiatric disorder.
  • the rescue medication can be either a benzodiazepine (lorazepam maximum dose of 4 milligram [mg] or oxazepam maximum dose of 60 mg) or any antipsychotic except clozapine, pimozide, or prochlorperazine, with a maximum dose approximately equivalent to 300 mg of chlorpromazine as specified by BioXcel and as chosen by the Investigator. [0548] The patient must remain in the clinic for a minimum of 8 hours of observation following administration of study treatment. [0549] Efficacy, safety, tolerability, and pharmacokinetics (PK) are assessed throughout the treatment period at various times.
  • PK pharmacokinetics
  • Part 2 Community (At-home) Setting Conduct: 129 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377
  • Part 2 is a randomized, double-blind, placebo-controlled, Phase 3, 12-week study in the at-home community setting to assess the safety and efficacy of an 80 mcg dose of dexmedetomidine sublingual film.
  • Eligible patients will be individuals receiving stable treatment for their underlying primary diagnosis for at least 3 months and who experience periodic episodes of agitation.
  • Eligible patients may be enrolled individually or with a reliable Informant who can participate in the study conduct when an episode of agitation is treated with the study medication and who can attend the monthly clinic visits. Patients who will be enrolled individually should have a point-of-contact who can help with outreach and follow-up with the patient if the site staff is unable to reach the patient for more than 1 week. Upon confirmation of eligibility, the patient or patient/Informant dyads will be randomized 1:1 to administer 80 mcg dexmedetomidine sublingual film or matching placebo film when an episode of agitation occurs at home.
  • patient or patient/Informant dyads will be trained on their responsibilities during the study, including how to recognize agitation signs and symptoms using the agitation behaviors scale and goal attainment scale, managing agitation episode with non-pharmacological methods (if appropriate), when to administer study treatment or rescue medication, how to take study medications and how to complete the Agitation Episode Diary and when to contact site staff.
  • a study reference guide will be provided to patient or patient/Informant dyads with these instructions.
  • the patient or patient/Informant dyad should complete an Agitation Episode Diary for each episode and contact the site staff as soon as possible (within a maximum of 48 hours after the episode has occurred).
  • episodes of agitation in the at-home environment are likely associated with an even greater risk of harm to the patient than those treated in a clinical environment. Additionally, 50% of patients will receive placebo as their study treatment. The patient or patient/Informant dyads will be trained on safety precautions, the assessment of risk when an agitation episode occurs and when to seek emergency services. [0554] After randomization at the Baseline visit, the patient or patient/Informant dyads will be dispensed 3 packages, each containing one 80 mcg strip of dexmedetomidine sublingual film or matching placebo.
  • the patient or patient/ Informant dyads will also be instructed on how the patient is to take the study treatment sublingually and retain the study treatment in the sublingual cavity until dissolved.
  • the Investigator will provide the patient or patient/Informant dyad with a prescription for a rescue medication of the Investigator’s choosing.
  • the patients will be guided to administer the study drug first for an agitation episode. Ideally, the patient should not take the rescue medication until 2 hours after study treatment. If rescue medication is taken to treat that episode of agitation, then study drug may not be used to treat that episode of agitation subsequently. If symptoms persist or escalate, then patients or patient/Informants should be advised to contact site staff and/or seek medical care.
  • the training for patients or patient/Informant dyads will include how to identify signs and symptoms of agitation in the patient using the agitation behaviors scale and goal attainment scale. Patients will be trained on when they can take study treatment or rescue medication on their own recognizance and on the circumstances when the Informant can recommend that the patient self-administer a dose of study treatment or rescue medication. The patients should be advised to administer the study drug at home and whenever possible throughout the study. For patient/Informant dyads, the Informant should be present when the patient is starting dosing with the study medication and whenever possible throughout the study. This is important to collect the study data.
  • the patient Once the patient becomes familiar with dosing and the subsequent effects of the study medication, they can dose without the Informant being present, but it is always preferable that the Informant is present with the patient. If the patient records an agitation episode independently, the Informant (as soon as feasible) and site should be informed (within 48 hours) to follow-up. [0558] If the patient is unable to self-administer study medication during their first episode of agitation where treatment is attempted, the event will be recorded as a missed agitation episode along with the reason, and the Investigator should determine if the patient is able to continue participation in the study.
  • C-SSRS Columbia-Suicide Severity Rating Scale
  • Part 1 and Part 2 The same sites may participate in Part 1 and Part 2.
  • Patients in Part 1 of the study should not have previously been treated with dexmedetomidine sublingual film or prescription IGALMI TM .
  • Patients in Part 2 of the study should not have been treated with prescription IGALMI TM and may have participated in Part 1 of the study or other double-blind dexmedetomidine sublingual film trial.
  • Diagnosis and Main Criteria for Eligibility [0564] Patient Inclusion Criteria (Parts 1 and 2) 1. Male and female patients 18 to 75 years old, inclusive. 2. Patients who can read, understand, and provide written informed consent.
  • Medically acceptable methods of contraception used by the participant and/or their partner include abstinence, birth control pills or patches, diaphragm with spermicide, intrauterine device (IUD), condom with foam, or spermicide, vaginal spermicidal suppository, surgical sterilization, and progestin implant or injection.
  • Prohibited methods include the rhythm method, withdrawal, condoms alone, or diaphragm alone.
  • hepatic moderate-severe hepatic impairment
  • renal gastroenterological
  • respiratory including ischemic heart disease, congestive heart failure
  • endocrinologic or hematologic disease.
  • Psychiatric comorbidities are generally allowed; however, substance use disorders (SUD) (within the past two years) are exclusionary if the substance involved is other than nicotine or caffeine.
  • marijuana/cannabis use is not an exclusion based on positive urine drug screen (UDS) or patient admission of use, provided its use meets the following criteria: a) marijuana is prescribed for medical use (medical marijuana); b) marijuana is not the sole focus of treatment; c) severity of a cannabis-related SUD is not greater than mild (as defined by the DSM-5 Substance Use Disorder criteria); 4) illicit or recreational use is not escalating to recover from the effects of cannabis or withdrawal symptoms related to its use (even agitation). 3. The Investigator believes the patient has a history of agitation episodes due to substance use. 4.
  • UDS positive urine drug screen
  • alpha-1 noradrenergic blockers terazosin, doxazosin, tamsulosin, alfuzosin, or prazosin
  • alpha-2 adrenergic agonists or other prohibited medications.
  • terazosin, doxazosin, tamsulosin, alfuzosin, or prazosin alpha-2 adrenergic agonists
  • other prohibited medications 134 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377.
  • Dexmedetomidine Patients considered by the Investigator to be unsuitable candidates for receiving dexmedetomidine (e.g., patients with a history of allergic reactions to dexmedetomidine) or considered to be unsuitable for participating in the study for any reason.
  • Additional Exclusion Criteria for patients to be enrolled in Part 1 16. Patients with agitation caused by acute intoxication, including identification of alcohol by breathalyzer or drugs of abuse (except for THC) during urine screening. 17. Use of benzodiazepines or other hypnotics or antipsychotic drugs in the 4 hours before study treatment. 18. Patients who have previously received dexmedetomidine sublingual film in a clinical trial.
  • Dosing delivers 60 mcg of dexmedetomidine in Part 1 and 80 mcg of dexmedetomidine in Part 2.
  • the product is a small, solid-dose film formulation, approximately 286 millimeters squared (mm 2 ) in area and 0.7 millimeters (mm) thick, designed to completely dissolve in the sublingual space within 1-3 minutes. Patients will receive a single film strip for sublingual placement in the oral cavity.
  • Reference Therapy, Dosage and Mode of Administration Matching placebo films to be taken sublingually as described above.
  • Duration of Treatment Part 1: 8 hours.
  • the Investigator should determine if the patient is able to continue participation in the study. [0580] Patients should be restricted from food or water intake for 15 minutes after taking the study treatment. [0581] In Part 1, patients will be evaluated for local irritation around the area where the study treatment has been placed. [0582] Patients and Informants will be advised that patients should avoid activities that require them to be alert, such as driving a car or operating machinery for at least 8 hours after receiving study drug. [0583] STUDY ASSESSMENTS: [0584] Efficacy [0585] The efficacy of study treatment will be evaluated during Part 1 using the validated instruments listed below.
  • CGI-C Clinical Global Impressions – Improvement Scale
  • CGI-C-PAT Clinical Global Impressions – Change Scale
  • the CGI-C will be focused on the severity of agitation rather than the severity of the overall illness of bipolar disorder or schizophrenia and related disorders.
  • mCGI-S Modified Clinical Global Impression – Severity Scale
  • the Handbook of Psychiatric Measures 2 nd Edition (Rush et al., 2008) describes an 8-point CGI-S where a rating of 0 is used when the CGI-S was not assessed, and scores of 1-7 rate increasing severities of the psychiatric disorder or symptom being assessed.
  • the CGI-S has been modified to a 4-point scale (mCGI-S) where 0 is no agitation, and scores of 1-3 describe increasing severities of agitation (mild, moderate, severe).
  • the mCGI-S is dichotomized into scores of ⁇ 1 or ⁇ 2.
  • the agitation behaviors scale consists of 14 observable agitation behaviors that were identified through literature review and qualitative interviews with caregivers of patients who experience agitation related to bipolar disorder.
  • Goal Attainment Scaling is a patient-focused method to score patient’s individual goals (a personalized endpoint) due to an intervention (Kiresuk and Sherman 1968).
  • the patient or patient/Informant dyads and the Investigator identify prespecified number of personal goals (up to 3 goals) related to managing their individual agitation episode.
  • the goal attainment levels are defined for each goal on a 5-point scale and scored at each clinic visit.
  • Pharmacokinetics [0587] Blood samples (4 milliliters [mL] each) for PK analysis will be collected in Part 1 at 2, 4, 6, and 8 hours post-dose per the Schedule of Events (Table 22).
  • a positive tetrahydrocannabinol (THC) in UDS is not exclusionary. If patients are being prescribed benzodiazepines, stimulants, or opiates, then a positive UDS is not exclusionary. 4 Resting vital signs and collection: pulse oximetry, temperature, heart rate, and blood pressure after resting 5 minutes in the supine position. 5 Orthostatic vital signs collection (systolic and diastolic blood pressure and heart rate) are collected immediately following the collection of resting vital signs; collected at 1 and 3 minutes after standing. 6 The PCRS must be performed just before the PEC rating. 7 A PK sample may not be collected if the Investigator indicates in source documents that the patient is in a mental state that is not conducive to PK sample collection.
  • Noncompliance or refusal of all or any PK draw is not exclusionary and does not result in early termination, nor will this be considered a protocol deviation.
  • the PEC is to be administered within 15 minutes before the administration of study treatment at the pre-dose time point.
  • the ACES is administered within 30 minutes before the administration of the study treatment at the pre-dose time point.
  • the mCGI-S is to be administered immediately prior to dosing at the pre-dose time point.
  • the window for all assessments at the 30-minute and 1-hour time points is ⁇ 5 minutes.
  • the window for all assessments at the 2-hour time point is ⁇ 15 minutes. 13
  • the ECG conducted at the 2, 4, and 8-hour times are collected before obtaining the PK samples.
  • ACES Agitation-Calmness Evaluation Scale
  • BMI body mass index
  • CGI Clinical Global Impression
  • C-SSRS Columbia-Suicide Severity Rating Scale
  • ECG electrocardiogram
  • hr hour
  • mCGI-S Modified Clinical Global Impression-Severity Scale
  • MINI Mini-International Neuropsychiatric Interview
  • PCRS Placebo-Control Reminder Script
  • PEC Positive and Negative Syndrome Scale Excited Component
  • PK pharmacokinetic(s)
  • TSQM Treatment Satisfaction Questionnaire for Medication
  • UDS urine drug screen.

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Abstract

The present disclosure relates to methods of treating agitation in a patient having schizophrenia or a bipolar disorder in a non-clinical setting, comprising administering oromucosally an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof to the patient. In embodiments, a caregiver administers dexmedetomidine or a pharmaceutically acceptable salt thereof to the patient or the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient.

Description

ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 METHODS FOR TREATING AGITATION IN COMMUNITY SETTINGS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to and benefit of U.S. Provisional Application No. 63/405,452, filed September 11, 2022, and U.S. Provisional Application No. 63/504,109, filed May 24, 2023, the contents of which are hereby incorporated in their entirety as set forth herein. FIELD [0002] The present disclosure relates to method of treating agitation in schizophrenia or bipolar disorder patients in a non-clinical setting, comprising administering oromucosally an effective amount of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant or self-administration by the patient. The agitation may be mild to moderate. BACKGROUND [0003] Agitation, represented by a state of motor restlessness and accompanying mental tension, is a serious medical problem that can be present in some psychiatric disorders and may escalate quickly to aggressive behaviour. Patients with neuropsychiatric disorders like schizophrenia and bipolar disorder are particularly vulnerable to acute episodes of agitation, especially during exacerbation of the disease. This becomes a frequent reason for emergency department visits and institutionalization of patients, and unless recognized early and managed effectively, can rapidly escalate to a potentially dangerous situation, including physical violence. Long-term hospitalization is not a desirable option because it confines patients to a hospital. Frequent outpatient clinic visits also present numerous logistical obstacles, which makes it impractical. The key to safety is to intervene early to prevent progression of agitation to aggression and violence. Therefore, there exists a need to enable caregivers or informant (e.g., family members) to evaluate and review the condition of such agitated patients in a non- clinical setting (e.g., at home) itself to provide anti-agitation treatment timely in order to calm the patient and prevent an agitation episode from recurrence. [0004] The present methods as described herein improve the health care service in non-clinical settings such as at home, group home, assisted living facility, correctional facility, hospice or long-term care facility, by allowing for a greater proportion of patients to be treated at a much lower cost than if they were still receiving inpatient services. 1 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 [0005] The technical effect of the methods of the present disclosure is to enable caregivers or informants and individuals to collect objective data with minimal patient inconvenience; to correlate patterns and changes in the data to an individual's state of mental health; and to regulate and, if necessary, change the individual's medication or other therapy regime based on patterns in the data and changes in the individual's types, responses, and level of activities. The overall result lessens the burden on the healthcare system and provides a more positive outcome for the patient. SUMMARY [0006] The present disclosure provides methods of treating agitation in schizophrenia or bipolar disorder patients in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 60 micrograms to the patient wherein the patient is 18 years or older. [0007] The present disclosure provides methods of treating agitation in schizophrenia or bipolar disorder patients in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 80 micrograms to the patient wherein the patient is 18 years or older. [0008] In embodiments, the present disclosure provides methods of treating acute agitation in schizophrenia or bipolar disorder patients in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a total daily dose of about 60 micrograms to about 360 micrograms to the patient, wherein the patient is 18 years or older. [0009] In embodiments, the present disclosure provides methods of treating acute agitation in a schizophrenia or bipolar disorder patient in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a total daily dose of about 60 micrograms to about 180 micrograms to the patient, wherein the patient is 18 years or older. [0010] In embodiments, the schizophrenia includes schizoaffective or schizophreniform disorder. In embodiments, the bipolar disorder includes bipolar disorder I or bipolar disorder II. [0011] In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered by the caregiver or informant of the patient. In embodiments, the caregiver or informant is a family member or a family friend. In embodiments, the caregiver or informant is a person employed by or for the patient. In embodiments, the caregiver or informant maintains close physical proximity to the patient for at least 8 hours after the administration of 2 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 dexmedetomidine or a pharmaceutically acceptable salt thereof. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient. [0012] In embodiments, the non-clinical setting is at home. In embodiments, the non-clinical setting is at group home, assisted living facility, correctional facility, hospice or long-term care facility. [0013] In embodiments, the patient experiences not more than 2 episodes of agitation per week. [0014] In embodiments, the patient experiences at least one episode of agitation in the past month. For example, the patient may have at least 1 episode per month, at least 2 episodes per month, or at least 3 episodes of agitation per month. In embodiments, the non-clinical setting may have an upper limit on episodes in a given time period; for example, the patient may have up to 1, up to 2, up to 3, up to 4, up to 5, or up to 6 episodes of agitation per month. [0015] In embodiments, the agitation is mild or moderate. In embodiments, the agitation is acute. In embodiments, the agitation is not severe. [0016] In embodiments, the route of administration is oromucosal (e.g., sublingual, buccal or gingival). In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in an oromucosal dosage form selected from the group consisting of a film, wafer, patch, lozenge, gel, spray, tablet and liquid drops. In embodiments, the dosage form is a thin film. In embodiments, the dosage form is a sublingual film. In embodiments, the dosage form is a buccal film. In embodiments, the dosage form is a gingival film. [0017] In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as a single dose per day. In embodiments, the total daily dose may be administered oromucosally multiple times (e.g., one to four times) as a single unit dose, as multiple unit doses, or as a fraction of one or more unit doses (e.g., half of a unit dose), or a combination thereof at an appropriate dosing interval (e.g., at least after 0.5 hours) to produce a desired effect. [0018] In embodiments, the total daily dose of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., hydrochloride salt) is administered as a first and optional second dose. [0019] In embodiments, the first dose is about 60 micrograms, about 70 micrograms, about 80 micrograms, about 90 micrograms, about 100 micrograms, about 110 micrograms, about 120 micrograms or about 180 micrograms of dexmedetomidine hydrochloride. In embodiments, 3 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 the first dose is 60 micrograms of dexmedetomidine hydrochloride. In embodiments, the first dose is 80 micrograms of dexmedetomidine hydrochloride. [0020] In embodiments, the second dose is administered at least about 2 hours after administration of the first dose if there is no improvement in PEC score by more than 2 points. In embodiments, the patient is hemodynamically stable. [0021] In embodiments, the second dose is administered at least about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours, about 8 hours, about 8.5 hours, about 9 hours, about 9.5 hours, about 10 hours, about 10.5 hours, about 11 hours, about 11.5 hours, about 12 hours, about 12.5 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours or about 24 hours after administration of the first dose. [0022] In embodiments, the optional second dose is about 60 micrograms, about 70 micrograms, about 80 micrograms, about 90 micrograms, about 100 micrograms, about 110 micrograms, about 120 micrograms or about 180 micrograms of dexmedetomidine hydrochloride. In embodiments, the optional second dose is about 60 micrograms of dexmedetomidine hydrochloride. In embodiments, the optional second dose is 80 micrograms of dexmedetomidine hydrochloride. [0023] In embodiments, the present disclosure provides methods of treating acute agitation in a schizophrenia patient with in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a total daily dose of about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant. [0024] In embodiments, the present disclosure provides methods of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant. [0025] In embodiments, the present disclosure provides methods of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a dose of about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant. 4 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 [0026] In embodiments, the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a total daily dose of about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant. [0027] In embodiments, the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g. bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a total daily dose of about 60 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant. [0028] In embodiments, the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant. [0029] In embodiments, the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a dose of about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant. [0030] In embodiments, the present disclosure provides methods of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising self-administering, by the patient, an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof. [0031] In embodiments, the present disclosure provides methods of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising an oromucosal dosage form comprising administering about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient. [0032] In embodiments, the present disclosure provides methods of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising self-administering, by the patient, 5 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 an oromucosal dosage form comprising about 60 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof. [0033] In embodiments, the present disclosure provides methods of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising administrating an oromucosal dosage form comprising about 60 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient. [0034] In embodiments, the present disclosure provides methods of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising self-administering, by the patient, an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof. [0035] In embodiments, the present disclosure provides methods of treating acute agitation in a schizophrenia patient in a non-clinical setting, administering an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self- administered by the patient. [0036] In embodiments, the present disclosure provides methods of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising self-administering, by the patient, an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof. [0037] In embodiments, the present disclosure provides methods of treating acute agitation in a schizophrenia patient in a non-clinical setting, administering an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self- administered by the patient. [0038] In embodiments, the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising self-administering, by the patient, an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof. [0039] In embodiments, the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 60 micrograms to 6 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self- administered by the patient. [0040] In embodiments, the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising self-administering, by the patient, an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof. [0041] In embodiments, the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting comprising administering an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient. [0042] In embodiments, the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising self-administering, by the patient, an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof. [0043] In embodiments, the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient. [0044] In embodiments, the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in two phases. [0045] In embodiments, phase 1 comprises administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof under medical supervision, wherein the duration of phase 1 is at least 8 hours. [0046] In embodiments, phase 2 comprises administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof under non-medical supervision (non-clinical setting), wherein the duration of phase 2 is up to 12 weeks. [0047] In embodiments, the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient, the method comprising: 7 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 (a) administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof under medical supervision for at least 8 hours; and (b) administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof under non-medical supervision (non-clinical setting) for up to 12 weeks. [0048] In embodiments, the present disclosure provides methods of treating acute agitation in a schizophrenia patient in two phases. [0049] In embodiments, phase 1 comprises oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof under medical supervision, wherein the duration of phase 1 is at least 8 hours. [0050] In embodiments, phase 2 comprises administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof under non-medical supervision (non-clinical setting), wherein the duration of phase 2 is up to 12 weeks. [0051] In embodiments, the present disclosure provides methods of treating acute agitation in a schizophrenia patient, the method comprising: (a) administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof under medical supervision for at least 8 hours; and (b) administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof under non-medical supervision (non-clinical setting) for up to 12 weeks. [0052] In embodiments, the oromucosal dosage form is selected from the group consisting of a film, wafer, patch, lozenge, gel, spray, tablet and liquid drops. In embodiments, the dosage form is a sublingual or buccal or gingival film. [0053] In embodiments, the administration of dexmedetomidine or the oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof produces anti- agitation effect within about 30 minutes after administration. In embodiments, the administration of dexmedetomidine or the oromucosal dosage form comprising 8 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 dexmedetomidine or a pharmaceutically acceptable salt thereof produces anti-agitation effect within about 20 minutes after administration. In embodiments, the administration of dexmedetomidine or the oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof produces anti-agitation effect within about 15 minutes after administration. [0054] In embodiments, the agitation is treated without also inducing significant sedation. In embodiments, the treatment is effective with reduced or no side effects (e.g., cardiac or respiratory side effects). [0055] In embodiments, the patient achieves a mean change in PEC score of greater than -7 relative to baseline within 30 minutes of administration. In embodiments, the patient achieves a CGI-I score improvement to about a 1 (very much improved) or about a 2 (much improved). In embodiments, the agitation is reduced to a 2 (moderate agitation), 3 (mild agitation) or 4 (normal behavior) 30 minutes after administration as measured by the Agitation-Calmness Evaluation Scale (ACES). [0056] In embodiments, a caregiver or informant is altered to a patient’s impending episode of agitation via Ecological Momentary Assessment (EMA) device or other remote compatible device. In embodiments, the EMA device is monitored by the caregiver or informant. In embodiments, the EMA device comprises a caregiver’s or informant’s smart phone or a tablet with an application installed to report the patient’s observations. [0057] In embodiments, a caregiver or an information is altered to a reduction in a patient’s agitation via Ecological Momentary Assessment (EMA) device or other remote compatible device. [0058] In embodiments, the alerts are received in the form of a text message, a call, a sound or a window flashing/display on the device of the caregiver or informant. [0059] In embodiments, the patient’s observations are recorded from one or more wearable devices (or wearable sensors) worn/placed/mounted on the body of the patient. [0060] In embodiments, the wearable device (or a wearable sensor) is in contact with the patient and may be selected from iPhone (BYOD or provisioned), accelerometers, gyroscopes, portable devices, digital devices, smart fabrics, bands and actuators like an Apple watch or iWatch, patch such as MC10 Patch, sensors like Microsoft Kinect and the like. In embodiments, the wearable device is a bracelet, anklet, shoe, armband, thigh band or a mitten. In embodiments, the wearable device is smartwatch, ring, patch, conductive tattoo, head wearable. 9 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 In embodiments, the wearable device is wrist worn multi-sensor device with networking capability (e.g., wearable watch such as Apple watch). [0061] In embodiments, the patient, the caregiver, or informant records observations in an agitation episode diary for each episode of agitation. In embodiments, the agitation episode diary comprises questions based on safety information, use of emergency services, use of other concomitant medications and sleepiness. In embodiments, the agitation episode diary comprises questions based on efficacy information after taking study medication (Yes/No), mCGI-S, CGI-C, the agitation behaviors scale (Informant only), use of study medication or use of rescue medication. [0062] In embodiments, the present disclosure provides an individual unit oromucosal film dosage form provided as a kit comprising: (i) about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; and (ii) instructions for the administration of (i) to schizophrenia or bipolar disorder patients in need thereof, wherein the dosage form is administered for treating acute agitation in the patient in a non- clinical setting. [0063] In embodiments, the present disclosure provides an individual unit oromucosal film dosage form provided as a kit comprising: (iii) about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; and (iv) instructions for the administration of (i) to schizophrenia or bipolar disorder patients in need thereof, wherein the dosage form is administered for treating acute agitation in the patient in a non- clinical setting. [0064] In embodiments, the present disclosure provides an individual unit oromucosal film dosage form provided as a kit comprising: (i) about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; and (ii) instructions for the administration of (i) to schizophrenia or bipolar disorder patients in need thereof, wherein the dosage form is administered for treating mild to moderate agitation in the patient in a non-clinical setting. 10 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 BRIEF DESCRIPTION OF THE DRAWINGS [0065] FIG. 1: depicts the mean change from baseline in PEC total score over time in schizophrenic and/or bipolar patients treated with a sublingual film containing dexmedetomidine hydrochloride (60 μg) versus a placebo group. [0066] FIG. 2: depicts the percentage of responders in the PEC total Score over time in schizophrenic and/or bipolar patients treated with a sublingual film containing dexmedetomidine hydrochloride (60 μg) versus a placebo group. [0067] FIG.3: depicts change in CGI- score over time in schizophrenic and/or bipolar patients treated with a sublingual film containing dexmedetomidine hydrochloride (60 μg) versus a placebo group. [0068] FIG.4: depicts percent of responders in CGI-I Score over time in schizophrenic and/or bipolar patients treated with a sublingual film containing dexmedetomidine hydrochloride (60 μg) versus a placebo group. [0069] FIG. 5A: depicts mean change from baseline in PEC total score over time by primary diagnosis in schizophrenia patients (n=129) subgroup treated with a sublingual film containing dexmedetomidine hydrochloride (60 μg) versus a placebo group. [0070] FIG. 5B. depicts mean change from baseline in PEC total score over time by primary diagnosis in bipolar disorder patients (n=72) subgroup treated with a sublingual film containing dexmedetomidine hydrochloride (60 μg) versus a placebo group (n=43). DETAILED DESCRIPTION: Abbreviations: [0071] Abbreviations ACES: Agitation-Calmness Evaluation Scale AEoSIs: adverse events of special interest AE: Adverse event BID: twice a day BMI: Body mass index CGI-I: Clinical Global Impression-Improvement CGI-S: Clinical Global Impression-Severity C-SSRS: Columbia Suicide Severity Rating Scale Dex or DEX: Dexmedetomidine 11 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 DSM: Diagnostic and Statistical Manual of Mental Disorders ECG: Electrocardiogram EDA: Electrodermal Activity EMA: Ecological Momentary Assessment HAM-D (or HDRS): Hamilton Depression Rating Scale MINI: Mini-International Neuropsychiatric Interview for DSM-5 MW: Molecular weight mm: Millimeter mcg: Microgram μg: Microgram PANSS: Positive and Negative Syndrome Scale PCRS: Placebo-Control Reminder Script PEC: PANSS Excitement Component PK: Pharmacokinetics SAE: Serious adverse event SAP: Statistical Analysis Plan SBP: Systolic Blood Pressure SL: Sublingual TEAE: Treatment emergent adverse event TSQM: Treatment Satisfaction Questionnaire for Medication Wt%: Weight percentage YMRS: Young Mania Rating Scale Definitions: [0072] Throughout the present specification, numerical ranges are provided for certain quantities. It is to be understood that these ranges comprise all subranges therein. Thus, the range “from 50 to 80” includes all possible ranges therein (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Furthermore, all values within a given range may be an endpoint for the range encompassed thereby (e.g., the range 50-80 includes the ranges with endpoints such as 55-80, 50-75, etc.). [0073] The term “a” or “an” refers to one or more of that entity. As such, the terms “a” (or “an”), “one or more” and “at least one” are used interchangeably herein. In addition, reference to “an agent” by the indefinite article “a” or “an” does not exclude the possibility that more 12 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 than one of the agents are present, unless the context clearly requires that there is one and only one of the agents. As used herein, “about” means plus or minus 10% of the indicated numerical value. [0074] As used herein, the term “comprise” as is used in this description and in the claims and its conjugations are used in its non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded. The present disclosure may suitably “comprise”, “consist of”, or “consist essentially of”, the steps, elements, and/or reagents described in the claims. [0075] The term “pharmaceutically acceptable salt” refers to a salt known to be non-toxic and commonly used in the pharmaceutical literature. Typical inorganic acids used to form such salt include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, and the like. Salts derived from organic acids, such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyl alkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids may also be used. A preferred salt is the hydrochloride salt. [0076] The term "an effective amount" is interchangeable with "therapeutically effective dose," or "therapeutically effective amount," and refers to an amount sufficient to produce the desired effect. An effective amount is sufficient to cause an improvement in a condition (e.g., agitation) of the patient. An effective amount can be administered in one or more administrations, applications, or dosages. [0077] The terms “formulation” and “composition” are used interchangeably, except where otherwise clearly intended to have different meanings. [0078] The term “unit dose,” “unit dosage,” or “unit dosage form” means a physically discrete unit that contains a predetermined quantity of dexmedetomidine or a pharmaceutically acceptable salt thereof. [0079] The term "pharmaceutically acceptable carrier" refers to a pharmacologically inert substance to be used as a carrier. As used herein, the phrase “carrier” and “excipients” are used interchangeably, except where otherwise clearly intended to have different meanings. The term “film” herein includes thin films, in any shape, including rectangular, square, or other desired shape. The film may be of any desired thickness and size, such that it can be conveniently placed oromucosally (i.e., sublingually or buccally or gingivally) in the patient. For example, the film may be a relatively thin film having a thickness of from about 20 micrometers to about 200 micrometers or may be a somewhat thicker film having a thickness of from about 20 13 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 micrometers to about 1000 micrometers. In embodiments, the film may be even thicker, e.g., having a thickness greater than about 30 millimeters (mm). [0080] The term “self-supporting” means the films herein maintain structural integrity upon handling without the need for a backing layer. Some flexibility in the film is contemplated and may be desirable. [0081] The term “therapeutic” as used herein, refers to treatment and/or prophylaxis, depending on context. [0082] The terms “treat”, "treating," and "treatment," as used herein refer to a particular disease or disorder includes lessening, improving, ameliorating or abrogating the symptoms and/or pathology of the disease or disorder. Treatment may be measured as a reduction level by at least 10% or higher, preferably 20% or higher, more preferably 40% or higher, even more preferably 60%. [0083] The term "agitation", as used herein, means a disorder characterized by signs and symptoms of irritability, emotional outburst, impaired thinking, or excess motor and verbal activity that may occur due to either dysfunction of specific brain regions such as frontal lobes or due to dysfunction of neurotransmitter systems such as the noradrenergic system. In embodiments, the agitation may be caused by noradrenergic hyperarousal. The “signs and/or symptoms of agitation" non-limitedly as used herein includes excessive motor activity (examples include: pacing, rocking, gesturing, pointing fingers, restlessness, performing repetitious mannerisms), verbal aggression (e.g., yelling, speaking in an excessively loud voice, using profanity, screaming, shouting, threatening other people), physical aggression (e.g., grabbing, shoving, pushing, clenching hands into fists, resisting, hitting others, kicking objects or people, scratching, biting, throwing objects, hitting self, slamming doors, tearing things, and destroying property). In the present disclosure, an agitated patient may also exhibit aggression. The agitation may be acute. The agitation may be mild to moderate. An occurrence of “agitation” is referred to herein as an “agitation episode” or an “agitation event”. [0084] The term "acute agitation" means agitation that occurs rapidly and sudden in onset. Acute agitation may be associated with, for example, neurodegenerative disorders and neuropsychiatric disorders, although it may particularly exist in neuropsychiatric conditions. Acute agitation may lead to chronic agitation if it remains untreated. [0085] The term “mild agitation” includes low level of symptoms and little interference in functioning; “moderate agitation” includes some prominent symptoms with some interference 14 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 in functioning and “severe agitation” includes agitation symptoms that interfere with all functioning. [0086] The term “schizoaffective disorder” refers to chronic mental health condition characterized primarily by symptoms of schizophrenia, such as hallucinations or delusions, and symptoms of a mood disorder, such as mania and depression. [0087] The term “schizophreniform disorder” refers to a type of psychotic illness with symptoms similar to those of schizophrenia, but lasting for less than 6 months. The symptoms of both disorders can include delusions, hallucinations, disorganized speech, disorganized or catatonic behavior, and social withdrawal. [0088] The term “mania” refers to a psychological condition that causes a person to experience unreasonable euphoria, very intense moods, hyperactivity, and delusions. Mania (or manic episodes) is a common symptom of bipolar disorder. A milder or less severe form of mania is called hypomania that lasts for a short period (usually a few days). [0089] The term “without significant sedation”, “without inducing significant sedation,” or “without causing significant sedation” and the like means that the patient experiences a level of sedation not greater than Level 3 on the Ramsay Sedation Scale. Level 3 means sedated but responds to commands. In embodiments, the dexmedetomidine may be dosed to achieve a Richmond Agitation Sedation Scale (RASS) of -1 (“light sedation”). [0090] The term “significantly reduced” refers to a reduction level by at least 10% or higher, preferably 20% or higher, more preferably 40% or higher, even more preferably 60% or higher, still more preferably 80% or higher, and 90% or higher, as compared to a control. [0091] The term “oromucosal delivery” or “oromucosal administration” and the like means administration to the oral mucosa. It includes delivery across any tissue of the mouth, pharynx, larynx, trachea, or upper gastrointestinal tract, particularly including the sublingual, buccal, gingival and palatal mucosal tissues. [0092] The term "sublingual" literally means "under the tongue" and refers to a method of administering substances via the mouth in such a way that the substances are rapidly absorbed via the blood vessels under the tongue rather than via the digestive tract. Sublingual absorption occurs through the highly vascularized sublingual mucosa, which allows a substance direct access to the blood circulation, thereby providing for direct systemic administration independent of gastrointestinal influences and avoiding undesirable first-pass hepatic metabolism. 15 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 [0093] The term “buccal” means administration of the dosage form against the gum and the inner lip or cheek. [0094] The term “gingival” means administration of the dosage form to the gingiva (gums) found in the oral cavity of humans surrounding part of their teeth. [0095] The term “clinical setting,” as used herein, refers to any service or treatment that must be administered by a medical professional or diagnosed by a medical professional. [0096] The term “non-clinical setting” is interchangeable with “home-care setting” or “home setting,” “community setting,” “ambulatory care,” or “outpatient” and refers to any service or treatment that does not require medical professional for diagnosis or administration. Typically, a non-clinical setting is outside of a hospital, for example, at home, a group home, an assisted living facility, a correctional facility, hospice, or long-term care facility. [0097] The term “caregiver” as used herein refers to a person who cares for the patient affected by bipolar I disorder, bipolar II disorder, schizophrenia, schizoaffective disorder, or schizophreniform disorder. Caregivers can be, for example, family members, friends, or social workers, or a paid person depending on the patient’s circumstances. [0098] The term “EDA” as used herein, refers to electrodermal activity/response, which is also known as skin conductance response (and in older terminology as "galvanic skin response"). [0099] The term “baseline” in medicine is information found at the beginning of a study or other initial known value which is used for comparison with later data. The concept of a baseline is essential to the daily practice of medicine in order to establish a relative rather than absolute meaning to data. PANSS-EC aka PEC for patients affected with schizophrenia. [0100] The term “heart rate variability” refers to the variability of the time interval between heartbeats and is a reflection of an individual's current health status. [0101] The term “EMA” or “Ecological momentary assessment” as used herein refers to repeated sampling of patients' current behaviors and experiences in real time, in patients' natural environments. The repeated measurements of data are for analyzing important characteristics of the dynamics of phenomena. [0102] The term “wearable device” or “wearable sensor” as used herein refers to any device that could be worn/placed/mounted on the body of the patient and that is able to detect, and process signals related to sympathetic nervous system activity and/or motor activity. The device may interact (e.g., remotely or otherwise) with any suitable compatible device, such as an end-user display terminal, and will normally include transducers, a transducer control module, a communications device, and a monitoring system or a computer database etc. 16 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 Physiological measures can also be measured using both standard technology and miniaturized wearable devices such as sensor devices (e.g., waist worn, wrist worn, finger worn, etc.) with networking capacity (e.g., an iPhone). [0103] The term “informant” as used herein refers to is a person who is present most (but not all) the time, to assist in recording the data and prompting the patient to consider taking mediation. The informant simply informs, meaning the informant just reports on the condition of the patient but does not give care. [0104] The term “EEG” as used herein, refers to electroencephalography (EEG). EEG is an electrophysiological monitoring method to record electrical activity of the brain. EEG reflects the electrical activity of the underlying neurons, and provides information regarding neuronal population oscillations, the information flow pathway, and neural activity networks. ACTIVE AGENT: [0105] Dexmedetomidine has the IUPAC name (+) 4-(S)-[1-(2,3-dimethylphenyl)ethyl]-1H- imidazole. As the monohydrochloride salt, it is predominantly used as a medication for the sedation of patients during treatment in an intensive care setting or to sedate patients prior to and/or during surgical and other procedures. Such medication is currently sold under the registered trade name "PRECEDEX®". [0106] Pharmaceutically acceptable salts of dexmedetomidine that may be included herein generally include any suitable salt that has been or may be approved by the U.S. FDA or other appropriate foreign or domestic agency for administration to a human. Non-limiting examples of suitable pharmaceutically acceptable salts include salts of inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrocarbonic, phosphoric, monohydrogen phosphoric, dihydrogen phosphoric, sulfuric, hydrogen sulfuric, and hydroiodic acid. Other examples include salts derived from non-toxic organic acids, including acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acids, or combinations of these acid salts. Exemplary salts include dexmedetomidine hydrochloride, dexmedetomidine hydrobromide, dexmedetomidine sulfate, dexmedetomidine sulfonate, dexmedetomidine phosphate, dexmedetomidine nitrate, dexmedetomidine formate, dexmedetomidine citrate, dexmedetomidine tartrate, dexmedetomidine malate, dexmedetomidine benzoate, dexmedetomidine salicylate, dexmedetomidine ascorbate or the like. In embodiments, 17 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 deuterated forms of dexmedetomidine or a pharmaceutically acceptable salt thereof may be included. Dosages: [0107] In embodiments, the dosage of dexmedetomidine or a pharmaceutically acceptable salt thereof is in the range of between about 5 micrograms to about 360 micrograms. Examples of suitable dosages include: about 5 micrograms to about 340 micrograms, about 5 micrograms to about 320 micrograms, about 5 micrograms to about 300 micrograms, about 5 micrograms to about 280 micrograms, about 5 micrograms to about 270 micrograms, about 5 micrograms to about 260 micrograms, about 5 micrograms to about 250 micrograms, about 5 micrograms to about 240 micrograms, about 5 micrograms to about 230 micrograms, about 5 micrograms to about 220 micrograms, about 5 micrograms to about 210 micrograms, about 5 micrograms to about 200 micrograms, about 5 micrograms to about 190 micrograms, about 5 micrograms to about 180 micrograms, about 5 micrograms to about 170 micrograms, about 5 micrograms to about 160 micrograms, about 5 micrograms to about 150 micrograms, about 5 micrograms to about 140 micrograms, about 5 micrograms to about 130 micrograms, about 5 micrograms to about 120 micrograms, about 5 micrograms to about 110 micrograms, about 5 micrograms to about 100 micrograms, about 10 micrograms to about 90 micrograms, about 10 micrograms to about 80 micrograms, about 10 micrograms to about 70 micrograms, about 10 micrograms to about 60 micrograms, about 10 micrograms to 50 micrograms, about 10 micrograms to about 40 micrograms, about 10 micrograms to about 35 micrograms, about 15 micrograms to about 35 micrograms, about 20 micrograms to about 50 micrograms, about 25 micrograms to about 40 micrograms, or about 25 micrograms to about 35 micrograms. The dose may be administered one or more times a day including twice, three times, four times, five times or six times per day. In embodiments, the dosage of dexmedetomidine or a pharmaceutically acceptable salt thereof may be administered twice a day. The dose may be administered on an “as needed basis” in one, two or more doses per day to the patient. [0108] In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof may be administered oromucosally (e.g., sublingually or buccally or gingivally). In embodiments, the per unit dose of dexmedetomidine or a pharmaceutically acceptable salt thereof is about 10 micrograms, about 15 micrograms, about 20 micrograms, about 25 micrograms, about 30 micrograms, about 35 micrograms, about 40 micrograms, about 45 micrograms, about 50 micrograms, about 55 micrograms, about 60 micrograms, about 65 micrograms, about 70 18 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 micrograms, about 75 micrograms, about 80 micrograms, about 85 micrograms, about 90 micrograms, about 95 micrograms, about 100 micrograms, about 110 micrograms, about 120 micrograms, about 130 micrograms, about 140 micrograms, about 150 micrograms, about 160 micrograms, about 170 micrograms, or about 180 micrograms. [0109] In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 30 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 40 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 50 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 60 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 70 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 80 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 90 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 100 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 110 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 120 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 130 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 140 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 150 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 160 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., 19 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 dexmedetomidine hydrochloride) is administered in an amount of about 170 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 180 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 190 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 200 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 210 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 220 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 230 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 240 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 260 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 280 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 300 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 320 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 340 micrograms. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered in an amount of about 360 micrograms. [0110] The dosages of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) may depend on a variety of factors such as the type and extent of the condition, the overall health status of the particular patient, the particular form of dexmedetomidine and the particular formulation used to treat the patient. 20 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 Methods and Administration: [0111] In embodiments, the present disclosure provides methods of treating agitation in schizophrenia or bipolar disorder patients in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 60 micrograms to the patients. [0112] In embodiments, the present disclosure provides methods of treating agitation in schizophrenia or bipolar disorder patients in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 80 micrograms to the patients. [0113] In embodiments, the present disclosure provides methods of treating agitation in schizophrenia or bipolar disorder patients in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 60 micrograms to the patients, wherein the patients are 18 years or older. [0114] In embodiments, the present disclosure provides methods of treating agitation in a schizophrenia or bipolar disorder patients in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 80 micrograms to the patients, wherein the patients are 18 years or older. [0115] In embodiments, the present disclosure provides methods of treating agitation in schizophrenia or bipolar disorder patients in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a total daily dose of about 60 micrograms to about 360 micrograms to the patients. [0116] In embodiments, the present disclosure provides methods of treating agitation in schizophrenia or bipolar disorder patients in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a total daily dose of about 60 micrograms to about 360 micrograms to the patients, wherein the patients are 18 years or older. [0117] In embodiments, the present disclosure provides methods of treating agitation in schizophrenia or bipolar disorder patients in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a total daily dose of about 60 micrograms to about 180 micrograms to the patient. [0118] In embodiments, the present disclosure provides methods of treating agitation in schizophrenia or bipolar disorder patients in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a total daily dose of about 21 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 60 micrograms to about 180 micrograms to the patients, wherein the patients are 18 years or older. [0119] In embodiments, the present disclosure provides methods of treating agitation in schizophrenia or bipolar disorder patients in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a total daily dose of about 80 micrograms to about 360 micrograms to the patients, wherein the patients are 18 years or older. [0120] In embodiment, the present disclosure provides methods of treating acute agitation in schizophrenia or bipolar disorder patients in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a total daily dose of about 60 micrograms to about 360 micrograms to the patients. [0121] In embodiment, the present disclosure provides methods of treating acute agitation in schizophrenia or bipolar disorder patients in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a total daily dose of about 60 micrograms to about 360 micrograms to the patients, wherein the patients are 18 years or older. [0122] In embodiment, the present disclosure provides methods of treating acute agitation in schizophrenia or bipolar disorder patients in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a total daily dose of about 60 micrograms to about 180 micrograms to the patients. [0123] In embodiment, the present disclosure provides methods of treating acute agitation in schizophrenia or bipolar disorder patients in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a total daily dose of about 60 micrograms to about 180 micrograms to the patients, wherein the patients are 18 years or older. [0124] In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered by the caregiver or informant of the patient. In embodiments, the caregiver or informant is a family member or a family friend. In embodiments, the caregiver or informant is dedicated for the patient. In embodiments, the caregiver or informant is a social worker. In embodiments, the caregiver or informant is a person employed by or for the patient. In embodiments, the caregiver or informant maintains close physical proximity to the patient for at least 8 hours after the administration of dexmedetomidine or a pharmaceutically acceptable salt thereof. 22 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 [0125] In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is self- administered by the patient. [0126] In embodiments, the bipolar disorder includes bipolar I disorder, bipolar II disorder, and bipolar mania. In embodiments, bipolar disorder is bipolar disorder I. In embodiments, bipolar disorder is bipolar disorder II. In embodiments, bipolar disorder is bipolar mania. [0127] In embodiments, the schizophrenia includes schizoaffective and schizophreniform disorder. In embodiments, the schizophrenia is schizoaffective disorder. In embodiments, the schizophrenia is schizophreniform disorder. [0128] In embodiments, the patient experiences periodic episodes of agitation. In embodiments, the patient has a score of ^4 on at least 1 of the 5 items on the PEC at baseline. In embodiments, the patient has a total score of ^14 on 5 items on PEC at baseline. In embodiments, the patient has a score ^4 on C-SSRS at baseline. [0129] In embodiments, the agitation is mild or moderate. In embodiments, the agitation is not severe. [0130] In embodiments, the route of administration is oromucosal (e.g., sublingual, buccal or gingival). In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in an oromucosal dosage form selected from the group consisting of a film, wafer, patch, lozenge, gel, spray, tablet and liquid drops. In embodiments, the dosage form is a thin film. In embodiments, the dosage form is a sublingual film. In embodiments, the dosage form is a buccal film. In embodiments, the dosage form is a gingival film. Suitable films are described in US Patent No.10,792,246, which is hereby incorporated by reference in its entirety for all purposes. [0131] In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as a single dose per day. In embodiments, the total daily dose may be administered oromucosally multiple times (e.g., one to four times) as a single unit dose, as multiple unit doses, or as a fraction of one or more unit doses (e.g., half of a unit dose), or a combination thereof at an appropriate dosing interval (e.g., at least after 0.5 hours) to produce a desired effect. In embodiments, the dosage of dexmedetomidine or a pharmaceutically acceptable salt thereof may be administered twice a day, for example, a 60 micrograms unit dose is administered two times at a dosing interval of about 2 hours to produce the effect of a 120 micrograms dose. 23 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 [0132] In embodiments, the total daily dose of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., dexmedetomidine hydrochloride) is administered as a first and optional second dose. [0133] In embodiments, the first dose is about 60 micrograms, about 70 micrograms, about 80 micrograms, about 90 micrograms, about 100 micrograms, about 110 micrograms, about 120 micrograms, or about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof. In embodiments, the first dose is about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof. [0134] In embodiments, the first dose is about 60 micrograms, about 70 micrograms, about 80 micrograms, about 90 micrograms, about 100 micrograms, about 110 micrograms, about 120 micrograms, or about 180 micrograms of dexmedetomidine hydrochloride. In embodiments, the first dose is about 60 micrograms of dexmedetomidine hydrochloride. [0135] In embodiments, the second dose is administered at least 2 hours after administration of the first dose if there is no improvement in PEC score by more than 2 points. In embodiments, the patient is hemodynamically stable. [0136] In embodiments, the optional second dose is about 60 micrograms, about 70 micrograms, about 80 micrograms, about 90 micrograms, about 100 micrograms, about 110 micrograms, about 120 micrograms, or about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof. In embodiments, the optional second dose is about 60 micrograms, about 70 micrograms, about 80 micrograms, about 90 micrograms, about 100 micrograms, about 110 micrograms, about 120 micrograms or about 180 micrograms of dexmedetomidine hydrochloride. In embodiments, the optional second dose is about 60 micrograms of dexmedetomidine hydrochloride. In embodiments, the optional second dose is 80 micrograms of dexmedetomidine hydrochloride. [0137] In embodiments, the second dose is administered at least about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours, about 8 hours, about 8.5 hours, about 9 hours, about 9.5 hours, about 10 hours, about 10.5 hours, about 11 hours, about 11.5 hours, about 12 hours, about 12.5 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours or about 24 hours after administration of the first dose. [0138] In embodiments, a rescue medication is optionally administered to the patient after the second dose of dexmedetomidine in case of persistent or uncontrolled agitation. In 24 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 embodiments, the rescue medication is selected from benzodiazepines (such as alprazolam, clonazepam, lorazepam, oxazepam, midazolam, triazolam, chlordiazepoxide, clorazepate, diazepam, estazolam, flurazepam, temazepam, quazepam) or antipsychotics selected from the group consisting of but not limited to aripiprazole, olanzapine, quetiapine, chlorpromazine, cariprazine, asenapine, clozapine, lurasidone, risperidone and ziprasidone. In embodiments, the rescue medicine is lorazepam at a dose of about 4 mg. In embodiments, the rescue medicine is oxazepam at a dose of about 60 mg. In embodiments, the rescue medicine is chlorpromazine at a dose of about 300 mg. [0139] In embodiments, the agitation is acute. [0140] In embodiments, the patient experiences not more than 5 episodes of agitation in a week. In embodiments, the patient experiences not more than 3 episodes of agitation in a week. In embodiments, the patient experiences not more than 2 episodes of agitation in a week. In embodiments, the patient experiences at least 1 episode of agitation in the past month. [0141] In embodiments, the patient experiences not more than 5 episodes of agitation in a month. In embodiments, the patient experiences not more than 3 episodes of agitation in a month. In embodiments, the patient experiences not more than 2 episodes of agitation in a month. [0142] In embodiments, the present disclosure provides methods of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a total daily dose of about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant. [0143] In embodiments, the present disclosure provides methods of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a total daily dose of about 60 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant. [0144] In embodiments, the present disclosure provides methods of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally) to the patient about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant. [0145] In embodiments, the present disclosure provides a method of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising administering oromucosally (e.g., 25 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 sublingually, buccally, or gingivally) to the patient about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant. [0146] In embodiments, the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a total daily dose of about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant. [0147] In embodiments, the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a total daily dose of about 60 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant. [0148] In embodiments, the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally) to the patient about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant. [0149] In embodiments, the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally) to the patient about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant. [0150] In embodiments, the present disclosure provides methods of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising self-administering by the patient an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof. [0151] In embodiments, the present disclosure provides methods of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient. [0152] In embodiments, the present disclosure provides methods of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising self-administering by the patient 26 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof. [0153] In embodiments, the present disclosure provides methods of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self- administered by the patient. [0154] In embodiments, the present disclosure provides a method of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising self-administering by the patient an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof. [0155] In embodiments, the present disclosure provides a method of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising adminsitering an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient. [0156] In embodiments, the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising self-administering by the patient an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof. [0157] In embodiments, the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self- administered by the patient. [0158] In embodiments, the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising self-administering by the patient an oromucosal dosage form comprising about 60 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof. 27 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 [0159] In embodiments, the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising adminsitering an oromucosal dosage form comprising about 60 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self- administered by the patient. [0160] In embodiments, the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising self-administering by the patient an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof. [0161] In embodiments, the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising adminstering an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient. [0162] In embodiments, the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising self-administering by the patient an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof. [0163] In embodiments, the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising adninstering an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient. [0164] In embodiments, the present disclosure provides a method of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient in two phases. [0165] In embodiments, phase 1 comprises administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof under medical supervision, wherein the duration of phase 1 is at least 8 hours. [0166] In embodiments, the duration of phase 1 is at least about 8 hours, at least about 8.5 hours, at least about 9 hours, at least about 9.5 hours, at least about 10 hours, at least about 10.5 hours, at least about 11 hours, at least about 11.5 hours, at least about 12 28 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 hours, at least about 12.5 hours, at least about 13 hours, at least about 13.5 hours, at least about 14 hours, at least about 14.5 hours, at least about 15 hours, at least about 20 hours, at least about 22 hours, or at least about 24 hours. [0167] In embodiments, phase 2 comprises administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof under non- medical supervision (non -clinical setting), wherein the duration of phase 2 is up to 12 weeks. [0168] In embodiments, the present disclosure provides methods of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient, the method comprising: (a) administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof under medical supervision for at least 8 hours; and (b) administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof under non-medical supervision (non-clinical setting) for up to 12 weeks. [0169] In embodiments, the present disclosure provides a method of treating acute agitation in a schizophrenia patient in two phases. [0170] In embodiments, phase 1 comprises administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof under medical supervision, wherein the duration of phase 1 is at least 8 hours. [0171] In embodiments, the duration of phase 1 is at least about 8 hours, at least about 8.5 hours, at least about 9 hours, at least about 9.5 hours, at least about 10 hours, at least about 10.5 hours, at least about 11 hours, at least about 11.5 hours, at least about 12 hours, at least about 12.5 hours, at least about 13 hours, at least about 13.5 hours, at least about 14 hours, at least about 14.5 hours, at least about 15 hours, at least about 20 hours, at least about 22 hours, or at least about 24 hours. [0172] In embodiments, phase 2 comprises administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof under non- medical supervision (non -clinical setting), wherein the duration of phase 2 is up to 12 weeks. 29 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 [0173] In embodiments, the present disclosure provides methods of treating mild to moderate agitation in a schizophrenia or bipolar disorder patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally) to the patient a dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant. [0174] In embodiments, the present disclosure provides methods of treating mild to moderate agitation in a schizophrenia or bipolar disorder patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally) to the patient a dosage form comprising about 60 micrograms to about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant. [0175] In embodiments, the present disclosure provides methods of treating mild to moderate agitation in a schizophrenia or bipolar disorder patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally) to the patient a dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant. [0176] In embodiments, the present disclosure provides methods of treating mild to moderate agitation in a schizophrenia or bipolar disorder patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally) to the patient a dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant. [0177] In embodiments, the present disclosure provides methods of treating mild to moderate agitation in a schizophrenia or bipolar disorder patient in a non-clinical setting, comprising self-administering by the patient an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof. [0178] In embodiments, the present disclosure provides methods of treating mild to moderate agitation in a schizophrenia or bipolar disorder patient in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient. [0179] In embodiments, the present disclosure provides methods of treating mild to moderate agitation in a schizophrenia or bipolar disorder patient in a non-clinical setting, comprising 30 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 self-administering by the patient an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof. [0180] In embodiments, the present disclosure provides methods of treating mild to moderate agitation in a schizophrenia or bipolar disorder patient in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient. [0181] In embodiments, the present disclosure provides methods of treating mild to moderate agitation in a schizophrenia or bipolar disorder patient in a non-clinical setting, comprising self-administering by the patient an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof. [0182] In embodiments, the present disclosure provides methods of treating mild to moderate agitation in a schizophrenia or bipolar disorder patient in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient. [0183] In embodiments, the diagnosis of schizophrenia or bipolar disorder is performed as per DSM-IV criteria. The Diagnostic and Statistical Manual of Mental Disorders (DSM) is the handbook widely used by clinicians and psychiatrists to diagnose psychiatric illnesses. It contains descriptions, symptoms, and other criteria necessary for diagnosing mental health disorders. The DSM-IV was originally published in 1994 and listed more than 250 mental disorders. An updated version, called the DSM-IV-TR, was published in 2000. (TR stands for "text revision.") This version utilized a multiaxial or multidimensional approach for diagnosing mental disorders. [0184] In embodiments, the patient experienced at least one clinical presentation of agitation requiring intervention in the previous month (i.e., the month prior to starting treatment). In embodiments, the patient experienced two or three (or more) episodes of agitation in the previous month (i.e., the month prior to starting treatment). In embodiments, the patient was clinically administered a medication for agitation. In embodiments, the patient experienced at least one episode of agitation in a previous month (i.e., the month prior to starting treatment) requiring emergency visit or medical service. [0185] In embodiments, the patient is suffering from one or more psychiatric comorbidities. In embodiments, the patient is not suffering from other psychiatric comorbidities . 31 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 [0186] In embodiments, the patient is not concurrently taking other medications (e.g., alpha-1 noradrenergic blockers and alpha-2 adrenergic agonists). [0187] In embodiments, the patient is about 18 years old to about 75 years old, e.g., about 18 years old, about 19 years old, about 20 years old, about 21 years old, about 22 years old, about 23 years old, about 24 years old, about 25 years old, about 26 years old, about 27 years old, about 28 years old, about 29 years old, about 30 years old, about 31 years old, about 32 years old, about 33 years old, about 34 years old, about 35 years old, about 36 years old, about 37 years old, about 38 years old, about 39 years old, about 40 years old, about 41 years old, about 42 years old, about 43 years old, about 44 years old, about 45 years old, about 46 years old, about 47 years old, about 48 years old, about 49 years old, about 50 years old, about 51 years old, about 52 years old, about 53 years old, about 54 years old, about 55 years old, about 56 years old, about 57 years old, about 58 years old, about 59 years old, about 60 years old, about 61 years old, about 62 years old, about 63 years old, about 64 years old, about 65 years old, about 66 years old, about 67 years old, about 68 years old, about 69 years old, about 70 years old, about 71 years old, about 72 years old, about 73 years old, about 74 years old, or about 75 years old including all values and ranges in between. [0188] In embodiments, the patient is older than 75 years old. In embodiments, the patient is about 65 years old to about 80 years old, e.g., about 76 years old, about 77 years old, about 78 years old, about 79 years old, about 80 years old, including all values and ranges in between. In embodiments, the patient is about 75 years old to about 80 years old, e.g., about 75 years old, about 76 years old, about 77 years old, about 78 years old, about 79 years old, or about 80 years old, including all values and ranges in between. In embodiments, the patient is older than 80 years old, e.g., about 81 years old, about 82 years old, about 83 years old, about 84 years old, about 85 years old, about 86 years old, about 87 years old, about 88 years old, about 89 years old, about 90 years old, about 91 years old, about 92 years old, about 93 years old, about 94 years old, about 95 years old, about 96 years old, about 97 years old, about 98 years old, about 99 years old, or about 100 years old, including all values and ranges in between. [0189] In embodiments, the oromucosal dosage form is selected from the group consisting of a film, wafer, patch, lozenge, gel, spray, tablet and liquid drops. In embodiments, the dosage form is a sublingual or buccal or gingival film. [0190] In embodiments, the administration of dexmedetomidine, a pharmaceutically acceptable salt thereof, or an oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof produces anti-agitation effect within about 120 32 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 minutes after administration without causing significant sedation. In embodiments, the administration of dexmedetomidine, a pharmaceutically acceptable salt thereof, or an oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof form produces anti-agitation effect within about 60 minutes after administration without causing significant sedation. In embodiments, the administration of dexmedetomidine, a pharmaceutically acceptable salt thereof, or an oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof produces anti-agitation effect within about 30 minutes after administration without causing significant sedation. In embodiments, the administration of dexmedetomidine, a pharmaceutically acceptable salt thereof, or an oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof produces anti-agitation effect within about 20 minutes after administration without causing significant sedation. In embodiments, the administration of dexmedetomidine, a pharmaceutically acceptable salt thereof, or an oromucosal dosage form comprising dexmedetomidine or a pharmaceutically acceptable salt thereof produces anti- agitation effect within about 15 minutes after administration without causing significant sedation. [0191] In embodiments, the treatment is effective without causing clinically significant cardiovascular effects. In embodiments, the treatment is effective with reduced or no side effects (e.g., respiratory side effects). PCT Publication No. 2018/126182, the disclosure of which is incorporated herein by reference, discloses the treatment of agitation in a patient by administering dexmedetomidine or a pharmaceutically acceptable salt thereof where agitation is effectively treated without also causing significant sedation. [0192] In embodiments, the clinical improvement in agitation is measured using PANSS, ACES, and/or CGI-I scales. In embodiments, the reduction in agitation is assessed by relative change in PEC score after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof. In embodiments, the reduction in agitation is assessed by relative change in modified CGI-S 4-point (0-3) scale after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof. [0193] In embodiments, the reduction in agitation is assessed after a suitable period of time such as 0.5 hours, 1 hour, 2 hours, 4 hours or 6 hours after administration of the first dose of dexmedetomidine or a pharmaceutically acceptable salt thereof administration. In embodiments, the reduction in agitation is assessed before the administration of rescue medication in the patient. 33 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 [0194] In embodiments, the patient achieves a mean change in PEC score of greater than -2, -3, -4, -5, -6, -7, -8, -9, or -10 relative to baseline within 30 minutes of administering the composition. In embodiments, the patient achieves a mean change in PEC score of greater than -7 relative to baseline within 2 hours of administering dexmedetomidine or a pharmaceutically acceptable salt thereof. In embodiments, the decrease in PEC score is maintained for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, hours following administration of dexmedetomidine or a pharmaceutically acceptable salt thereof. In embodiments, the agitated patient has a baseline score in PEC scale of about 14 or higher. [0195] In embodiments, the patient achieves a CGI-I score improvement to about a 1 (very much improved) or about a 2 (much improved). In embodiments, the agitation is reduced to a 2 (moderate agitation), 3 (mild agitation) or 4 (normal behavior) 30 minutes after administration, as measured by the Agitation-Calmness Evaluation Scale (ACES). In embodiments, the score improvement is sustained for a period of about 2 hours to about 6 hours. In embodiments, the agitated patient has a baseline score in CGI-I of about 3 or higher. [0196] In embodiments, the agitation is reduced to 2 (moderate agitation), 3 (mild agitation) or 4 (normal behavior) 30 minutes after administering the composition, as measured by the Agitation-Calmness Evaluation Scale (ACES). In embodiments, the agitation is reduced to a 3 (mild agitation). For example, the improved ACES score may be obtained within about 5 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 70 minutes, about 80 minutes, about 90 minutes, about 100 minutes, about 110 minutes, or about 120 minutes. In embodiments, the agitated patient has a baseline score in ACES score of about 3 or below. [0197] In embodiments, the ACES score improvement is sustained for about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, or about 24 hours following administration of dexmedetomidine or a pharmaceutically acceptable salt thereof. [0198] In embodiments, the decrease in the PEC, CGI-S and ACES scores is maintained for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, hours following administration. In embodiments, the single administration of dexmedetomidine or a pharmaceutically acceptable salt thereof treats agitation and maintains calming effect for at least 12 hours. 34 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 [0199] In embodiments, the methods describe herein provides improvement in the residual signs and symptoms of schizophrenia following administration of dexmedetomidine or a pharmaceutically acceptable salt thereof as measured by reduction in PEC score of greater than -7 relative to baseline. [0200] In embodiments, the methods describe herein provides improvement in duration of calming as measured using reduction in ACES score of 2 or more following administration of dexmedetomidine or a pharmaceutically acceptable salt thereof. Wearable devices/EMA devices: [0201] Agitation in patients with neuro-psychiatric or neuro-degenerative disorders results in patients that are uncooperative to treatment, and are also potentially violent and aggressive, making them a danger to themselves and to caregivers or informants. By detecting a signal that indicates a patient is about to become agitated, the present disclosure pairs a diagnostic with a treatment component using dexmedetomidine, to prevent the manifestation of an agitation episode. Thus, according to the present disclosure, dexmedetomidine can be used as a prophylactic or preventive therapeutic agent. [0202] In embodiments, the impending episode of agitation is alerted to the caregiver or informant via Ecological Momentary Assessment (EMA) device or other remote compatible device. In embodiments, the EMA device is monitored by the caregiver or informant. In embodiments, the EMA device comprises a caregiver’s or informant’s smart phone or a tablet with an application installed to report the patient’s observations. In embodiments, the application on the caregiver’s or informant’s device provides prompt to report on adverse effects after dexmedetomidine administration. In embodiments, the application on the caregiver’s or informant’s device provides prompt to report on absence or presence of episode of agitation. In embodiments, the caregiver or informant reports information on frequency or number of episodes of agitation on the application installed on EMA device. In embodiments, the EMA device may be an end user terminal capable of alerting the caregiver or informant by means of the sound/alarm and/or display. In embodiments, the alerts are received in the form of a text message, a call, a sound or a window flashing/display on the caregiver’s or informant’s device. Suitable examples of such devices are described in PCT Publication Nos.2021/055595, 2021/163482 and 2021/163482, the contents of which are herein incorporated by reference. [0203] In embodiments, the prediction of the agitation episode (or event) includes determining a time period within which the agitation episode of the patient will occur and also includes 35 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 determining a degree of the agitation episode of the patient. In embodiments, the prediction involves comparing the physiological data with the baseline value of at least one physiological parameter. In embodiments, the signal/alert is generated when physiological data exceeds threshold of baseline value. [0204] In embodiments, the impending episode of agitation is diagnosed by the steps comprising: monitoring one or more physiological signals of sympathetic nervous system activity in the patient using a wearable device (or sensor) placed or mounted on the patient’s skin surface; identifying, via the processing of incoming data in the wearable device, when the patient is about to have an agitation episode; sending a signal from the wearable device to an EMA device or a remote compatible device monitored by a caregiver or informant alerting the caregiver or informant to an impending agitation episode in the patient. [0205] In embodiments, the reduction in agitation is alerted to the caregiver or informant via Ecological Momentary Assessment (EMA) device or other remote compatible device. [0206] In embodiments, the alerts are sent to the patient for self-administration of oral mucosal dosage form comprising dexmedetomidine or a salt thereof. In embodiments, the caregiver or informant determines that the patient would benefit from administration of dexmedetomidine, and the caregiver or informant alerts the patient to administer the oral mucosal dosage form comprising dexmedetomidine or a salt thereof. [0207] In embodiments, patient’s observations are recorded from one or more wearable devices (or wearable sensors) worn/placed/mounted on the body of the patient. [0208] In embodiments, the wearable device (or a wearable sensor) is in contact with the patient and may be selected from iPhone (BYOD or provisioned), accelerometers, gyroscopes, portable devices, digital devices, smart fabrics, bands and actuators like an Apple watch or iWatch, patch such as MC10 Patch, sensors like Microsoft Kinect, wireless communication networks and power supplies, and data capture technology for processing and decision support or any conventional or non-conventional device/sensor performing similar functions. [0209] In embodiments, the wearable device is a bracelet, anklet, shoe, armband, thigh band or a mitten. In embodiments, the wearable device is smartwatch, ring, patch, conductive tattoo, head wearable. In embodiments, the wearable device is wrist worn multi-sensor device with networking capability (e.g., wearable watch such as Apple watch). [0210] In embodiments, the wearable device monitors the change in sympathetic nervous system activity in the patient by measuring EDA over time. 36 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 [0211] EDA is the phenomenon where the skin momentarily becomes a better conductor of electricity when either external or internal stimuli occur that are physiologically arousing. EDA is considered one of the fastest-responding physiological measures of stress response and arousal. The study of EDA has led to important tools such as EEG. A wearable device placed on the skin of the patient, monitors the EDA by recording the changes in the patient’s skin’s electrical resistance. Any change in sympathetic nervous system activity results in a slight increase in perspiration, which lowers skin resistance (because perspiration contains water and electrolytes). Such changes in the skin’s electrical resistance are recorded by the wearable or sensoring device. [0212] In embodiments, the measurement of electrodermal activity is done by clipping the monitoring device to the finger of a patient with attaching electrodes to the middle phalanges of adjacent fingers of a hand and measuring/analyzing EDA waveforms. The data obtained by the clipped device is then transferred to the computer database, connected the monitoring device, wherein the computer database includes one or more of early warning algorithms. Based on the data analyzed, early warning algorithms operates to predict the early signs of the emergence of agitation of a patient and generates patient alerts/warnings based upon the operation of the early warning algorithm to the caregiver or informant that an anti-agitation agent should be administered. [0213] The wearable device may also monitor other physiological signals, including heart rate variability such as resting EEG, cognitive assessments such as pupil size, secretion of salivary amylase, blood pressure; pulse; respiratory rate, level of oxygen in the blood and other signals related to increased sympathetic nervous system activity. [0214] In embodiments, the wearable device records and collect objective data on integrated physiological parameters (such as EDA, resting EEG, blood pressure, mobility/ motor, memory/processing, speech/sleep patterns, social engagement, etc.) The baseline value is calculated for a patient to statistically classify any change in the physiological parameters such as EDA and/or resting EEG levels etc. on a defined scale (from 0 to 5). [0215] In embodiments, the wearable device signals information related to increases in sympathetic nervous system activity and motor activity to an EMA device (such as smartphone or tablet) or an apparatus (for example, a computer database) that is monitored by a caregiver or informant. In embodiments, the wearable device comprises one or more early warning algorithm, alerting unit and a storage unit for storing data regarding one or more alerts provided by the alerting unit, i.e., previous detections increase in the sympathetic nervous activities, data 37 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 about the patient, predetermined acceptable ranges and thresholds etc. In embodiment, the wearable device comprises a display unit for displaying the stored data or measured values of one or more parameters. [0216] In embodiments, the wearable device also detects the severity of the agitation (e.g., mild, moderate or elevated). In embodiments, the wearable device predicts the probability of specific patient to move from mild to moderate to elevated agitation and the wearable devices can also predict a severity change probability. In embodiments, the severity change probability can be measured using at least one machine learning model’s (e.g., an agitation state detection model’s) predictions to create and/or define a chain of events. In embodiments, the severity change probability involves the estimation of the conditional probabilities of changing state using conditional random fields or a similar approach. [0217] In embodiments, the patient, the caregiver or informant records the observations in an agitation episode diary for each episode of agitation. In embodiments, the agitation episode diary comprises questions based on safety information, use of emergency services, use of other concomitant medications and sleepiness. In embodiments, the agitation episode diary comprises questions based on efficacy information after taking study medication (Yes/No), mCGI-S, CGI-C, the agitation behaviors scale (Informant only), use of study medication or use of rescue medication. PHARMACEUTICAL COMPOSITIONS: [0218] The composition may conveniently be presented in a unit dosage form and may be prepared by any of the methods well known in the art. Typically, these methods include the step of bringing into association the active ingredient (e.g., dexmedetomidine or a pharmaceutically acceptable salt thereof) with the carrier which constitutes one or more accessory ingredients. [0219] In embodiments, the dosage form is an oromucosal dosage form comprising: (i) about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) one or more mucoadhesive agents; and (iii) one or more pharmaceutically acceptable excipients or carriers, wherein the dosage form disintegrates within about 5 seconds to about 10 minutes upon contact with an oral mucosa and wherein the dosage form is administered for the treatment of acutely agitated schizophrenia or bipolar disorder patients in a non-clinical setting. 38 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 [0220] In embodiments, the non-clinical setting is at home. In embodiments, the non-clinical setting is at group home, assisted living facility, correctional facility, hospice or long-term care facility. In embodiments, the dosage form is self-administered by the patient or is administered by the caregiver or informant. [0221] In embodiments, the dosage form is an oromucosal dosage form comprising: (i) about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) one or more mucoadhesive agents; and (iii) one or more pharmaceutically acceptable excipients or carriers, wherein the dosage form disintegrates within about 5 seconds to about 10 minutes upon contact with an oral mucosa and wherein the dosage form is administered for the treatment of acutely agitated schizophrenia or bipolar disorder patients in a non-clinical setting. [0222] In embodiments, the dosage form is an oromucosal dosage form comprising: (i) about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) one or more mucoadhesive agents; and (iii) one or more pharmaceutically acceptable excipients or carriers, wherein the dosage form disintegrates within about 5 seconds to about 10 minutes upon contact with an oral mucosa and wherein the dosage form is administered for the treatment of acutely agitated schizophrenia or bipolar disorder patients in a non-clinical setting. [0223] In embodiments, the non-clinical setting is at home. In embodiments, the non-clinical setting is at group home, assisted living facility, correctional facility, hospice or long-term care facility. In embodiments, the dosage form is self-administered by the patient or is administered by the caregiver or informant. [0224] In embodiments, the oromucosal dosage form is a tablet, capsules, patch, film, sachet, wafer, powder, minitablet, pellet, paste, gel, ointment, cream, drops, liquid (e.g., solution, suspension or emulsion), spray, microspheres or nanospheres which can be formulated in accordance with methods that are standard in the art. [0225] In embodiments, the composition comprising dexmedetomidine or a pharmaceutically acceptable salt thereof is administered oromucosally (sublingually/buccally or gingivally) in the form of a tablet, film, spray, gel or drops. In embodiments, the composition is in the form of a tablet or packed powder. In embodiments, the composition is in the form of a film. In embodiments, the composition is a thin film. In embodiments, the film is placed under the 39 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 tongue, close to the base of the tongue, on the left or right side. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered buccally in the form of a film, patch or tablet, particularly a film. In embodiments, the film is placed against the inner lip or check, close to the jaw line. [0226] In embodiments, the dosage form is an oromucosal tablet for sublingual or buccal, or gingival administration. In embodiments, the dosage form is lyophilized (or freeze-dried). Examples of oromucosal dosage forms includes orally disintegrating tablets disclosed in US Patent No. 6,509,040, US Patent No. 7,972,621, US Patent No. 10,548,839, US Patent No. 9,775,819, US Patent No. 5,188,825, US Patent No. 5,631,023, US Patent No. 6,297,240, US Patent No. 6,413,549, US Patent No. 5,976,577, US Patent No. 6,156,339, US Patent No. 5,827,541, US Patent No. 5,729,958, US Patent No. 6,726,928, US Patent No. 9,192,580, US Patent No. 6,709,669, US Appl. Publication No. 20200138721, US Appl. Publication No. 20190276707, US Appl. Publication No. 20190314274, US Appl. Publication No. 20040156894, PCT Publication No. 1999038496, PCT Publication No. 2000044351, and US Appl. Publication No. 20090226522 and related patents/patent applications, which are herein incorporated by reference in their entirety, for all purposes. [0227] In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to the patient intranasally or by inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. [0228] In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to the patient in a single dosage form. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to the patient in a single dosage form multiple times a day (e.g., two, three, four, five, etc. times a day). [0229] In embodiments, the composition is an intra-nasal spray, particularly a spray comprising dexmedetomidine or a pharmaceutically acceptable salt thereof, for example, as described in PCT Publication No. 2013/090278, the contents of which are herein incorporated by reference. [0230] In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to the patient by oral route. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally in the form of tablets, orally 40 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 disintegrating tablets (ODTs), effervescent tablets, capsules, pellets, pills, lozenges or troches, powders, dispersible granules, catchets, aqueous solutions, syrups, emulsions, suspensions, solutions, soft gels, dispersions and the like. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is administered orally to the patient in the form of an orally disintegrating tablet. [0231] In embodiments, the composition or the dosage form is conveniently delivered on an "as needed basis" in one, two or more doses per day to the patient. In embodiments, the dosage form effectively treats agitation in a patient without causing significant sedation. Oromucosal formulations (Sublingual and/or buccal or gingival formulations) [0232] Formulations suitable for use according to the present disclosure are described in US Appl. Publication No.2020/0000717, which is hereby incorporated by reference in its entirety for all purposes. [0233] Dexmedetomidine or a pharmaceutically acceptable salt thereof can be formulated, according to the present disclosure, into dosage forms suitable for oromucosal (e.g., sublingual or buccal or gingival) administration. Such dosage forms include tablets, powders, pills, films, capsules, liquids, gels, syrups, slurries, suspensions, and the like. In embodiments, dexmedetomidine or a pharmaceutically acceptable salt thereof is formulated as a film product. [0234] Carriers suitable for inclusion in oromucosal (e.g., sublingual or buccal or gingival) formulations include, but are not limited to, sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulphate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffered solutions, emulsifiers, isotonic saline, pyrogen - free water and combinations thereof. Carriers which readily dissolve in saliva may be preferred. [0235] Oromucosal (e.g., sublingual or buccal or gingival) formulations may also include other pharmaceutically acceptable carriers and/or excipients such as binders, lubricants, diluents, coatings, disintegrants, barrier layer components, glidants, coloring agents, solubility enhancers, gelling agents, fillers, proteins, co-factors, emulsifiers, solubilizing agents, suspending agents and mixtures thereof. Particular excipients, which may be used according to this disclosure, are known in the art, for example as described in Handbook of Pharmaceutical Excipients, fifth edition, 2005 edited by Rowe et al., Mcgraw Hill. 41 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 Films [0236] Suitable films for sublingual or buccal or gingival administration (i.e. oromucosal administration) according to the present disclosure comprise dexmedetomidine or a pharmaceutically acceptable salt thereof either (i) disposed within a polymer matrix or (ii) deposited on the surface of a polymer matrix, e.g., on the surface of a “placebo” film. Polymer component of film [0237] The polymer component consists of one or more water-soluble polymers within the film matrix and/or as part of the drug-containing deposit (e.g., one or more droplets) on the surface of the polymer. In embodiments, the polymer component consists of a single water-soluble polymer. In embodiments, the polymer component consists of two or more water-soluble polymers, including two or more of the same water-soluble polymers having different molecular weights. [0238] The polymer component in the film matrix is of a suitable composition and present in a sufficient amount to ensure rapid disintegration of the film matrix in the oral mucosa. For example, the presence of the polymer component may allow the film matrix to disintegrate completely oromucosally in about 15 seconds to about 180 seconds, for example, about 30 seconds to about 180 seconds, including about 120 seconds. The polymer component in the film matrix also provides the film with sufficient strength (i.e., the film is self-supporting). [0239] When present in one or more droplets of the dexmedetomidine composition deposited onto the surface of the polymer matrix/substrate, the polymer component may, for example, consist of the water-soluble polymer hydroxypropyl cellulose, although different water-soluble polymers are also contemplated as described hereinafter under the definition “first water- soluble polymer” and “second water soluble polymer”. For example, the polymer component may consist of one, two or three hydroxypropyl celluloses having different molecular weights. The molecular weights of the different hydroxypropyl celluloses may conveniently range from (i) less than about 60,000 Daltons (e.g., about 5,000 Daltons to about 49,000 Daltons) (ii) about 90,000 Daltons to about 200,000 Daltons and (iii) about 200,000 Daltons to about 500,000 Daltons. The two or more hydroxypropyl celluloses may be mixed in any suitable ratio to achieve the desired droplet viscosity. The viscosity of the dexmedetomidine composition solution or suspension can be measured using a Brookfield viscometer with a small sample adapter at a temperature of 25ƕC and may range from about 5 cps to about 3700 cps. For example, it may range from about 5 cps to about 500 cps, about 6 cps to about 200 cps, about 42 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 6 cps to about 100 cps or about 6 cps to about 50 cps. In some embodiments of the present disclosure, the viscosity of the dexmedetomidine composition solution or suspension is from about 6 cps to about 20 cps at 25ƕC and a shear rate of about 7 (1/s). [0240] In embodiments, there is provided a self-supporting, dissolvable, film, comprising: (i) about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt); (ii) one or more water-soluble polymers; (iii) a polyethylene oxide; and (iv) optionally, one or more pharmaceutically acceptable carriers, wherein the film is to be administered in a non-clinical setting by a caregiver or informant to acutely agitated schizophrenia or bipolar disorder patients. In embodiments, the agitation is mild to moderate. In embodiments, the agitation is not severe. [0241] In embodiments, there is provided a self-supporting, dissolvable, film, comprising: (i) about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt); (ii) one or more water-soluble polymers; (iii) a polyethylene oxide; and (iv) optionally, one or more pharmaceutically acceptable carriers, wherein the film is self-administered in a non-clinical setting by an acutely agitated schizophrenia or bipolar disorder patients. In embodiments, the agitation is mild to moderate. In embodiments, the agitation is not severe. [0242] In embodiments, there is provided a self-supporting, dissolvable, film, comprising: (i) about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt); (ii) one or more water-soluble polymers; (iii) a polyethylene oxide; and (iv) optionally, one or more pharmaceutically acceptable carriers, wherein the film is self-administered in a non-clinical setting by an acutely agitated schizophrenia or bipolar disorder patients. In embodiments, the agitation is mild to moderate. In embodiments, the agitation is not severe. [0243] In embodiments, there is provided a self-supporting, dissolvable, film, comprising: (i) about 90 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt); 43 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 (ii) one or more water-soluble polymers; (iii) a polyethylene oxide; and (iv) optionally, one or more pharmaceutically acceptable carriers, wherein the film is to be administered in a non-clinical-setting by a caregiver or informant to acutely agitated schizophrenia or bipolar disorder patients. In embodiments, the agitation is mild to moderate. In embodiments, the agitation is not severe. [0244] In embodiments, there is provided a self-supporting, dissolvable, film, comprising: (i) about 90 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt); (ii) one or more water-soluble polymers; (iii) a polyethylene oxide; and (iv) optionally, one or more pharmaceutically acceptable carriers, wherein the film is self-administered in a non-clinical-setting by an acutely agitated schizophrenia or bipolar disorder patients. In embodiments, the agitation is mild to moderate. In embodiments, the agitation is not severe. [0245] In embodiments, there is provided a self-supporting, dissolvable, film, comprising: (i) about 120 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt); (ii) one or more water-soluble polymers; (iii) a polyethylene oxide; and (iv) optionally, one or more pharmaceutically acceptable carriers, wherein the film is to be administered in a non-clinical-setting by a caregiver or informant to acutely agitated schizophrenia or bipolar disorder patients. [0246] In embodiments, the film is self-administered in a non-clinical-setting by an acutely agitated patient. In embodiments, the agitation is mild to moderate. In embodiments, the agitation is not severe. [0247] In embodiments, there is provided a self-supporting, dissolvable, film, comprising: (i) about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt); (ii) one or more water-soluble polymers; (iii) a polyethylene oxide; and (iv) optionally, one or more pharmaceutically acceptable carriers, 44 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 wherein the film is to be administered in a non-clinical setting by a caregiver or informant to acutely agitated schizophrenia or bipolar disorder patients. In embodiments, the film is self- administered in a non-clinical setting by the patient. In embodiments, the agitation is mild to moderate. In embodiments, the agitation is not severe. Medical kits: [0248] The present disclosure provides an individual unit dosage form provided as a kit comprising the compositions as described herein in a container with or without instructions for administration to a patient in need thereof. In embodiments, the composition is a film for oromucosal administration. to a patient in non-clinical settings. [0249] In embodiments, the present disclosure provides an individual unit oromucosal film dosage form provided as a kit comprising: (i) about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; and (ii) instructions for the administration of (i) to schizophrenia or bipolar disorder patients in need thereof, wherein the dosage form is administered for treating acute agitation in the patients in a non- clinical setting. [0250] In embodiments, the present disclosure provides an individual unit oromucosal film dosage form provided as a kit comprising: (i) about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; and (ii) instructions for the administration of (i) to schizophrenia or bipolar disorder patients in need thereof, wherein the dosage form is administered for treating mild to moderate agitation in the patients in a non-clinical setting. [0251] In embodiments, the present disclosure provides an individual unit oromucosal film dosage form provided as a kit comprising: (i) about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; and (ii) instructions for the administration of (i) to schizophrenia or bipolar disorder patients in need thereof, 45 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 wherein the dosage form is administered for treating mild to moderate agitation in the patients in a non-clinical setting. [0252] In embodiments, the present disclosure provides an individual unit oromucosal film dosage form provided as a kit comprising: (i) about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; and (ii) instructions for the administration of (i) to schizophrenia or bipolar disorder patients in need thereof, wherein the dosage form is administered for treating mild to moderate agitation in the patients in a non-clinical setting. [0253] In embodiments, the agitation is not severe. In embodiments, the dosage form is administered through a caregiver or informant to the patient. In embodiments, the dosage form is self-administered by the patient. [0254] In embodiments, the film dosage form comprises about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt). In embodiments, the film dosage form comprises about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt). In embodiments, the film dosage form comprises about 90 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt). In embodiments, the film dosage form comprises about 120 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt). In embodiments, the film dosage form comprises about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt). In embodiments, the dosage form is administered sublingually. In embodiments, the dosage form is administered buccally. In embodiments, the dosage form is administered gingivally. [0255] In embodiments, the kit comprises a package insert comprising instructions for using the compositions described herein for treatment of agitation in a patient. In embodiments, the agitation is acute. In embodiments, the agitation is mild to moderate. [0256] In embodiments, the total daily dose of dexmedetomidine is administered as a first dose and optional second dose. [0257] In embodiments, the kit comprising dexmedetomidine or pharmaceutically acceptable salt thereof is provided as two dosage forms for administration of one dosage form after the other dosage form separated by a suitable period of time (e.g., 2 hours or more). In 46 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 embodiments, the two film dosage forms may be packaged separately and provided in same or different containers. In embodiments, one or both dosage forms contain about 60 micrograms of dexmedetomidine hydrochloride. In embodiments, the dosage forms contain about 120 micrograms of dexmedetomidine hydrochloride. In embodiments, the dosage forms contain about 180 micrograms of dexmedetomidine hydrochloride. [0258] In embodiments, the kit comprises a container that includes, but is not limited to bottles, vials (e.g., dual chamber vials), syringes (such as single or dual chamber syringes) and test tubes. The container may be formed from a variety of materials such as glass or plastic. In embodiments, the kit may comprise a label (e.g., on or associated with the container) or a package insert. [0259] The label or the package insert may indicate that the compound contained therein may be useful or intended for treating acute agitation in a schizophrenia or bipolar disorder patients. SPECIFIC EMBODIMENTS [0260] Embodiment 1. A method of treating agitation in a schizophrenia or bipolar disorder patient in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 60 micrograms to the patient, wherein the patient is 18 years or older. [0261] Embodiment 2. A method of treating agitation in a schizophrenia or bipolar disorder patient in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a dose of about 80 micrograms to the patient, wherein the patient is 18 years or older. [0262] Embodiment 3. A method of treating acute agitation in a schizophrenia patient in a non- clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a total daily dose of about 60 micrograms to about 360 micrograms to the patient, wherein the patient is 18 years or older. [0263] Embodiment 4. A method of treating acute agitation in a bipolar disorder patient in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a total daily dose of about 60 micrograms to about 360 micrograms to the patient, wherein the patient is 18 years or older. [0264] Embodiment 5. A method of treating acute agitation in a schizophrenia patient in a non- clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable 47 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 salt thereof at a total daily dose of about 60 micrograms to about 180 micrograms to the patient, wherein the patient is 18 years or older. [0265] Embodiment 6. A method of treating acute agitation in a bipolar disorder patient in a non-clinical setting, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof at a total daily dose of about 60 micrograms to about 180 micrograms to the patient, wherein the patient is 18 years or older. [0266] Embodiment 7. The method of any one of embodiments 1 to 6, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered by the caregiver or informant of the patient. [0267] Embodiment 8. The method of embodiment 7, wherein the caregiver or informant is a family member, a family friend, social worker or any person employed by or for the patient. [0268] Embodiment 9. The method of any one of embodiments 1 to 6, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient. [0269] Embodiment 10. The method of embodiments 1, 2, or 4, wherein the bipolar disorder includes bipolar I disorder, bipolar II disorder and bipolar mania. [0270] Embodiment 11. The method of any one of embodiments 1 to 3, wherein the schizophrenia includes schizoaffective and schizophreniform disorder. [0271] Embodiment 12. The method of any one of embodiments 1 to 11, wherein the agitation is mild or moderate. [0272] Embodiment 13. The method of any one of embodiments 1 to 11, wherein the agitation is not severe. [0273] Embodiment 14. A method of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a total daily dose of about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant. [0274] Embodiment 15. A method of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient at a dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant. [0275] Embodiment 16. A method of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or 48 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 gingivally), to the patient at a dose of about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant. [0276] Embodiment 17. A method of treating acute agitation in a bipolar disorder patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a total daily dose of about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant. [0277] Embodiment 18. A method of treating acute agitation in a bipolar disorder patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient at a dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant. [0278] Embodiment 19. A method of treating acute agitation in a bipolar disorder patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient at a dose of about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant. [0279] Embodiment 20. A method of treating acute agitation in a schizophrenia patient in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self- administered by the patient. [0280] Embodiment 21. A method of treating acute agitation in a bipolar disorder patient in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self- administered by the patient. [0281] Embodiment 22. A method of treating acute agitation in a bipolar disorder patient in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient. [0282] Embodiment 23. A method of treating acute agitation in a bipolar disorder patient in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the 49 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient. [0283] Embodiment 24. A method of treating mild to moderate agitation in a schizophrenia or bipolar disorder patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally) to the patient a dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant. [0284] Embodiment 25. A method of treating mild to moderate agitation in a schizophrenia or bipolar disorder patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally) to the patient a dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant. [0285] Embodiment 26. A method of treating mild to moderate agitation in a schizophrenia or bipolar disorder patient in a non-clinical setting, comprising administering oromucosally (e.g., sublingually, buccally, or gingivally) to the patient a dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof through a caregiver or informant. [0286] Embodiment 27. A method of treating mild to moderate agitation in schizophrenia patient in a non-clinical setting, comprising adminstering an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient. [0287] Embodiment 28. A method of treating mild to moderate agitation in a schizophrenia patient with in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self- administered by the patient. [0288] Embodiment 29. A method of treating mild to moderate agitation in a schizophrenia patient with in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self- administered by the patient. 50 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 [0289] Embodiment 30. A method of treating mild to moderate agitation in a bipolar disorder (bipolar disorder I or bipolar disorder II) patient in a non-clinical setting, comprising administering an oromucosal dosage form comprising about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self-administered by the patient. [0290] Embodiment 31. A method of treating mild to moderate agitation in a bipolar disorder patient in a non-clinical setting, comprising adminsitering an oromucosal dosage form comprising about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self- administered by the patient. [0291] Embodiment 32. A method of treating mild to moderate agitation in a bipolar disorder patient in a non-clinical setting, comprising adminsitering an oromucosal dosage form comprising about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is self- administered by the patient. [0292] Embodiment 33. A method of treating acute agitation in a bipolar disorder (e.g., bipolar disorder I or bipolar disorder II) patient, comprising: (a) administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof under medical supervision for at least 8 hours (“phase 1”); and (b) administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a unit dose of about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof under non- medical supervision (non -clinical setting) for up to 12 weeks (“phase 2”). [0293] Embodiment 34. A method of treating acute agitation in a schizophrenia patient, comprising: (a) administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a unit dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof under medical supervision for at least 8 hours (“phase 1”). (b) administering oromucosally (e.g., sublingually, buccally, or gingivally), to the patient a unit dose of about 80 micrograms of dexmedetomidine or a pharmaceutically 51 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 acceptable salt thereof under non- medical supervision (non -clinical setting) for up to 12 weeks (“phase 2”). [0294] Embodiment 35. The method of any one of embodiments 1 to 34, wherein the patient experiences periodic episodes of agitation. [0295] Embodiment 36. The method of any one of embodiments 1 to 34, wherein the patient has a score of ^4 on at least 1 of the 5 items on the PEC at baseline. [0296] Embodiment 37. The method of any one of embodiments 1 to 34, wherein the patient has a total score of ^14 on 5 items on PEC. [0297] Embodiment 38. The method of any one of embodiments 1 to 34, wherein the patient has a score ^4 on C-SSRS. [0298] Embodiment 39. The method of any one of embodiments 1 to 34, wherein the patient experiences not more than 2 episodes of agitation in a week [0299] Embodiment 40. The method of any one of embodiments 1 to 34, wherein the patient is suffering from one or more psychiatric comorbidities. [0300] Embodiment 41. The method of any one of embodiments 1 to 34, wherein the patient is not suffering from one or more psychiatric comorbidities. [0301] Embodiment 42. The method of any one of embodiments 1 to 34, wherein the patient is not concurrently taking other medications. [0302] Embodiment 43. The method of any one of embodiments 1 to 34, wherein the patient is about 18 years to about 75 years old. [0303] Embodiment 44. The method of any one of embodiments 1 to 34, wherein the patient is about 75 years or older. [0304] Embodiment 45. The method of any one of embodiments 1 to 34, wherein the route of administration is oromucosal (e.g., sublingual, buccal or gingival). [0305] Embodiment 46. The method of embodiment 45, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered in an oromucosal dosage form selected from the group consisting of a film, wafer, patch, lozenge, gel, spray, tablet and liquid drops [0306] Embodiment 47. The method of embodiment 45, wherein the dosage form is a thin film. [0307] Embodiment 48. The method of embodiment 46 or 47, wherein the dosage form is a sublingual film. [0308] Embodiment 49. The method of embodiment 46 or 47, wherein the dosage form is a buccal film. 52 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 [0309] Embodiment 50. The method of embodiment 46 or 47, wherein the dosage form is a gingival film. [0310] Embodiment 51. The method of any one of the preceding embodiments, wherein dexmedetomidine or a pharmaceutically acceptable salt thereof is administered as a single dose per day. [0311] Embodiment 52. The method of any preceding embodiments, wherein the total daily dose of dexmedetomidine, or a pharmaceutically acceptable salt thereof (e.g., hydrochloride salt) is administered as a first and optional second dose. [0312] Embodiment 53. The method of embodiment 52, wherein the first dose is about 30 micrograms, about 40 micrograms, about 50 micrograms, about 60 micrograms, about 70 micrograms, about 80 micrograms, about 90 micrograms, about 100 micrograms, about 110 micrograms, about 120 micrograms or about 180 micrograms of dexmedetomidine hydrochloride. [0313] Embodiment 54. The method of embodiment 52 or 53, wherein the first dose is about 60 micrograms of dexmedetomidine hydrochloride. [0314] Embodiment 55. The method of embodiment 52 or 53, wherein the first dose is about 80 micrograms of dexmedetomidine hydrochloride. [0315] Embodiment 56. The method of embodiment 52, wherein the second dose is administered at least about 2 hours after administration of the first dose if there is no improvement in PEC score by more than 2 points. [0316] Embodiment 57. The method of embodiment 54 or 56, wherein the second dose is administered at least about 0.5 hour, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours, about 8 hours, about 8.5 hours, about 9 hours, about 9.5 hours, about 10 hours, about 10.5 hours, about 11 hours, about 11.5 hours, about 12 hours, about 12.5 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours or about 24 hours after administration of the first dose. [0317] Embodiment 58. The method of embodiment 52, 56, or 57, wherein the optional second dose is about 30 micrograms, about 40 micrograms, about 50 micrograms, about 60 micrograms, about 70 micrograms, about 80 micrograms, about 90 micrograms, about 100 micrograms, about 110 micrograms, about 120 micrograms, or about 180 micrograms of dexmedetomidine hydrochloride. 53 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 [0318] Embodiment 59. The method of embodiment 52 or 58, wherein the optional second dose is about 60 micrograms. [0319] Embodiment 60. The method of embodiment 52 or 58, wherein the optional second dose is about 80 micrograms. [0320] Embodiment 61. The method of any one of the preceding embodiments, wherein the administration of dexmedetomidine, a pharmaceutically acceptable salt thereof, or the oromucosal dosage comprising dexmedetomidine or a pharmaceutically acceptable salt thereof form produces anti-agitation effect within about 30 minutes after administration. [0321] Embodiment 62. The method of any one of the preceding embodiments, wherein the administration of dexmedetomidine, a pharmaceutically acceptable salt thereof, or the oromucosal dosage comprising dexmedetomidine or a pharmaceutically acceptable salt thereof form produces anti-agitation effect within about 90 minutes after administration. [0322] Embodiment 63. The method of any one of the preceding embodiments, wherein the administration of dexmedetomidine, a pharmaceutically acceptable salt thereof, or the oromucosal dosage comprising dexmedetomidine or a pharmaceutically acceptable salt thereof produces anti-agitation effect within about 120 minutes after administration. [0323] Embodiment 64. The method of any one of the preceding embodiments, wherein the agitation is treated without also inducing significant sedation. [0324] Embodiment 65. The method of any one of the preceding embodiments, wherein the treatment is effective with reduced or no side effects (e. g. cardiac or respiratory side effects). [0325] Embodiment 66. The method of any one of the preceding embodiments, wherein the clinical improvement in agitation is measured using PANSS, ACES, and/or CGI-I scales. [0326] Embodiment 67. The method of any one of the preceding embodiments, wherein the reduction in agitation is assessed by relative change in PEC score after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof. [0327] Embodiment 68. The method of any one of the preceding embodiments, wherein the reduction in agitation is assessed by relative change in modified CGI-S 4-point (0-3) scale after administration of dexmedetomidine or a pharmaceutically acceptable salt thereof. [0328] Embodiment 69. The method of any one of the preceding embodiments, wherein the patient achieves a mean change in PEC score of greater than -7 relative to baseline within 30 minutes of administration. 54 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 [0329] Embodiment 70. The method of any one of the preceding embodiments, wherein the patient achieves a CGI-I score improvement to about a 1 (very much improved) or about a 2 (much improved). [0330] Embodiment 71. The method of any one of the preceding embodiments, wherein the agitation is reduced to a 2 (moderate agitation), 3 (mild agitation) or 4 (normal behavior) 30 minutes after administration, as measured by the Agitation-Calmness Evaluation Scale (ACES). [0331] Embodiment 72. The method of any one of the preceding embodiments, wherein the decrease in the PEC, CGI-S and ACES scores is maintained for at least about 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, hours following administration. [0332] Embodiment 73. The method of any one of the preceding embodiments, wherein the single administration of dexmedetomidine treats agitation and maintains calming effect for at least 12 hours. [0333] Embodiment 74. The method of any one of the preceding embodiments, wherein the administration of dexmedetomidine provides improvement in duration of calming as measured using reduction in ACES score to 2 or more following administration of dexmedetomidine or a pharmaceutically acceptable salt thereof. [0334] Embodiment 75. The method of any one of the preceding embodiments, wherein the administration of dexmedetomidine provides improvement in the residual signs and symptoms of schizophrenia following administration of dexmedetomidine or a pharmaceutically acceptable salt thereof as measured by reduction in PEC score of greater than -2 relative to baseline. [0335] Embodiment 76. The method of any one of the preceding embodiments, wherein the impending episode of agitation is alerted to the caregiver or informant via Ecological Momentary Assessment (EMA) device or other remote compatible device. [0336] Embodiment 77. The method of any one of the preceding embodiments, wherein the reduction in agitation is alerted to the caregiver or informant via Ecological Momentary Assessment (EMA) device or other remote compatible device. [0337] Embodiment 78. The method of any one of the preceding embodiments, wherein the reduction in agitation is assessed after a suitable period of time such as 0.5 hours, 1 hour, 2 hours, 4 hours or 6 hours after administration of the first dose of dexmedetomidine administration 55 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 [0338] Embodiment 79. The method of any one of the preceding embodiments, wherein a rescue medication is optionally administered to the patient after the second dose of dexmedetomidine. [0339] Embodiment 80. The method of any one of the preceding embodiments, wherein the reduction in agitation is assessed before the administration of rescue medication in the patient. [0340] Embodiment 81. The method of embodiment 76 or 77, wherein the method comprises a wearable device (or a wearable sensor) in contact with the patient. [0341] Embodiment 82. The method of embodiment 81, wherein the wearable device (or a wearable sensor) is selected from iPhone (BYOD or provisioned), accelerometers, gyroscopes, portable devices, digital devices, smart fabrics, bands and actuators like an Apple watch or iWatch, patch such as MC10 Patch, sensors like Microsoft Kinect and the like. [0342] Embodiment 83. The method of embodiment 81 or 82, wherein the wearable device may be embodied with the patient as a bracelet, anklet, shoe, armband, thigh band or a mitten. [0343] Embodiment 84. The method of embodiment 81 or 82, wherein the wearable device is wrist worn multi-sensor device with networking capability (e.g., wearable watch such as Apple watch). [0344] Embodiment 85. The method of embodiment 76 or 77, wherein the EMA device comprises a smartphone or a tablet with an application installed to report the patient’s observations. [0345] Embodiment 86. The method of embodiment 85, wherein the application on the caregiver’s or informant’s EMA device provides prompt to report on absence or presence of episode of agitation [0346] Embodiment 87. The method of embodiment 85, wherein the caregiver or informant reports information on frequency or number of episodes of agitation on the application installed on EMA device. [0347] Embodiment 88. The method of embodiment 81, wherein the wearable device detects the severity of the agitation (e.g., mild, moderate or elevated). [0348] Embodiment 89. The method of embodiment 81, wherein the wearable device predicts the probability of specific patient to move from mild to moderate to elevated agitation. [0349] Embodiment 90. The method of embodiment 81, wherein the wearable device predicts a severity change probability. 56 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 [0350] Embodiment 91. The method of embodiment 90, wherein the severity change probability can be measured using at least one machine learning model’s (e.g., an agitation state detection model’s) predictions to create and/or define a chain of events. [0351] Embodiment 92. The method of any one of the preceding embodiments, wherein the patient, caregiver, or informant records the observations in an agitation episode diary for each episode of agitation. [0352] Embodiment 93. The method of any one of the preceding embodiments, wherein the agitation episode diary comprises questions based on safety information, use of emergency services, use of other concomitant medications and sleepiness. [0353] Embodiment 94. The method of any one of the preceding embodiments, wherein the agitation episode diary comprises questions based on efficacy information after taking study medication (Yes/No), mCGI-S, CGI-C, the agitation behaviors scale (Informant only), use of study medication or use of rescue medication. [0354] Embodiment 95. An oromucosal dosage form for the treatment of acutely agitated schizophrenia or bipolar disorder patients in a non-clinical setting, comprising: (i) about 5 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) one or more mucoadhesive agents; and (iii) one or more pharmaceutically acceptable excipients or carriers, wherein the dosage form disintegrates within about 5 seconds to about 10 minutes upon contact with an oral mucosa. [0355] Embodiment 96. An oromucosal dosage form for the treatment of acutely agitated schizophrenia or bipolar disorder patients in a non-clinical setting, comprising: (i) about 60 micrograms to about 300 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) one or more mucoadhesive agents; and (iii) one or more pharmaceutically acceptable excipients or carriers, wherein the dosage form disintegrates within about 5 seconds to about 10 minutes upon contact with an oral mucosa. [0356] Embodiment 97. An oromucosal dosage form for the treatment of acutely agitated schizophrenia or bipolar disorder patients in a non-clinical setting, comprising: (i) about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; 57 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 (ii) one or more mucoadhesive agents; and (iii) one or more pharmaceutically acceptable excipients or carriers, wherein the dosage form disintegrates within about 5 seconds to about 10 minutes upon contact with an oral mucosa. [0357] Embodiment 98. An oromucosal dosage form for the treatment of acutely agitated schizophrenia or bipolar disorder patients in a non-clinical setting, comprising: (i) about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) one or more mucoadhesive agents; and (iii) one or more pharmaceutically acceptable excipients or carriers, wherein the dosage form disintegrates within about 5 seconds to about 10 minutes upon contact with an oral mucosa. [0358] Embodiment 99. An oromucosal dosage form for the treatment of acutely agitated schizophrenia or bipolar disorder patients in a non-clinical setting, comprising: (i) about 120 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) one or more mucoadhesive agents; and (iii) one or more pharmaceutically acceptable excipients or carriers, wherein the dosage form disintegrates within about 5 seconds to about 10 minutes upon contact with an oral mucosa. [0359] Embodiment 100. An oromucosal dosage form for the treatment of acutely agitated schizophrenia or bipolar disorder patients in a non-clinical setting, comprising: (i) about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; (ii) one or more mucoadhesive agents; and (iii) one or more pharmaceutically acceptable excipients or carriers, wherein the dosage form disintegrates within about 5 seconds to about 10 minutes upon contact with an oral mucosa. [0360] Embodiment 101. The oromucosal dosage form of embodiment 95 to 100, wherein non- clinical setting is at home or group home, assisted living facility, correctional facility, hospice or long-term care facility. [0361] Embodiment 102. The oromucosal dosage form of embodiment 95 to 100, wherein the dosage form is self-administered by the patient. 58 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 [0362] Embodiment 103. The oromucosal dosage form of any one of embodiments 95 to 100, wherein the dosage form is administered by the caregiver or informant. [0363] Embodiment 104. The oromucosal dosage form of any one of embodiments95 to 100, wherein the oromucosal dosage form is a tablet, capsules, patch, film, sachet, wafer, powder, minitablet, pellet, paste, gel, ointment, cream, drops, liquid (e.g., solution, suspension or emulsion), spray, microspheres or nanospheres. [0364] Embodiment 105. The oromucosal dosage form of embodiment 104, wherein the dosage form is an oromucosal film (sublingual or buccal or gingival). [0365] Embodiment 106. The oromucosal dosage form of embodiment 105, wherein the dosage form is an oromucosal tablet. [0366] Embodiment 107. The oromucosal dosage form of embodiment 106, wherein the tablet is lyophilized. [0367] Embodiment 108. The oromucosal dosage form of any one of embodiments 95 to 107, wherein the dosage form is conveniently delivered on an "as needed basis" in one, two or more doses per day to the patient. [0368] Embodiment 109. The oromucosal dosage form of any one of embodiments 95 to 107, wherein the dosage form effectively treats agitation in a patient without causing significant sedation. [0369] Embodiment 110. A self-supporting, dissolvable, film, comprising: (i) about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt); (ii) one or more water-soluble polymers; (iii) a polyethylene oxide; and (iv) optionally, one or more pharmaceutically acceptable carriers, wherein the film is to be administered in a non-clinical setting by a caregiver or informant to acutely agitated schizophrenia or bipolar patients. [0370] Embodiment 111. A self-supporting, dissolvable, film, comprising: (i) about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt); (ii) one or more water-soluble polymers; (iii) a polyethylene oxide; (iv) optionally, one or more pharmaceutically acceptable carriers, 59 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 wherein the film is self-administered in a non-clinical setting by acutely agitated schizophrenia or bipolar disorder patients. [0371] Embodiment 112 A self-supporting, dissolvable, film, comprising: (i) about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt); (ii) one or more water-soluble polymers; (iii) a polyethylene oxide; (iv) optionally, one or more pharmaceutically acceptable carriers, wherein the film is self-administered in a non-clinical setting by acutely agitated schizophrenia or bipolar disorder patients. [0372] Embodiment 113. A self-supporting, dissolvable, film, comprising: (i) about 80 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt); (ii) one or more water-soluble polymers; (iii) a polyethylene oxide; and (iv) optionally, one or more pharmaceutically acceptable carriers wherein the film is to be administered in a non-clinical setting by a caregiver or informant to acutely agitated schizophrenia or bipolar patients. [0373] Embodiment 114. A self-supporting, dissolvable, film, comprising: (i) about 120 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt); (ii) one or more water-soluble polymers; (iii) a polyethylene oxide; and (iv) optionally, one or more pharmaceutically acceptable carriers, wherein the film is to be administered in a non-clinical setting by a caregiver or informant to acutely agitated schizophrenia or bipolar disorder patients. [0374] Embodiment 115. A self-supporting, dissolvable, film, comprising: (i) about 120 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof (e.g., the hydrochloride salt); (ii) one or more water-soluble polymers; (iii) a polyethylene oxide; and (vi) optionally, one or more pharmaceutically acceptable carriers, 60 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 wherein the film is self-administered in a non-clinical setting by acutely agitated schizophrenia or bipolar disorder patients. [0375] Embodiment 116. An individual unit oromucosal film dosage form provided as a kit comprising: (i) about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; and (ii) instructions for the administration of (i) to schizophrenia or bipolar disorder patients in need thereof, wherein the dosage form is administered for treating acute agitation in the patients in a non- clinical setting. [0376] Embodiment 117. An individual unit oromucosal film dosage form provided as a kit comprising: (i) about 60 micrograms to about 360 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof; and (ii) instructions for the administration of (i) to schizophrenia or bipolar disorder patients in need thereof, wherein the dosage form is administered for treating mild to moderate agitation in the patients in a non-clinical setting. [0377] Embodiment 118. The kit of embodiment 116 or 117, wherein the dosage form is administered through a caregiver or informant to the patients. [0378] Embodiment 119. The kit of embodiment 116 or 117, wherein the dosage form is self- administered by the patients. [0379] Embodiment 120. The kit of embodiment 116, wherein the kit comprises a package insert comprising instructions for using the dosage forms for treatment of acute agitation in a patient. [0380] Embodiment 121. The kit or the oromucosal dosage form of any one of embodiments 97 to 120, wherein the bipolar disorder includes bipolar I disorder, bipolar II disorder and bipolar mania. [0381] Embodiment 122. The kit or the oromucosal dosage form of any one of embodiments 97 to 120, wherein the schizophrenia includes schizoaffective and schizophreniform disorder. [0382] Embodiment 123. The kit of any one of embodiments 96 to 122, wherein the kit comprises dexmedetomidine or pharmaceutically acceptable salt thereof provided as two 61 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 dosage forms for administration of one dosage form after the other dosage form separated by a suitable period of time. [0383] Embodiment 124. The kit of embodiment 123, wherein the two film dosage forms are packaged separately and provided in same containers. [0384] Embodiment 125. The kit of embodiment 123, wherein the two film dosage forms are packaged separately and provided in different containers. [0385] Embodiment 126. The kit of any one of embodiments 116 to 125, wherein dexmedetomidine or pharmaceutically acceptable salt thereof is present in an amount of about 60 micrograms, about 70 micrograms, about 80 micrograms, about 90 micrograms, about 100 micrograms, about 110 micrograms, about 120 micrograms or about 180 micrograms. [0386] Embodiment 127. The kit of any one of embodiments 116 to 126, wherein dexmedetomidine or pharmaceutically acceptable salt thereof is present in an amount of about 60 micrograms. [0387] Embodiment 128. The kit of any one of embodiments 116 to 126, wherein dexmedetomidine or pharmaceutically acceptable salt thereof is present in an amount of about 80 micrograms. [0388] Embodiment 129. The kit of any one of embodiments 116 to 128, wherein the film dosage forms are administered sublingually, buccally, or gingivally. [0389] Embodiment 130. The method, the oromucosal dosage form or the kit of any one of the preceding embodiments, wherein the agitation is mild to moderate. [0390] Embodiment 131. The method, the oromucosal dosage form or the kit of any one of the preceding embodiments, wherein the agitation is not severe. [0391] The details of the disclosure, its objects and advantages are explained hereunder in greater detail in relation to non-limiting exemplary illustrations. EXAMPLES Example 1: To determine the efficacy and safety of Dexmedetomidine hydrochloride sublingual film evaluated for at-home use in a Multisite Double-Blind Placebo Controlled Trial for agitation associated with Schizophrenia and Bipolar Disorder OBJECTIVES: Primary objectives: Part 1: 62 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 [0392] To determine if a 60 micrograms dose of dexmedetomidine hydrochloride sublingual film, effectively reduces symptoms of agitation assessed using the Positive and Negative Syndrome Scale – Excited Component (PEC) change from baseline compared to change from baseline with placebo. Part 2: [0393] To assess the safety of dexmedetomidine hydrochloride sublingual film when used in an at-home environment based on serious adverse events (SAEs), and treatment-emergent adverse events (TEAEs) collected by both the Informant and the clinical Investigator. Secondary objectives: Part 1: • To determine the overall clinical improvement after study treatment administration as measured by the Clinical Global Impression – Improvement Scale (CGI-I). • To determine the overall clinical improvement after drug administration as measured by the modified Clinical Global Impression – Severity Scale (mCGI- S) administered by the investigator. • To describe the duration of calming as measured by PEC and ACES. • To determine the safety profile of dexmedetomidine hydrochloride sublingual film assessed by TEAEs, serious TEAEs, vital signs measurements, Electrocardiograms (ECGs), and clinical laboratory results. • To describe the overall tolerability in terms of treatment-emergent adverse event reports. Part 2: • To assess reduction of signs and symptoms of agitation based on the modified CGI-S scale at 2 hours following study treatment administration or before administering rescue medication whichever comes first. • To determine the number / frequency of agitation episodes and the number and frequency of those that are treated in the at-home environment. • To determine the number of interactions with emergency services (specifically hospitalization, emergency room visits, urgent care clinic visits and law enforcement intervention) because of agitation episodes. Exploratory objectives: 63 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 Part 1: • To describe the patient’s opinion on taste, acceptability, and likability of dexmedetomidine hydrochloride sublingual film. • To assess patient satisfaction with dexmedetomidine hydrochloride sublingual film in the treatment of episodes of agitation. The Treatment Satisfaction Questionnaire for Medication (TSQM) will be administered for this purpose at the end of the treatment period. Part 2: • To assess patient satisfaction with dexmedetomidine hydrochloride sublingual film in the treatment of episodes of agitation. The Treatment Satisfaction Questionnaire for Medication (TSQM) will be administered for this purpose at the end of the treatment period. Primary Endpoints • Part 1: Change in PEC score from Baseline as compared to placebo at 2 hours after drug administration. • Part 2: Comparison of Serious Adverse Events (SAEs) and TEAEs as compared to placebo. Secondary Endpoints Part 1: • The CGI-I will assess overall clinical improvement after drug administration. • The mCGI-S will assess overall clinical improvement after drug administration. • The duration of calming will be measured by the PEC and ACES. • The safety profile of dexmedetomidine hydrochloride sublingual film will be measured by reports of adverse events (AE), vital signs measurements, ECGs and clinical laboratory results. • The overall tolerability of oral film will be assessed by TEAE reports and local site (oral/sublingual) tolerability Part 2: • Reduction of signs and symptoms of agitation will be assessed by the modified CGI-S scores at 2 hours following the drug administration. 64 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 • Number and frequency of agitation episodes. • Number of interactions with emergency services related to agitation episodes that are reported by the Informant. Exploratory Endpoints Part 1: • Patients’ opinion on taste, acceptability, and likability of study treatment will be assessed with a likability questionnaire. • Patient satisfaction with dexmedetomidine hydrochloride sublingual film in the treatment of episodes of agitation will be assessed with the TSQM. Part 2: • Patient satisfaction with dexmedetomidine hydrochloride sublingual film in the treatment of episodes of agitation will be assessed with the TSQM. STUDY DESIGN: [0394] This is a randomized, double-blind, placebo-controlled, 2-part, Phase III study to assess efficacy, safety and tolerability of a 60 micrograms dose of dexmedetomidine hydrochloride sublingual film dosing in adult (18-75 years old) males and females with agitation episodes associated with a primary diagnosis of bipolar I disorder, bipolar II disorder, schizophrenia, schizoaffective disorder, or schizophreniform disorder. Part 1 of the study is a one-day, in- clinic treatment, and post-treatment observation period with patients experiencing an acute episode of agitation. Part 2 of the study is a 12-week study to determine the safety of dexmedetomidine hydrochloride sublingual film when used in an at-home setting when treating episodes of agitation in patients. [0395] Each patient may only participate in one part of the study. All patients enrolled will be individuals who have never previously received a dose of dexmedetomidine hydrochloride sublingual film or IGALMITM. [0396] Part 1: In-clinic period Setting Conduct: The in-clinic study period will randomize patients 1:1 to receive 60 mcg of dexmedetomidine hydrochloride sublingual film or a matching placebo. Eligible patients may be identified in outpatient clinics, mental health centers, psychiatric or medical emergency services including medical/psychiatric observation units, or as newly admitted patients to a hospital setting for acute agitation or already hospitalized for their underlying, primary psychiatric disorder. Patients will be domiciled in 65 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 clinical research setting or hospitalized to remain under medical supervision while undergoing screening procedures to assess eligibility, during treatment, and during the post-treatment observation period of at least 8 hours. [0397] While randomization will not be formally stratified, the randomization scheme will be designed so that no more than 70% of the patients in each arm of the study will have a primary diagnosis of bipolar disorder (bipolar I or bipolar II) or schizophrenia (including schizoaffective and schizophreniform disorder). [0398] Upon confirmation of eligibility, patients will be randomized to receive either 60 micrograms of dexmedetomidine hydrochloride sublingual film or matching placebo. When dosing, patients will be instructed on how to take the dexmedetomidine hydrochloride film sublingually, and that they should retain it in the sublingual cavity until dissolved. The patient will self-administer under the supervision of a trained staff member. If the patient is unable to self-administer, the event will be recorded, and the patient's participation will conclude. [0399] Patients are also evaluated for local irritation in the film’s placement area. Efficacy and safety assessments are conducted periodically before and after dosing. [0400] All efforts should be made to have all the protocol-defined assessments completed for the patient. [0401] If the patient’s status warrants (as determined by the Investigator), a rescue medication can be administered. The rescue medication can be either a benzodiazepine (lorazepam maximum dose of 4 milligram (mg) or oxazepam maximum dose of 60 mg) or any antipsychotic except clozapine, pimozide, or prochlorperazine, with a maximum dose approximately equivalent to 300 mg of chlorpromazine as specified by BioXcel and as chosen by the Investigator. [0402] The patient must remain in the clinic for a minimum of 8 hours of observation following administration of study treatment [0403] Efficacy, safety, tolerability, and pharmacokinetics (PK) will be measured throughout the treatment period at various times. (Please refer to the Table 1: Part 1 Schedule of Events for details). [0404] Part 2: Community (At-home) Setting Conduct: The at-home study period will randomize patients 1:1 to receive 60 micrograms of dexmedetomidine hydrochloride sublingual film or matching placebo film when an episode of agitation occurs at home. Eligible patients will be individuals who experience periodic episodes of agitation related to a primary diagnosis of bipolar disorder or schizophrenia. In addition, patients must have a reliable 66 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 informant who can participate in the study conduct at times when an episode of agitation is treated with the study treatment and during monthly clinic visits. While randomization is not formally stratified, the randomization scheme is designed so that no more than 70% of the patients in each arm of the study have a primary diagnosis of bipolar disorder (bipolar I or bipolar II) or schizophrenia (including schizoaffective and schizophreniform disorder). [0405] Upon confirmation of eligibility, patients and informants will be instructed on how the patient is to take the study treatment sublingually, and that they should retain the study treatment in the sublingual cavity until dissolved. The patient will self-administer under the supervision of the informant. If the patient is unable to self-administer during their first episode of agitation where treatment is attempted, the event will be recorded, and the patient's participation will conclude. Informants and patients will also be trained at Screening on their responsibilities during the study, rating the severity of agitation using the mCGI-S, and the circumstances in which the Informant can recommend that a patient self-administers a dose of study treatment and rescue medication. Patients are trained as to when they can take study treatment and rescue medication on their recognizance. Ideally, the informant will be present when study treatment is taken, however the patient may self-administer study treatment when the Informant is not present, if the patient feels that they need to do so. [0406] The Informant is responsible for recording the onset time and cessation time of the agitation event time via an ecological momentary assessment (EMA) application, along with the time study treatment and rescue medication (if needed) is taken. At several timepoints (see Table 3: At Home Informant Assessments), the Informant and the patient rate will be asked to rate severity of the agitation episode; the Informant will record both ratings in the EMA application. [0407] The Informant also records all adverse events (AEs) reported by the patient during the 8 hours following study treatment administration or 8 hours following rescue medication administration (whichever comes last) as well as any medications taken by the patient within 4 hours prior to dosing and within 4 hours post-dose. [0408] The Informant also records any interactions with emergency services (specifically, hospitalizations, emergency room visits, urgent care clinic visits, interventions by other emergency services such as ambulance services, and interventions by law enforcement) via the EMA application. [0409] In addition, the Informant is prompted by the EMA application once daily to ask if an agitation episode occurred that was not reported when it occurred, and to ask if any emergency 67 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 services interventions were required for such an unreported episode. The Informant and patient will be prompted by EMA application twice daily to provide current mCGI-S rating (see Table 3, At Home Patient and Informant Assessments). [0410] The patient and Informant return to the clinic for follow-up visits one month and two months (28 and 56 days) after the Baseline visit, as well as for a final study visit at the end of the 3-month (84 days) study period (see Table 2: Part 2 Schedule of Events). [0411] At the time of randomization, and at Follow-Up Visits 1 and 2, the patient will be dispensed two packages, each containing one 60 mcg strip of Dexmedetomidine sublingual film or matching placebo. If both packages are used before the next scheduled clinic visit, the patient or Informant will need to return to the clinic to obtain two additional packages. [0412] The Investigator will also provide the patient with a prescription for a rescue medication of the Investigator’s choosing. The rescue medication can be either a benzodiazepine (lorazepam maximum dose of 4 mg or oxazepam maximum dose of 60 mg) or any antipsychotic except clozapine, pimozide, or prochlorperazine, with a maximum dose approximately equivalent to 300 mg of chlorpromazine as specified by BioXcel and as chosen by the Investigator. [0413] Number of patients (planned): In Part 1 of the study approximately 200 patients will be enrolled at up to 20 study sites in the United States. In Part 2 approximately 250 patients - Informant dyads will be enrolled at up to 20 study sites in the United States. The same sites will participate in Part 1 and Part 2. A patient may only participate in one part of the study (Part 1 or Part 2). Patients in both parts of the study have not previously been treated with dexmedetomidine sublingual film or IGALMITM. DIAGNOSIS AND MAIN CRITERIA FOR ELIGIBILITY: Stage 1: [0414] Inclusion Criteria (Parts 1 and 2) 1. Male and female patients 18 to 75 years old, inclusive. 2. Patients who can read, understand, and provide written informed consent. 3. Patients who meet DSM-5/5-TR criteria for a primary diagnosis of bipolar I or bipolar II disorder, schizophrenia, schizoaffective or schizophreniform disorder. 4. Patients who, in the opinion of the Principal Investigator, are in good general health prior to study participation based on a detailed medical history, physical examination, 12-lead ECG with rhythm strip, blood chemistry profile, hematology, and urinalysis. 68 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 5. Female participants, if of child-bearing potential and sexually active, and male participants, if sexually active with a partner of child-bearing potential, agree to use a medically acceptable and effective birth control method throughout the study and for one week following the end of the study. Medically acceptable methods of contraception that may be used by the participant and/or his/her partner include abstinence, birth control pills or patches, diaphragm with spermicide, intrauterine device (IUD), condom with foam or spermicide, vaginal spermicidal suppository, surgical sterilization and progestin implant or injection. Prohibited methods include: the rhythm method, withdrawal, condoms alone, or diaphragm alone. [0415] Additional Inclusion Criteria for patients to be enrolled into Part 1: 6. Patients who are judged to be clinically agitated at Screening and Baseline with a total score of ^ 14 on the 5 items (poor impulse control, tension, hostility, uncooperativeness, and excitement) comprising the PANSS)- Excited Component (PEC). 7. Patients who have a score of ^4 on at least 1 of the 5 items on the PEC at Baseline. [0416] Additional Inclusion Criteria for patients to be enrolled into Part 2: 8. Based on history, in the past month patients must have had at least one clinical presentation of agitation requiring an intervention (e.g., receipt of PRN medication for the episode, clinic visit, emergency room visit, emergency medical services intervention, law enforcement intervention). 9. The patient can understand and follow the study procedures, including completing the EMA application ratings. 10. The patient has an informant who can read and write and provide written informed consent and follow the study procedures including completing the EMA application ratings and other EMA application required procedures during the study. Finally, the Informant must be able to accompany the participant to the monthly clinic visits and be interviewed by the Investigator for the Investigator to rate the average mCGI-S for the interval since the preceding clinic mCGI-S rating. [0417] Exclusion Criteria (Parts 1 and 2) 1. Patients with serious or unstable medical illnesses. These include current hepatic (moderate-severe hepatic impairment), renal, gastroenterological, respiratory, 69 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 cardiovascular (including ischemic heart disease, congestive heart failure), endocrinologic, or hematologic disease. 2. Psychiatric comorbidities are generally allowed; however, substance use disorders (within part two years) are exclusionary if the substance involved is other than nicotine or caffeine. Mild cannabis use is allowed. Tetrahydrocannabinol (THC) in the urine is not exclusionary if the Investigator judges the severity of the cannabis use disorder as mild. 3. The Investigator believes the patient has a history of episodes of agitation that are due to substance use. 4. A diagnosis of antisocial personality disorder, borderline personality disorder, or narcissistic personality disorder that predated the diagnosis of schizophrenia or bipolar disorder, or in the opinion of the investigator is independent of the signs and symptoms of the schizophrenia or bipolar disorder. 5. Suicidality as assessed with a C-SSRS (Columbia Suicide Severity Rating Scale). A score (assessed as meeting criteria for Scale items) of ^4 is exclusionary. Clinically significant risk of risk of suicide based on the investigator’s clinical opinion or a history of an actual suicide attempt in the last year are also exclusionary. 6. Self-injurious behavior that is active. 7. Female patients who have a positive pregnancy test at screening or are breastfeeding. 8. Patients currently treated with alpha-1 noradrenergic blockers (terazosin, doxazosin, tamsulosin, alfuzosin, or prazosin), alpha-2 adrenergic agonists, or other prohibited medications. 9. Patients who have hydrocephalus, seizure disorder, or history of significant head trauma, stroke, transient ischemic attack, subarachnoid bleeding, brain tumor, encephalopathy, meningitis, Parkinson’s disease, or focal neurological findings. 10. History of syncope or other syncopal attacks, current evidence of hypovolemia, orthostatic hypotension, a decrease in SBP of ^20 mmHg or a decrease in DBP of ^10 mmHg at 1 or 3 minutes after standing from 5 minutes of supine rest, a screening and baseline heart rate of <55 beats per minutes or systolic blood pressure <100 mmHg or diastolic BP <60 mmHg. 11. Patients with laboratory or ECG abnormalities considered clinically significant by the investigator or qualified designee [Advanced heart block (second-degree or above 70 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 atrioventricular block without pacemaker), diagnosis of Sick sinus syndrome] that would have clinical implications for the patient's participation in the study. 12. Patients with known personal or family history of genetic long QT syndrome. 13. Patients who have received investigational drug within 30 days prior to study start (30 days prior to initial dose in Stage 1; 30 days prior to Day 0 in Stage 2). 14. Patients who have previously received dexmedetomidine hydrochloride sublingual film in either a clinical trial or via prescription (under the trade name IGALMI). 15. Patients considered by the investigator to be an unsuitable candidate for receiving dexmedetomidine, e.g., patients with a history of allergic reactions to dexmedetomidine or considered to be unsuitable for participating in the study for any reason. [0418] Additional Exclusion Criteria for patients to be enrolled into Part 1: 16. Patients with agitation caused by acute intoxication, including positive identification of alcohol by breathalyzer or drugs of abuse (with the exception of THC) during urine screening. 17. Use of benzodiazepines or other hypnotics or antipsychotic drugs in the 4 hours before study treatment. TEST PRODUCT, DOSE, AND MODE OF ADMINISTRATION: Product: [0419] The product is a thin film formulation of dexmedetomidine for sublingual (SL) or buccal (BL) administration. Dosing delivers 60 micrograms of dexmedetomidine. The product is a small, solid-dose film formulation, approximately 286 mm2 in area and 0.7 mm thick, designed to completely dissolve in the sublingual space within 1-3 minutes. Patients will receive a single film strip for sublingual placement in the oral cavity. [0420] Reference therapy, dosage, and mode of Administration: Matching placebo films to be taken sublingually as described above. Duration of Treatment: • Part 1: 8 hours • Part 2: 12 weeks Criteria for Evaluation: Part 1: 71 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 [0421] Efficacy: Assessment of efficacy for acute agitation is based primarily on the Positive and Negative Syndrome Scale – Excited Component (PEC). The PEC comprises 5 items associated with agitation: poor impulse control, tension, hostility, uncooperativeness, and excitement; each scored 1 (minimum) to 7 (maximum). The PEC, the sum of these 5 subscales, thus ranges from 5 to 35. [0422] Overall agitation and sedation are evaluated with the Agitation-Calmness Evaluation Scale (ACES), where 1 indicates marked agitation; 2 - moderate agitation; 3 - mild agitation; 4 - normal behavior; 5 - mild calmness; 6 - moderate calmness; 7 - marked calmness; 8 - deep sleep; and 9 – unarousable. [0423] The overall clinical improvement in agitation in response to treatment will also be measured by the Clinical Global Impressions – Improvement (CGI-I). CGI-I scores range from 1 to 7: 0=not assessed (missing), 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, 7=very much worse. [0424] The overall agitation clinical improvement in response to treatment is also measured with the mCGI-S scale administered by the Investigator. mCGI-S scores range from 0 to 3: 0=no agitation, 1=mild agitation, 2=moderate agitation, 3=severe agitation. [0425] Safety and tolerability assessments: AEs, clinical laboratory tests, ECG, percent oxygen saturation measured by pulse oximetry, and vital signs (including under orthostatic stress) will be monitored for tolerability and safety assessment. All observed and volunteered AEs will be recorded. The relationship of AEs to the study treatment will be graded as not related, unlikely/remotely related, possibly related, probably related or definitely related by the investigators. Vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate will be monitored both at rest and under orthostatic stress. The application site will be inspected for any signs of local irritation. Clinical laboratory analytes are assayed, and urinalyses are performed. [0426] Additional Assessments: Demographics, medical and psychiatric history, smoking history, prior and concomitant medications, physical examination, pregnancy. [0427] Pharmacokinetics: A sparse PK sampling of plasma concentrations at specified timepoints will be reported. A population PK/PD analysis of plasma concentration vs. clinical response will be explored using a separate Statistical Analysis Plan (SAP) and reported separately. A graphical assessment of PK vs. vital signs and other potential PD parameters may also be explored. Part 2: 72 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 [0428] Safety and tolerability assessments: AEs, clinical laboratory tests, ECG, pulse oximetry, and vital signs are monitored for tolerability assessment at clinic visits. The Informant collects AEs during the 8 hours following the study treatment or 8 hours after the rescue medication (if taken), whichever comes last. All observed and volunteered AEs are recorded by the Informant via the EMA application during these 8 hours. In addition, the Investigator will assess and record additional AEs at all in-clinic visits. The relationship of AEs to the study treatment is graded as not related, unlikely/remotely related, possibly related, probably related, or definitely related by the Investigator. Vital signs, including SBP, DBP, at rest and under orthostatic stress, and heart rate is monitored during the monthly clinic visits. ECGs are obtained at these clinic visits. Blood for clinical laboratory assays is obtained during clinic visits. Finally, the application site is inspected for any signs of local irritation during clinic visits. [0429] Efficacy: The mCGI-S, as rated by both the Informant and the patient, assesses efficacy in Part 2. The Informant’s ratings are primary. This modified scale is expected to have greater reliability between and within raters without necessary psychiatric training to complete a PEC rating. [0430] Additional Assessments: Demographics, medical and psychiatric history, smoking history, prior and concomitant medications, physical examination, pregnancy, duration of agitation episodes and emergency services interventions. [0431] Statistical Plan: [0432] General: In general, summary statistics (number, mean, standard deviation, median, minimum, and maximum values for continuous variables, and number and percentage of subjects in each category for categorical variables) will be provided by treatment group for evaluated variables. All statistical tests and confidence intervals, unless stated otherwise, are 2-sided, and will be set at alpha (Į)=0.05. [0433] Efficacy Analyses: The primary efficacy endpoint for Part 1 is the absolute change from baseline in the PEC total score at 2 hours post-dose. The null and alternative hypotheses to be tested are stated as H01: ǻ Dexmedetomidine sublingual film_60 = ǻPBO and HA1: ǻ Dexmedetomidine sublingual film _60
Figure imgf000075_0001
ǻPBO where ǻ Dexmedetomidine sublingual film _60 denotes the change from baseline in the PEC at 2 hours post-dose in the Dexmedetomidine sublingual film 60 mcg group and ǻPBO denotes the change from baseline in the PEC at 2 hours post-dose in the placebo group. This hypothesis will be tested using a mixed model repeated measures (MMRM) model. 73 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 [0434] Safety Analyses: Safety data analysis will be conducted on all subjects receiving at least 1 dose of study treatment. The number and percentage of subjects experiencing 1 or more AEs will be summarized by treatment, relationship to study drug, and severity. AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) terminology. Listings of subjects who experience withdrawal due to an AE, serious adverse event (SAE) and/or death will be presented. Laboratory parameters will be summarized by treatment using descriptive statistics and data listings of clinically significant abnormalities. Vital signs and ECG data will be summarized by changes from baseline values using descriptive statistics. [0435] Sample Size Determination: The sample size of Part 1 was based on an assumed mean difference between active Dexmedetomidine sublingual film and placebo in the PEC score at 2 hours of 2.0 with a common standard deviation of 5.00. With these assumptions, 200 patients assigned to drug and placebo in a 1:1 ratio provide 80% power to detect a significant difference with Į=0.05. [0436] A blinded re-estimation of the sample size will be computed after 40% of subjects (n=80) have completed Part 1 of the study. The pooled standard deviation for both the placebo and the Dexmedetomidine sublingual film treatment groups will be completed by an unblinded statistician with the appropriate firewall between any person or entity involved in any way with the study. The sample size computation will again use a treatment difference of 2.0, use the pooled standard deviation derived from the 80 completed patients, and find a sample size with 90% power with Į=0.05. However, the sample size will not be increased to greater than 266 patients and the sample size will not be decreased from 200. [0437] The sample size of 250 patients, 125 per treatment group (1:1 randomization Dexmedetomidine sublingual film: placebo), for the at-home Part 2 is believed to provide enough patients to find the adverse drug reactions that might occur in at-home use, along with their incidences, without false positive findings. Any new adverse drug reactions would be considered additions to those already found and included in the labelling for Dexmedetomidine sublingual film. 74 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 Table 1: Part 1 Schedule of Events
Figure imgf000077_0001
75 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377
Figure imgf000078_0001
Notes to Table 1: 1 For females of childbearing potential only. 2 If a urine sample cannot be obtained at the time of Screening for a pregnancy test because the patient is unable to provide one, this is not exclusionary, nor will it be considered a protocol violation 3 Resting vital signs and collection: pulse oximetry, temperature, heart rate, and blood pressure after resting 5 minutes in the supine position 4 Orthostatic vital signs collection (systolic and diastolic blood pressure and heart rate) are collected immediately following the collection of resting vital signs; collected at 1 and 3 minutes after standing 5 The PCRS must be performed just before the PEC rating 6 A PK sample may not be collected if the Investigator indicates in source documents that the patient is in a mental state that is not conducive to PK sample collection. Non-compliance or refusal of all or any PK draw is not exclusionary and does not result in early termination, nor will this be considered a protocol deviation. 7 The PEC is to be administered within 15 minutes before the administration of study treatment at the pre-dose time point. 8 The ACES is administered within 30 minutes before the administration of the study treatment at the pre-dose time point. 9The mCGI-S is to be administered immediately prior to dosing at the pre-dose time point 10The window for all assessments at the 30 minute and 1-hour timepoints is +/- 5 minutes 11The window for all assessments at the 2-hour time point is +/- 15 minutes 12 The ECG conducted at the 2,4 and 8-hour times are collected before obtaining the PK samples 13 The resting vital signs and orthostatic vital signs collected at the 2, 4, 6, and 8-hour times are to be collected before obtaining the PK sample 14 The window for all assessments at the 4 hr, 6 hr, and 8 hr times is +/- 30 minutes 15 If the patient is determined to be not ready for discharge at the 8-hour timepoint, the Likability Questions and TSQM should not be completed. 16 If the patient is not discharged at the 8-hour timepoint, these procedures should be conducted when re-evaluating the patient for discharge, and repeated on each occasion that the patient is re-evaluated for discharge. 17 The Likability Questions and the TSQM should only be completed when it has been determined that the patient is ready for discharge. 76 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 Table Part 2 Schedule of Events
Figure imgf000079_0001
77 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377
Figure imgf000080_0001
Notes to Table 2: 1 Resting vital signs and collection: pulse oximetry, temperature, heart rate, and blood pressure after resting 5 minutes in the supine position 2 Orthostatic vital signs collection (systolic and diastolic blood pressure and heart rate) are collected immediately following the collection of resting vital signs; collected at 1 and 3 minutes after standing 3 For women of childbearing potential 4Install EMA application on both the patient’s and informant’s smart phone or tablet (or provide device if required) 5Rates average severity since the last clinic rating based on interviews of both the patient and Informant 6The patient and Informant are to be trained on how to use the EMA application, and on their responsibilities for the application’s use between Screening and Baseline 7The patient and Informant are to be trained on when to administer study treatment, as well as how to take it. They should also be reminded of how to use the EMA application during the study 8Only if additional rescue medication is required by the patient 9Uninstall EMA application on both the patient’s and informant’s smart phone or tablet (or collect device(s) if distributed at Screening) 78 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 Table 3: Part 2 At-home Patient and Informant Assessments
Figure imgf000081_0001
Notes to Table 3: All assessments are completed in the EMA application installed on the patient’s and Informant’s smartphone or tablet at Screening (or on the device provided by the site at Screening). With the exception of the patient completed mCGI-S scale, all ratings are performed by the Informant only. 1 Adverse events occurring during the 8 hours after taking study treatment and rescue medication (if it is taken), whichever is the last treatment taken. 2 To be assessed before administration of the dose of study treatment. 3 To be assessed 2 hours after the last dose of study treatment is taken (or immediately before rescue medication) 4 The EMA application will prompt the patient and Informant to enter this information twice per day [0438] Example 2. Efficacy and Safety of Dexmedetomidine hydrochloride sublingual film evaluated for At-Home Use in a Multisite Double-Blind Placebo-Controlled Trial for Agitation associated with Schizophrenia and Bipolar Disorder. 79 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 Objectives Primary Objectives [0439] Part 1: To determine if a 60-microgram (mcg) dose of dexmedetomidine sublingual film effectively reduces symptoms of agitation, assessed using the Positive and Negative Syndrome Scale – Excited Component (PEC) change from Baseline compared with change from Baseline with placebo. [0440] Part 2: To assess the safety of dexmedetomidine sublingual film when used in an at- home environment based on treatment-emergent adverse events (TEAEs) and Serious TEAEs collected by both the Informant and the clinical Investigator. Secondary Objectives Part 1: 1. To determine the overall clinical improvement after study treatment administration as measured by the Clinical Global Impression – Improvement scale (CGI-I) 2. To determine the overall clinical improvement after drug administration as measured by the modified Clinical Global Impression - Severity scale (mCGI- S) 3. To describe the duration of calming as measured by the Agitation-Calmness Evaluation Scale (ACES) 4. To determine the safety profile of dexmedetomidine sublingual film as assessed by TEAEs, serious TEAEs, vital signs measurements, Electrocardiograms (ECGs), and clinical laboratory results. 5. To describe the overall tolerability in terms of TEAEs Part 2: 1. To assess reduction of signs and symptoms of agitation based on the CGI-C and mCGI-S scales at 2 hours following study treatment administration 2. To describe the duration of calming as measured by the Agitation-Calmness Evaluation Scale (ACES) 3. To assess the continued efficacy of dexmedetomidine sublingual film in the treatment of episodes of agitation, as measured by the Clinical Global 80 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 Impression – Change scale (CGI-C) and mCGI-S scales and frequency of agitation episodes. 4. To determine the number of interactions with emergency services (specifically hospitalization, emergency room visits, urgent care clinic visits, and law enforcement intervention) because of agitation episodes Exploratory Objectives Part 1: 1. To describe the patient’s opinion on the taste, acceptability, and likability of dexmedetomidine sublingual film 2. To assess patient satisfaction with dexmedetomidine sublingual film in the treatment of episodes of agitation. The Treatment Satisfaction Questionnaire for Medication (TSQM) is administered for this purpose at the end of the treatment period. 3. To determine the overall clinical improvement after drug administration as measured by the use of rescue medications. 4. To assess agreement between PEC scores and mCGI-S rating Part 2: 1. To assess reduction of signs and symptoms of agitation based on the agitation behaviors scale, the Karolinska Sleep Scale (KSS), and Item 9 of the Beck Depression Inventory-II (BDI-II) 2. To assess patient satisfaction with dexmedetomidine sublingual film in the treatment of episodes of agitation. The TSQM is administered for this purpose at the end of the treatment. 3. To determine the overall clinical improvement after drug administration as measured by the use of rescue medications. 4. To assess agreement between Informant and patient ratings on the mCGI-S and CGI-C scales. 81 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 Primary Endpoints [0441] Part 1: Change in PEC score from Baseline as compared with placebo at 2 hours following drug administration. [0442] Part 2: Comparison of Serious Adverse Events (SAEs) and TEAEs as compared with placebo. Secondary Endpoints Part 1: 1. The number of PEC responders (patients who achieve a ^40% decrease from Baseline in PEC total score) at or before 2 hours after drug administration. 2. Change in PEC score from Baseline as compared with placebo over time measured from 30 minutes through 8 hours following drug administration. 3. CGI-I scores at 2 hours after drug administration. 4. The number of CGI-I responders (patients who achieve a CGI-I score of 1 or 2) at 2 hours after drug administration. 5. Change in mCGI-S scores from Baseline as assessed at 2 hours after drug administration. 6. The number of mCGI-S responders (patients who achieve a mCGI-S score of 0 or 1) at 2 hours after drug administration. 7. Change in ACES score from Baseline at 2, 4, and 8 hours after drug administration. 8. The safety profile of dexmedetomidine sublingual film will be measured by frequency of adverse events (AE), vital signs measurements, ECGs and clinical laboratory results. 9. The overall tolerability of oral film will be measured by frequency of TEAEs reports and incidence of local site (oral/sublingual) tolerability. Part 2: 1. Change in mCGI-S for Informants (mCGI-S-INF) scores from predose to 2 hours following drug administration for the first treated episode. 82 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 2. The number of mCGI-S-INF responders (patients who achieve a mCGI-S-INF score of 0 or 1) at 2 hours following drug administration for the first treated episode. 3. Change in ACES scores (as measured by the Informant) from Baseline at 2 hours after drug administration for the first treated episode. 4. CGI-C-INF scores at 2 hours following drug administration for the first treated episode. 5. The number of CGI-C-INF responders (patients who achieve a CGI-C-INF score of 1 or 2) at 2 hours following drug administration for the first treated episode. 6. Change in mCGI-S-INF scores from predose to 2 hours following drug administration for the last treated episode (measures continued efficacy). 7. The number of mCGI-S-INF responders at 2 hours following drug administration for the last treated episode (measures continued efficacy). 8. CGI-C-INF scores at 2 hours following drug administration for the last treated episode (measures continued efficacy). 9. The number of CGI-C-INF responders at 2 hours following drug administration for the last treated episode (measures continued efficacy). 10. Percentage of all treated episodes of agitation satisfying the definition of mCGI- S-INF responder (patients who achieve a mCGI-S-INF score of 0 or 1) at 2 hours (measures continued efficacy) 11. Percentage of all treated episodes of agitation satisfying the definition of CGI- C-INF responder (patients who achieve a CGI-C score of 1 or 2 as determined by the Informant) at 2 hours (measures continued efficacy) 12. Number and frequency of agitation episodes (measures continued efficacy) 13. Number of interactions with emergency services related to agitation episodes that are reported by the Informant. Exploratory Endpoints Part 1: 83 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 Patients’ opinion on taste, acceptability, and likability of study treatment will be assessed with a likability questionnaire. 2. Patient satisfaction with dexmedetomidine sublingual film in the treatment of episodes of agitation will be assessed with the TSQM. 3. Time to rescue medication during the 8-hour post-treatment evaluation period for subjects receiving dexmedetomidine sublingual film compared to placebo. 4. Proportion of subjects per treatment group who received rescue medication during the 8-hour post-treatment evaluation period for subjects receiving dexmedetomidine sublingual film compared to placebo. 5. Correlation between PEC and the mCGI-S at baseline and 2 hours. Part 2: 1. Change in agitation behaviors scale, the KSS, and Item 9 from the BDI-II from predose to 2 hours following drug administration. 2. Patient satisfaction with dexmedetomidine sublingual film in the treatment of episodes of agitation will be assessed with the TSQM. 3. Time to rescue medication for subjects receiving dexmedetomidine sublingual film compared to placebo. 4. Proportion of subjects per treatment group who received rescue medication for subjects receiving dexmedetomidine sublingual film compared to placebo. 5. Correlation between Informant and patient ratings on the mCGI-S and CGI-C scales.at baseline and 2 hours. STUDY DESIGN: [0443] This was a randomized, double-blind, placebo-controlled, 2-part, Phase III study to assess the efficacy, safety and tolerability of dexmedetomidine sublingual film dosing in adult (18-75 years old) males and females with agitation episodes associated with bipolar I disorder, bipolar II disorder, schizophrenia, schizoaffective disorder, or schizophreniform disorder. [0444] Parts 1 and 2 enrolled concurrently. All patients enrolled in Part 1 were individuals who had never previously received a dose of dexmedetomidine sublingual film or prescription IGALMITM. Patients in Part 2 of the study should not have been treated with prescription IGALMITM and might have participated in Part 1 of the study or other dexmedetomidine sublingual film trial. 84 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 Part 1: In-Clinic Period [0445] Part 1 of the study duration was 8 hours, in-clinic treatment, and post-treatment observation period with patients experiencing an acute episode of agitation. The in-clinic study period randomized patients 1:1 to receive 60 mcg of dexmedetomidine sublingual film or a matching placebo. Eligible patients were identified in outpatient clinics, mental health centers, psychiatric or medical emergency services including medical/psychiatric observation units, or as newly admitted patients to a hospital setting for acute agitation or already hospitalized for underlying conditions. Patients were domiciled in clinical research setting or hospitalized to remain under medical supervision while undergoing Screening procedures to assess eligibility and during study participation. [0446] While randomization was not formally stratified, the randomization scheme was designed so that no more than 70% of the patients in each arm of the study had a primary diagnosis of bipolar disorder (bipolar I or bipolar II) or schizophrenia (including schizoaffective and schizophreniform disorder). [0447] Upon confirmation of eligibility, patients were randomized to receive either 60 mcg of dexmedetomidine sublingual film or a matching placebo. At the time of dosing, patients were instructed on how to take the investigational product sublingually, and that they should retain it in the sublingual cavity until dissolved. The patient self-administered under the supervision of a trained staff member. If the patient was unable to self-administer, the event was recorded, and the patient's participation in the study was concluded. Such patients were replaced. [0448] Participants were also evaluated for local irritation around the area where the film was placed. Efficacy and safety assessments were conducted periodically before and after dosing. All efforts were made to have the patient perform all assessments as per protocol. [0449] If the patient’s status warranted (as determined by the Investigator), a rescue medication was administered. The rescue medication can be either a benzodiazepine (lorazepam maximum dose of 4 mg or oxazepam maximum dose of 60 mg) or any antipsychotic except clozapine, pimozide, or prochlorperazine with a maximum dose approximately equivalent to 300 mg of chlorpromazine as specified by BioXcel and as chosen by the Investigator. [0450] The patient must remain in the clinic for a minimum of 8 hours of observation following administration of study treatment; if rescue medication is administered, the patient should remain in the clinic for a minimum of 8 hours following administration. [0451] Efficacy, safety, tolerability, and pharmacokinetics (PK) were assessed throughout the treatment period at various times (see Table 4: Part 1 Schedule of Events for details). 85 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 Part 2: Community (At-Home) Setting Conduct [0452] Part 2 of the study was a 12-week study to evaluate the safety of dexmedetomidine sublingual film when used as needed for episodes of agitation at home. The at-home study period randomized patients 1:1 to receive 60 mcg of dexmedetomidine sublingual film or matching placebo film when an episode of agitation occurred at-home. Eligible patients were individuals who experienced periodic episodes of agitation. In addition, patients had a reliable Informant who participated in the study conduct at times when an episode of agitation was treated with the study treatment and who attended the monthly clinic visits. [0453] While randomization was not formally stratified, the randomization scheme was designed so that no more than 70% of the patients in each arm of the study had a primary diagnosis of bipolar disorder (bipolar I or bipolar II) or schizophrenia (including schizoaffective and schizophreniform disorder). [0454] Patients and Informants were trained at Screening on their responsibilities during the study, including how to rate the severity of agitation using the mCGI-S, and how to use the Ecological Momentary Assessment (EMA) application. At the Baseline Visit, patients and Informants were trained on the circumstances in which the Informant could recommend that the patient self-administer a dose of study treatment or rescue medication. In addition, patients were trained as to when they can take study treatment or rescue medication on their own recognizance. Patients and Informants were also instructed on how the patient was to take the study treatment sublingually, and that they should retain the study treatment in the sublingual cavity until dissolved. Additionally, patients and Informant dyads were trained on assessment of risk when agitation episode occurs and appropriate response if the risk was elevated. A study reference card was provided to patients and Informants which provided guidance on administration of study medication or rescue medication, safety precautions and management of risks during an agitation episode and self-injurious behaviors, suicide or violence. [0455] At home, when an agitation episode occurred, the patient self-administered the study treatment under the supervision of the Informant. If the patient was unable to self-administer during their first episode of agitation where treatment was attempted, the event was recorded, and the patient's participation will conclude. Such patients will be replaced. [0456] If the Informant was not present when a patient felt that they need to treat their agitation symptoms, the patient rated the severity of their agitation using the EMA application, and they took the study treatment at that time if they choose to do so. If the patient recorded an agitation 86 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 episode independently, the Informant was notified via the EMA application to follow up and if readily available, record the data for the episode. [0457] The patient and the Informant were also responsible for entering information into the EMA application installed on their devices. Specific information was entered when an agitation episode occurred. On days on which an agitation episode did not occur, other information was collected through the EMA application (the application prompted the patient and Informant to enter this information). [0458] In addition, the patient and Informant returned to the clinic for follow-up visits one month and two months (28 and 56 days) after the Baseline visit, as well as for a final study visit at the end of the 3-month (84 days) study period (see Table 5: Part 2 Schedule of Events). [0459] At the time of randomization at the Baseline visit, the patient was dispensed four packages, each containing one 60 mcg strip of dexmedetomidine sublingual film or matching placebo. If all packages were used before the next scheduled clinic visit, the patient or Informant need to return to the clinic to return the used packages and obtain four additional doses of study treatment. [0460] Patients were allowed a maximum of 2 doses of study drug within 8 hours. At the Baseline visit, the Investigator provided the patient with a prescription for a rescue medication of the Investigator’s choosing. In the event of persistent agitation, patients may choose to repeat the study drug administration (re-dose) after at least 30 minutes had passed since the first dose. If re-dose was taken, patients may take rescue medications after an additional 30 minutes had passed. The patients were guided to administer the study drug first for an agitation episode. However, patients may choose to use the rescue medication to treat any episode of agitation at any time after the study medication. If rescue medication was taken, then study drug may not be used to treat that episode of agitation. The rescue medication can be either a benzodiazepine (lorazepam maximum dose of 4 mg or oxazepam maximum dose of 60 mg) or any antipsychotic except clozapine, pimozide, or prochlorperazine, with a maximum dose approximately equivalent to 300 mg of chlorpromazine as specified by BioXcel and as chosen by the Investigator. SUBJECT POPULATION Selection of Study Population [0461] All patients enrolled in Part 1will be individuals who never previously received a dose of dexmedetomidine sublingual film or prescription IGALMITM. Patients in Part 2 of the study 87 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 should not have been treated with prescription IGALMITM and might have participated in Part 1 of the study or other dexmedetomidine sublingual film trial. Part 1 [0462] In Part 1 of the study approximately 200 patients were initially planned to be enrolled at up to 20 study sites in the US. When 40% of the 200 patients (80 patients) completed Part 1 of the study, a blinded analysis of the combined standard deviation of the change in both treatment groups was obtained to compute a final sample size, which might be increased up to a maximum of 266 patients. Part 2 [0463] In Part 2 approximately 250 patients were enrolled at up to 30 study sites in the United States. Part 1 and Part 2 were expected to enroll concurrently. Inclusion Criteria [0464] A patient was eligible for inclusion in the study if they met all of the following criteria: Inclusion Criteria (Parts 1 and 2) 1. Male and female patients 18 to 75 years old, inclusive. 2. Patients who could read, understand, and provide written informed consent. 3. Patients who met the Diagnostic and Statistical Manual of Mental Disorders, v5, Text Revision (DSM-5/5-TR) criteria for a primary diagnosis of bipolar I or bipolar II disorder, schizophrenia, schizoaffective or schizophreniform disorder. 4. Patients who, in the opinion of the Principal Investigator, were in good general health prior to study participation as determined by a detailed medical history, physical examination, 12-lead ECG with rhythm strip, blood chemistry profile, hematology, and urinalysis. 5. Female participants, if of child-bearing potential and sexually active, and male participants, if sexually active with a partner of child-bearing potential, agreed to use a medically acceptable and effective birth control method throughout the study and for one week following the end of the study. Medically acceptable methods of contraception that may be used by the patient and their partner include abstinence, birth control pills or patches, diaphragm with spermicide, intrauterine device (IUD), condom with foam or spermicide, vaginal spermicidal suppository, surgical sterilization and 88 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 progestin implant or injection. Prohibited methods included: the rhythm method, withdrawal, condoms alone, or diaphragm alone. Additional Inclusion Criteria for patients to be enrolled into Part 1: 6. Patients who were judged to be clinically agitated at Screening and Baseline with a total score of ^ 14 on the 5 items (poor impulse control, tension, hostility, uncooperativeness, and excitement) comprising the PEC. 7. Patients with a score of ^4 on at least 1 of the 5 items on the PEC at Baseline. Additional Inclusion Criteria for patients to be enrolled into Part 2: 8. Based on history, in the past 2 months patients must have had at least one clinical presentation of agitation requiring intervention (e.g., receipt of as needed (PRN) medication for the episode, clinic visit, emergency room visit, emergency medical services intervention, law enforcement intervention). 9. The patient could understand and follow the study procedures, including completing the EMA application ratings. 10. The patient had an Informant who can read, understand, and provide written informed consent and understand and follow the study procedures, including completing the EMA Application ratings and other EMA application required procedures during the study. Finally, the Informant must be able to accompany the participant to the monthly clinic visits and be interviewed by the Investigator for the Investigator to rate the average mCGI-S for the interval since the preceding clinic mCGI-S rating. Exclusion Criteria [0465] A subject was excluded from the study if he or she meets any of the following criteria: Exclusion Criteria (Parts 1 and 2) 1. Patients with serious or unstable medical illnesses. These included current hepatic (moderate-severe hepatic impairment), renal, gastroenterological, respiratory, cardiovascular (including ischemic heart disease, congestive heart failure), endocrinologic, or hematologic disease. 2. Psychiatric comorbidities were generally allowed; however, substance use disorders (within the past two years) were exclusionary if the substance involved was other than 89 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 nicotine or caffeine. Note, marijuana/cannabis use was not an exclusion based on positive UDS or subject admission of use, provided its use meets the following criteria: a) marijuana is prescribed for medical use (medical marijuana); b) marijuana is not the sole focus of treatment; c) severity of a cannabis-related SUD is not greater than mild (as defined by the DSM-5 Substance Use Disorder criteria); 4) illicit or recreational use is not escalating to recover from the effects of cannabis or withdrawal symptoms related to its use (even agitation). 3. The Investigator believed the patient had a history of agitation episodes due to substance use. 4. A diagnosis of antisocial personality disorder, borderline personality disorder, or narcissistic personality disorder that predated the diagnosis of schizophrenia or bipolar disorder, or in the opinion of the Investigator, was independent of the signs and symptoms of the schizophrenia or bipolar disorder. 5. Suicidality as assessed with the Columbia Suicide Severity Rating Scale (C-SSRS). A score of ^4 on the Ideational Component in the last year is exclusionary. Clinically significant risk of suicide based on the Investigator’s clinical opinion or a history of an actual suicide attempt in the last year are also exclusionary. 6. Self-injurious behavior that was active. 7. Female patients who had a positive pregnancy test at Screening or Baseline, or were breastfeeding. 8. Patients currently treated with alpha-1 noradrenergic blockers (terazosin, doxazosin, tamsulosin, alfuzosin, or prazosin), alpha-2 adrenergic agonists, or other prohibited medications. 9. Patients with hydrocephalus, seizure disorder, or history of significant head trauma, stroke, transient ischemic attack, subarachnoid bleeding, brain tumor, encephalopathy, meningitis, Parkinson’s disease, or focal neurological findings. 10. History of syncope or other syncopal attacks, current evidence of hypovolemia, orthostatic hypotension, a decrease in systolic blood pressure (SBP) of ^20 millimeters of mercury (mmHg) or a decrease in diastolic blood pressure (DBP) of ^10 mmHg at 1 or 3 minutes after standing from 5 minutes of supine rest, a Screening and Baseline heart rate of <55 beats per minutes or SBP <100 mmHg or DBP <60 mmHg. 90 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 11. Patients with laboratory or ECG abnormalities considered clinically significant by the Investigator or qualified designee (Advanced heart block [second-degree or above atrioventricular block without pacemaker], diagnosis of Sick sinus syndrome) with clinical implications for the patient’s participation in the study. 12. Patients with known personal or family history of genetic long QT syndrome. 13. Patients who received an investigational drug within 30 days prior to study start (30 days prior to initial dose in Part 1; 30 days prior to Day 0 in Part 2). 14. Patients who previously received dexmedetomidine sublingual film via prescription (under the trade name IGALMITM). 15. Patients considered by the Investigator to be unsuitable candidates for receiving dexmedetomidine (e.g., patients with a history of allergic reactions to dexmedetomidine) or considered to be unsuitable for participating in the study for any reason. Additional Exclusion Criteria for patients to be enrolled into Part 1: 16. Patients with agitation caused by acute intoxication, including identification of alcohol by breathalyzer or drugs of abuse (except for THC) during urine screening. 17. Use of benzodiazepines or other hypnotics or antipsychotic drugs in the 4 hours before study treatment. 18. Patients who previously received dexmedetomidine sublingual film in a clinical trial. Informant Inclusion Criteria [0466] Informants who met following criteria will be eligible for Part 2 of the study: 1. At least 18 years of age at the time of screening 2. Was a spouse, significant other, family member, friend, or home health aide, residence manager of an adult patient who is determined to be eligible for the study per the patient inclusion/exclusion criteria. 3. Had known the patient for at least 12 months. 4. Currently living with or routinely contacting the patient at least five days a week. 5. Did not plan to discontinue seeing or caring for the patient during the study period. 91 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 6. Willing and able to provide written informed consent. 7. Willing and able to follow the study procedures, including completing the EMA application ratings and other EMA application required procedures during the study 8. Willing and able to accompany patient and remain present at the clinical site during the clinic visits and be interviewed by the Investigator. STUDY TREATMENTS Method of Assigning Patients to Treatment Groups [0467] Upon confirmation of eligibility, patients were randomized as follows: [0468] Part 1: 1:1 to receive 60 mcg of dexmedetomidine sublingual film or matching placebo. [0469] Part 2: 1:1 to receive 60 mcg of dexmedetomidine sublingual film or matching placebo. [0470] Study randomization was computer generated. TEST PRODUCT, DOSE, AND MODE OF ADMINISTRATION Product: [0471] The product was a thin film formulation of dexmedetomidine for sublingual (SL) or buccal (BL) administration. Dosing delivers 60 micrograms of dexmedetomidine. The product was a small, solid-dose film formulation, approximately 286 mm2 in area and 0.7 mm thick, designed to completely dissolve in the sublingual space within 1-3 minutes. Patients received a single film strip for sublingual placement in the oral cavity. [0472] (a) Study Treatment Administration [0473] Patients were instructed on how to take the study treatment sublingually, and that they should retain the study treatment in the sublingual cavity until dissolved; although the study treatment can be taken sublingually or buccally, all patients in this study will only take the study treatment sublingually. The patient self-administered dexmedetomidine sublingual film If the patient was unable to self-administer in Part 1, or during their first episode of agitation where treatment was attempted in Part 2, the event was recorded, and the patient’s participation in the study concluded. If it was found, in Part 2, that a patient was unable to consistently self- administer treatment during subsequent episodes of agitation, the Investigator should determine if the patient was capable of remaining in the study. 92 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 [0474] Patients should be restricted from food or water intake for 15 minutes after taking the study treatment. [0475] In Part 1, patients were evaluated for local irritation around the area where the study treatment has been placed. [0476] Patients and Informants were advised that patients should avoid activities that require them to be alert, such as driving a car or operating machinery for at least 8 hours after receiving study drug. At-home Patient and Informant assessments [0477] When the Informant identified an agitation episode as having begun, based on excess verbal or physical activity of the patient and the Informant’s first-hand experiences with the patient’s episodes of agitation, the Informant rated the severity of agitation at that time with the mCGI-S-INF. The patient also rated the severity of their agitation at that time with the mCGI-S-PAT. The patient and Informant entered their ratings into their respective EMA applications. [0478] When the patient rated the severity of agitation as 2 (moderate) or 3 (severe), a notification was sent to the Informant. The patient can also tell the Informant that they have begun to experience an agitation episode. If this occurred, the patient and Informant rated the severity of agitation at that time and entered those ratings into their respective EMA applications. [0479] If the Informant was not present when a patient feels that they need to treat their agitation symptoms, the patient should rate the severity of their agitation using the EMA application, and they may take the study treatment at that time if they choose to do so. If the patient records an agitation episode independently, the Informant is notified via the EMA application to follow up and if readily available, will record the data for the episode. [0480] If the Informant rated the severity of agitation as 2 (moderate) or 3 (severe), they can recommend to the patient to take study treatment. The patient might refuse to take the study treatment when the Informant recommends it. If refusal occurs, this information was entered into the EMA application by the Informant, along with the reason for refusal. If the patient took the study treatment at a later time, this information was entered into the EMA Application by the Informant. The patient could decide that study treatment is needed and take it irrespective of their rated mCGI-S score or the Informant’s recommendation. 93 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 [0481] If the patient cannot self-administer during their first episode of agitation where treatment is attempted, the event was recorded, and the Investigator should determine if the patient was able to continue participation in the study. If the patient was unable to self- administer during subsequent episodes, the Investigator should determine if the patient was able to continue participation in the study. [0482] The Informants were also asked to complete a series of questions via the EMA application; some questions were only assessed when an agitation episode occurred , others were asked daily (see Table 6). Patient and Informant assessments conducted when an agitation episode occurred [0483] When an agitation episode occurred the EMA application was used by Informants and patients to record the duration of the agitation episode, use of study drug or rescue medication, efficacy and safety assessments, side effects, other medications (able ). The time when each question or assessment was completed was captured in the EMA application. Any end of agitation episode outcomes including interactions with emergency services (specifically, hospitalizations, emergency room visits, urgent care clinic visits, interventions by other emergency services such as ambulance services, and interventions by law enforcement) were also recorded via the EMA application. Patient and Informant assessments conducted on a daily basis [0484] The Informants were asked to provide the following information via the EMA Application on a daily basis, when prompted by the application twice per day (see Table 6: At- home Patient and Informant Assessments). The application prompted the Informant to enter this information: i. Query for the mCGI-S (Informant and patient) score twice per day; once in the morning and once in the evening) ii. Query for whether the patient experienced an agitation episode that day that was not previously reported (once per day, only in the evening) iii. Query for any interaction with emergency services (once per day, only in the evening, and only if an agitation episode occurred that was not reported) [0485] At the same time each day, the patient was prompted by the EMA application to enter their mCGI-S score. It was suggested that the patient and the Informant do not share their ratings with each other. 94 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 STUDY ASSESSMENTS Efficacy [0486] The efficacy of study treatment was evaluated during Part 1 using the validated instruments listed below. Efficacy assessments were completed in Part 2 using the mCGI-S rated by the Informant at each observed agitation episode (primary), rated by the patient at each observed agitation episode (secondary), and rated by the Investigator at each during study clinic visit for the 1-month period overall based on interviews of the patient and the Informant. i. Positive and Negative Syndrome Scale Excited Component (PEC) ii. Agitation-Calmness Evaluation Scale (ACES) iii. Karolinska Sleep Scale (KSS)- The Karolinska Sleep Scale is a single item scale to subjectively measure sleepiness at a given timepoint (Akerstedt and Gillberg, 1990). The responses are: 1 – extremely alert, 2 – very alert, 3 – alert, 4 – rather alert, 5 – neither alert nor sleepy, 6 – some signs of sleepiness, 7 – sleepy, but no effort to keep awake, 8 –sleepy, but some effort to keep awake, 9 – very sleepy, great effort to keep awake, fighting sleep and 10 – extremely sleepy, can’t keep awake. The patients rated their sleepiness in the EMA App. iv. Clinical Global Impressions – Improvement Scale (CGI-I) [0487] Clinical Global Impressions – Change Scale (CGI-C): The CGI-C is scale completed by the Informant (CGI-C-INF) and patient (CGI-C-PAT) to measure the overall change in the patient’s agitation after administration of the study drug. The CGI-C scores range from 1 to 5: 0 = not assessed (missing), 1 = much better, 2 = a little better, 3 = no change, 4 = a little worse, 5 = much worse [0488] The CGI-C focused on the severity of agitation rather than the severity of the overall illness of bipolar disorder or schizophrenia and related disorders. v. Modified Clinical Global Impression – Severity Scale (mCGI-S) 95 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 vi. Agitation Behaviors Scale Pharmacokinetics [0489] Blood samples (4 milliliters (mL) each) for PK analysis were collected in Part 1 at 2, 4, 6, and 8 hours post-dose per the Schedule of Events (Table 4). Efficacy Analyses Primary Endpoints [0490] The primary efficacy endpoint for Part 1 was the absolute change from Baseline in the PEC total score at 2 hours post-dose. Secondary Endpoints [0491] The secondary efficacy endpoints for Part 1 were: 1. The number of PEC responders (patients who achieve a ^40% decrease from Baseline in PEC total score) at or before 2 hours after drug administration. 2. Change in PEC score from Baseline as compared with placebo over time measured from 30 minutes through 8 hours following drug administration. 3. Change in CGI-I scores from Baseline at 2 hours after drug administration. 4. The number of CGI-I responders (patients who achieve a CGI-I score of 1 or 2) at 2 hours after drug administration. 5. Change in mCGI-S scores from Baseline as assessed at 2 hours after drug administration. 6. Number of mCGI-S responders (patients who achieve a mCGI-S score of 0 or 1) at 2 hours after drug administration. 7. Change in ACES scores from Baseline at 2, 4 and 8 hours after drug administration [0492] The secondary efficacy endpoints for Part 2 were: 1. Change in mCGI-S for Informants (mCGI-S-INF) scores from predose to 2 hours following drug administration for the first treated episode. 2. The number of mCGI-S-INF responders (patients who achieve a mCGI-S-INF score of 0 or 1) at 2 hours following drug administration for the first treated episode. 3. Change in ACES scores (as measured by the Informant) from Baseline at 2 hours after drug administration for the first treated episode. 4. CGI-C-INF scores at 2 hours following drug administration for the first treated episode. 96 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 5. The number of CGI-C-INF responders (patients who achieve a CGI-C-INF score of 1 or 2) at 2 hours following drug administration for the first treated episode. 6. Change in mCGI-S-INF scores from predose to 2 hours following drug administration for the last treated episode (measures continued efficacy). 7. The number of mCGI-S-INF responders at 2 hours following drug administration for the last treated episode (measures continued efficacy). 8. CGI-C-INF scores at 2 hours following drug administration for the last treated episode (measures continued efficacy). 9. The number of CGI-C-INF responders at 2 hours following drug administration for the last treated episode (measures continued efficacy). 10. Percentage of all treated episodes of agitation satisfying the definition of mCGI-S-INF responder (patients who achieve a mCGI-S-INF score of 0 or 1) at 2 hours (measures continued efficacy) 11. Percentage of all treated episodes of agitation satisfying the definition of CGI-C-INF responder (patients who achieve a CGI-C score of 1 or 2 as determined by the Informant) at 2 hours (measures continued efficacy) 12. Number and frequency of agitation episodes (measures continued efficacy) Part 1: [0493] Secondary efficacy endpoints for Part 1, including change in agitation in response to treatment as measured by the PEC, CGI-I and the mCGI-S scales and change from baseline in the ACES scores were analyzed using an MMRM model. The MMRM model for the PEC, mCGI-S and ACES scores included the change from baseline through 2 hours post-dose as the outcome and the baseline value of the outcome and treatment group as covariates. The model for the CGI-I scores included scores 30 minutes through 2 hours post-dose as the outcome and the baseline mCGI-S score and treatment group as covariates. The number of PEC responders (patients who achieved a ^40% decrease from baseline in PEC total score at or before 2 hours after drug administration), the number of CGI-I responders (patients who achieved a mCGI-S score of 0 or 1 at 2 hours after drug administration) and the number of mCGI-S responders (patients who achieved a mCGI-S score of 0 or 1 at 2 hours after drug administration) were analyzed using a Chi-Square test. [0494] All values collected after the use of rescue treatment and withdrawal from study were set to missing. Part 2: 97 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 [0495] The secondary efficacy endpoints for Part 2, change in agitation in response to treatment as measured by the CGI-C-INF and the mCGI-S-INF scales and change from predose in the ACES scores were analyzed using MMRM models as described above for the analysis of the secondary efficacy endpoints for Part 1. The number of CGI-C-INF responders (patients who achieve a CGI-C-INF score of 1 or 2) at 2 hours after drug administration and the number of mCGI-S-INF responders (patients who achieve a mCGI-S-INF score of 0 or 1) at 2 hours after drug administration were analyzed with a Chi-Square test. [0496] All values collected after the use of rescue treatment and withdrawal from study were set to missing. [0497] The frequency of treated agitation episodes was assessed with a Poisson model that includes treatment group as a covariate. This was a single outcome defined as the number of treated episodes of agitation for each subject. The results were summarized as an incidence rate ratio and the significance level for the test of the null hypothesis of no difference between active dose and placebo were obtained from the significance level for the test of each dose level versus placebo. [0498] The percentage of all treated episodes of agitation satisfying the definition of mCGI-S- INF responder were analyzed using an ANCOVA model with the percentage of episodes meeting the definition of an mCGI-S-INF responder as the outcome and treatment group a covariate. The percentage of all treated episodes of agitation satisfying the definition of CGI- C-INF responder were analyzed similarly. [0499] Other secondary and exploratory endpoints for both Part 1 and Part 2 were analyzed using a variety of techniques depending on the outcome and including two-sample t-tests, Fisher’s exact test, Kaplan-Meier curves for time-to event outcomes and descriptive methods such as box plots, frequency distributions and shift tables. All significance levels will be reported as nominal levels. Details of these analyses were specified in the SAP. Safety Analyses [0500] All safety analyses were performed using the Safety Population. All patients who received at least one dose of study treatment were included in the population for safety analysis. [0501] Adverse events were characterized by type, severity, seriousness, and relationship to treatment. Adverse events were coded by preferred term and system organ class using the most current version of MedDRA. 98 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 Table 4. Part 1 Schedule of Events
Figure imgf000101_0001
99 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377
Figure imgf000102_0001
Notes to Table 4: 1 For females of childbearing potential only. 2 If a urine sample cannot be obtained at the time of Screening for a pregnancy test because the patient was unable to provide one, patient may still be enrolled into the study and this was not exclusionary, nor will it be considered a protocol violation. 3 The UDS (on-site dipstick) must be completed with a negative result before dosing with the study drug. A positive tetrahydrocannabinol (THC) in UDS was not exclusionary. If patients were being prescribed benzodiazepines, stimulants or opiates, then a positive UDS was not exclusionary. 4 Resting vital signs and collection: pulse oximetry, temperature, heart rate, and blood pressure after resting 5 minutes in the supine position 5 Orthostatic vital signs collection (systolic and diastolic blood pressure and heart rate) were collected immediately following the collection of resting vital signs; collected at 1 and 3 minutes after standing 6 The PCRS must be performed just before the PEC rating 7 A PK sample may not be collected if the Investigator indicates in source documents that the patient is in a mental state that was not conducive to PK sample collection. Non-compliance or refusal of all or any PK draw was not exclusionary and did not result in early termination, nor will this be considered a protocol deviation. 8 The PEC was to be administered within 15 minutes before the administration of study treatment at the pre-dose time point. 9 The ACES was administered within 30 minutes before the administration of the study treatment at the pre-dose time point. 10 The mCGI-S was to be administered immediately prior to dosing at the pre-dose time point 11 The window for all assessments at the 30 minute and 1-hour timepoints is +/- 5 minutes 12 The window for all assessments at the 2-hour time point was +/- 15 minutes 13 The ECG conducted at the 2, 4 and 8-hour times were collected before obtaining the PK samples 14 The resting vital signs and orthostatic vital signs collected at the 2, 4, 6, and 8-hour times were to be collected before obtaining the PK sample 15 The window for all assessments at the 4 hr, 6 hr, and 8 hr times was +/- 30 minutes 16 If the patient was determined to be not ready for discharge at the 8-hour timepoint, the Likability Questions and TSQM should not be completed. 17 If the patient was not discharged at the 8-hour timepoint, these procedures should be conducted when re-evaluating the patient for discharge, and repeated on each occasion that the patient was re-evaluated for discharge 100 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 Table 5. Part 2 Schedule of Events
Figure imgf000103_0001
101 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377
Figure imgf000104_0001
Notes to Table 5: 1 Resting vital signs and collection: pulse oximetry, temperature, heart rate, and blood pressure after resting 5 minutes in the supine position 2 Orthostatic vital signs collection (systolic and diastolic blood pressure and heart rate) are collected immediately following the collection of resting vital signs; collected at 1 and 3 minutes after standing 3 For women of childbearing potential 4 If a urine sample cannot be obtained at the time of Screening for a pregnancy test because the patient is unable to provide one, patient may still be enrolled into the study and this is not exclusionary, nor will it be considered a protocol violation. 5 The UDS (on-site dipstick) must be completed with a negative result before randomization and dispensing the study drug. In addition, the on-site dipstick UDS result at Visit 1 and Visit 2 must be negative in order for the patient to continue participation in the study. A positive tetrahydrocannabinol (THC) in UDS is not exclusionary. If patients are being prescribed benzodiazepines, stimulants or opiates, then a positive UDS is not exclusionary. 6 Investigator will collect and record AEs during the monthly clinic visits and based on review of the side effects recorded in the EMA application. 7 Install EMA application on both the patient’s and informant’s smart phone or tablet (or provide device if required) 8 The patient and Informant are to be trained on how to use the EMA application, and on their responsibilities for the application’s use between Screening and Baseline 9 The patient and Informant are to be trained on when to administer study treatment or rescue medication, as well as how to take it, and manage risk when agitation episode occurs and appropriate response if risk is elevated. They should also be reminded of how to use the EMA application during the study 10 Only if additional rescue medication is required by the patient 11 Uninstall EMA application on both the patient’s and informant’s smart phone or tablet (or collect device(s) if distributed at Screening) Table 6. Part 2 At-home Patient and Informant Assessments
Figure imgf000104_0002
102 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377
Figure imgf000105_0001
Notes to Table 6: All assessments are completed in the EMA application installed on the patient’s and Informant’s smartphone or tablet at Screening (or on the device provided by the site at Screening). With the exception of the patient completed mCGI-S, KSS and BDI-II Item 9 scales, all ratings are performed by the Informant only. 103 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 1Informant will be asked to report if any medications were taken (Yes/No) by patient in the 4 hours before and after study treatment administration 2 Adverse events occurring during the 8 hours after taking study treatment. 3 To be assessed before administration of the dose of study treatment 4 To be assessed 2 hours after the initial dose of study treatment is taken on a given day 5 The EMA application will prompt the patient and Informant to enter this information twice per day 6 The EMA application will prompt the Informant to enter this information once per day. 7 Will only be asked if an agitation episode occurred that was unreported. 104 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 Table 7: Assessments and Data for Informants and Patient in EMA Application
Figure imgf000107_0001
1 Time stamps, responses and scores were recorded. 2 A score of 1, 2 or 3 on the BDI-II item 9 will trigger a notification to the medical monitor, Informant and site staff and require follow-up with the patient. Patients and Informants will be advised to seek emergency care services. [0502] Results and Discussion: The results of the study are provided in below Tables 8 to 21. [0503] PEC data were collected at 0.5, 1, 2, 4, 6, and 8 hours subsequent to the administration of sublingual film of dexmedetomidine or the placebo. As shown in FIG.1 and Table 10, while reductions in PEC scores were observed within both the treatment cohort and the placebo cohort, a significant separation was sustained at each time point. Notably, at the two-hour post- administration, the least square mean PEC score experienced a reduction of 4.8 in the treatment cohort and 3.8 in the placebo cohort with a P-value of 0.077. In a similar manner, four hours post-administration, the least square mean PEC score underwent a reduction of 5.4 in the treatment cohort and 4.3 in the placebo cohort with a P-value of 0.049 (Refer Table 10). [0504] An alternative metric for quantifying the efficacy of the medication is the responder rate defined as the percentage of patients who manifest a 40% reduction in PEC score. In the current study, the responder rates at two hours post-administration were 50% and 33% for the treatment cohort and the placebo cohort, respectively. Similarly, at four hours post- 105 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 administration, the responder rates were 51% and 39% for the treatment cohort and the placebo cohort, respectively (Refer Table 10 and Fig 2). [0505] In this study, a secondary endpoint was the score reduction as evaluated by the Clinical Global Impression-improvement scale (CGI-I). Two hours post-dosing, the CGI-I scores for the treatment and placebo groups were 2.8 and 3.1, respectively, with a P-value of 0.059 (Refer Table 13 and Fig 3). Similarly, the responder rates for the treatment and placebo groups stood at 38.6% and 26.0%, respectively, with a P-value of 0.039 (Refer Table 13 and Fig 4). [0506] The 60-mcg dose was safe and well tolerated across all time points. Dexmedetomidine sublingual film at 120 mcg and 180 mcg was approved by the FDA based on previously reported clinical studies, where the safety profiles for both dosages were deemed acceptable by the FDA. Compared to those previously approved dosages, the 60-mcg dose exhibited an enhanced safety profile across all monitored adverse event (AE) categories in the current clinical study (Refer Tables 21). For instance, 13% of patients experienced somnolence (defined as feelings of drowsiness, sleepiness, fatigue, or sluggishness), compared to 7% in the placebo group. In comparison, the frequencies for somnolence at dosages of 120 mcg and 180 mcg were 23% and 22%, respectively. Only a single incident (1%) of orthostatic hypotension occurred in the 60-mcg treatment group (none in the placebo group), while incidences were reported at rates of 3% and 5% in the earlier groups with 120 mcg and 180 mcg dosages, respectively (Refer Table 21). [0507] A subgroup analysis of the data indicated that, when the results were assessed by diagnosis of the underlying disease, the efficacy for the schizophrenia group is superior to the efficacy for the bipolar group. As shown in Tables 11 and 12 and FIGs. 5A and 5B, the PEC score reductions at 2 hours post dosing for the schizophrenia group were 4.9 and 3.3 for the dexmedetomidine sublingual film cohort and the placebo, respectively, with a P value of 0.013. In contrast, the PEC score reductions at the same time for the bipolar group were 4.8 and 4.3 for the dexmedetomidine sublingual film cohort and the placebo, respectively, with a P value of 0.663. An increased placebo response was observed in the bipolar group, where the PEC score changed about 4.5 versus 3.2 in the schizophrenia group (Tables 11 and 12). 106 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 Table 8: Patient disposition – All Enrolled patients
Figure imgf000109_0001
Percentages are based on the number of randomized patients by treatment group and overall, apart from reason for discontinuation where the percentages are based on the number of patients that discontinue the study by treatment group and overall. Table 9: Demographics and Baseline Characteristics- Safety Population
Figure imgf000109_0002
107 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377
Figure imgf000110_0001
108 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377
Figure imgf000111_0001
109 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377
Figure imgf000112_0001
SD: Standard deviation; BMI: Body mass index Percentages are based on the number of patients in the Safety Population with non-missing data by treatment group and overall. [1] Percentages are based on number of female patients in the Safety Population with non-missing data by treatment group and overall. Patients that selected more than one race are included in the ‘Multiple’ category. BMI (kg/m²) was calculated as 10000*weight(kg)/height(cm)^2, rounded to 1 decimal place. 110 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 Table 10. Change from Baseline in the PEC Total Score and percentage of responders in the PEC total score over time-ITT Population
Figure imgf000113_0002
Figure imgf000113_0001
111 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 Table 11. Change from Baseline in PEC total score and percentage of responders in the PEC Total score over time – ITT population of Schizophrenia population.
Figure imgf000114_0001
Estimates were obtained from a MMRM including treatment group, study site, timepoint, timepoint by treatment group interaction, baseline PEC score and baseline PEC score by timepoint interaction. PEC scores collected after the start of rescue medication were not included in the analysis. 2 Patients who had a ^ 40% decrease from baseline in PEC total score after dosing were considered responders. Percent change from baseline is calculated as 100*(change from Baseline)/(Baseline - 5). P-values for the difference between treatments based on Fisher’s exact test. 3 LS Means Change from Baseline. 4 Baseline (Pre-Dose) Mean (SD) PEC Total Score. 5 Responders up to 2 hours are patients that satisfy the PEC response criteria at least once up to, and including, the 2 hours timepoint. 6 N=56 at the 6 and 8 Hour Post-Dose timepoints for Placebo 112 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 Table 12. Change from Baseline in PEC total score and percentage of responders in the PEC Total score over time – ITT population of Bipolar population.
Figure imgf000115_0001
1 Estimates were obtained from a MMRM including treatment group, study site, timepoint, timepoint by treatment group interaction, baseline PEC score and baseline PEC score by timepoint interaction. PEC scores collected after the start of rescue medication were not included in the analysis. 2 Patients who had a ^ 40% decrease from baseline in PEC total score after dosing were considered responders. Percent change from baseline is calculated as 100*(change from Baseline)/(Baseline - 5). P-values for the difference between treatments based on Fisher’s exact test. 3 LS Means Change from Baseline. 4 Baseline (Pre-Dose) Mean (SD) PEC Total Score. 5 Responders up to 2 hours are patients that satisfy the PEC response criteria at least once up to, and including, the 2 hours timepoint. 113 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 Table 13. CGI-I Score and percentage of responders in CGI-I score over Time - ITT Population
Figure imgf000116_0001
1 Estimates were obtained from a MMRM including treatment group, study site, timepoint, timepoint by treatment group interaction, baseline mCGI-S score and baseline mCGI-S score by timepoint interaction. CGI-I scores collected after the start of rescue medication were not included in the analysis. 2 Patients who achieved a CGI-I score of 1 or 2 (“very much improved” or “much improved”, respectively) after dosing were considered as responders. P-values for the difference between treatments based on Fisher’s exact test. 3 Baseline (Pre-Dose) Mean (SD) mCGI-S. 4 N=99 at the 6 and 8 Hour Post-Dose timepoints. 114 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 Table 14. Change from Baseline in CGI-I score and percentage of responders in CGI-I score over time -ITT population of Schizophrenia population.
Figure imgf000117_0001
1 Estimates were obtained from a MMRM including treatment group, study site, timepoint, timepoint by treatment group interaction, baseline mCGI-S score and baseline mCGI-S score by timepoint interaction. CGI-I scores collected after the start of rescue medication were not included in the analysis. 2 Patients who achieved a CGI-I score of 1 or 2 (“very much improved” or “much improved”, respectively) after dosing were considered as responders. P-values for the difference between treatments based on Fisher’s exact test. 3 Baseline (Pre-Dose) Mean (SD) mCGI-S. 4 N=56 at the 6 and 8 Hour Post-Dose timepoints. 115 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 Table 15. Change from Baseline in CGI-I score and percentage of responders in CGI-I score over time -ITT population of Bipolar population.
Figure imgf000118_0001
1 Estimates were obtained from a MMRM including treatment group, study site, timepoint, timepoint by treatment group interaction, baseline mCGI-S score and baseline mCGI-S score by timepoint interaction. CGI-I scores collected after the start of rescue medication were not included in the analysis. 2 Patients who achieved a CGI-I score of 1 or 2 (“very much improved” or “much improved”, respectively) after dosing were considered as responders. P-values for the difference between treatments based on Fisher’s exact test. 3 Baseline (Pre-Dose) Mean (SD) mCGI-S. 116 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 Table 16. Exploratory Efficacy Endpoint – Time to Rescue Medication- ITT Population
Figure imgf000119_0001
Percentages are based on the number of patients in the ITT Population by treatment group. Only the first use of rescue medication, if more than one occasion, is included. Table 17. Overall Summary of Treatment-Emergent Adverse Events (TEAEs)- Safety Population
Figure imgf000119_0002
117 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377
Figure imgf000120_0001
TEAE: Treatment-Emergent Adverse Event; TESAE: Treatment-Emergent Serious Adverse Event. Percentages are based on the number of patients in the Safety Population by treatment group and overall. Table 18. Treatment-Emergent Adverse Events (TEAEs) by System Organ Class and Preferred Term Safety Population
Figure imgf000120_0002
118 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377
Figure imgf000121_0001
119 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377
Figure imgf000122_0001
E: number of events. Percentages are based on the number of patients in the Safety Population by treatment group and overall. Subjects are counted once within each system organ class and preferred term. Adverse events were coded using MedDRA version 25.1. 120 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 Table 19. Incidence of Orthostatic Hypotension-Safety Population
Figure imgf000123_0001
SBP: Systolic Blood Pressure; DBP: Diastolic Blood Pressure. Percentages are based on the number of patients in the Safety Population by treatment group. A patient is counted under either column if the relevant decrease in blood pressure has been observed at either the 1- or 3-minutes measurement after standing. For supine vital signs with repeated assessments, the result of the last repeat assessment was used for any particular time point. 121 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 Table 20. Incidence of Resting Hypotension-Safety Population
Figure imgf000124_0001
SBP: Systolic Blood Pressure; DBP: Diastolic Blood Pressure; HR: Heart Rate. Percentages are based on the number of patients in the Safety Population by treatment group. For supine vital signs with repeated assessments, the result of last repeat assessment was used for any particular time point. Decreases are calculated from the last pre-dose measurement. 122 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 Table 21. AEs Incidence Reported by Dexmedetomidine sublingual film-treated patients in schizophrenia or bipolar disorder.
Figure imgf000125_0001
1 IGALMITM(dexmedetomidine) USPI, April 2022 2 Somnolence includes the terms 'feeling drowsy', feeling sleepy, fatigue and sluggishness 3 Abdominal discomfort includes dyspepsia, gastroesophageal reflux disease 123 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 [0522] Example 3. Efficacy and Safety of Dexmedetomidine Hydrochloride Sublingual Film Evaluated for At-home Use in a Multisite Double-blind Placebo-controlled Trial for Agitation associated with Schizophrenia and Bipolar Disorder. [0523] Objectives: [0524] Primary objectives: [0525] Part 1: To determine if a 60-microgram (mcg) dose of dexmedetomidine sublingual film effectively reduces symptoms of agitation, assessed using the Positive and Negative Syndrome Scale – Excited Component (PEC) change from Baseline compared with change from Baseline with placebo. [0526] Part 2: To assess the safety of 80 mcg dexmedetomidine sublingual film when used in an at-home environment based on serious adverse events (SAE) and treatment-emergent adverse events (TEAEs). [0527] Secondary objectives: [0528] Part 1: 1. To determine the overall clinical improvement after study treatment administration as measured by the Clinical Global Impression – Improvement scale (CGI-I). 2. To determine the overall clinical improvement after drug administration as measured by the modified Clinical Global Impression - Severity scale (mCGI-S). 3. To describe the duration of calming as measured by the Agitation-Calmness Evaluation Scale (ACES). 4. To determine the safety profile of dexmedetomidine sublingual film as assessed by TEAEs, serious TEAEs, vital signs measurements, electrocardiograms (ECGs), and clinical laboratory results. 5. To describe the overall tolerability in terms of TEAEs. [0529] Part 2: 1. To evaluate the impact of dexmedetomidine sublingual film on the use of healthcare and emergency service resources because of agitation episodes. 2. To evaluate the safety and tolerability profile of 80 mcg dexmedetomidine sublingual film. 124 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 3. To evaluate the effect of 80 mcg dexmedetomidine sublingual film on the signs and symptoms of agitation following study drug administration in patients with schizophrenia and bipolar disorder. 6. To assess the continued efficacy of dexmedetomidine sublingual film in the treatment of episodes of agitation. 7. To evaluate effect of dexmedetomidine sublingual film on patient-directed goals for the management of agitation behavior. 8. To determine the overall clinical improvement after drug administration as measured by the use of rescue medications. [0530] Exploratory objectives: [0531] Part 1: 1. To describe the patient’s opinion on the taste, acceptability, and likability of dexmedetomidine sublingual film. 2. To assess patient satisfaction with dexmedetomidine sublingual film in the treatment of episodes of agitation. The Treatment Satisfaction Questionnaire for Medication (TSQM) is administered for this purpose at the end of the treatment period. 3. To determine the overall clinical improvement after drug administration as measured by the use of rescue medications. 4. To assess agreement between PEC scores and mCGI-S rating. [0532] Part 2: 1. To assess patient satisfaction with dexmedetomidine sublingual film in the treatment of episodes of agitation. 2. To assess agreement between Informant and patient ratings on the mCGI-S and Clinical Global Impression—Corrections (CGI-C) scales. [0533] Endpoints: [0534] Primary endpoints: Part 1: Change in PEC score from Baseline as compared with placebo at 2 hours following drug administration. Part 2: The incidence of SAEs and TEAEs compared with placebo. [0535] Secondary endpoints: 125 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 Part 1: 1. The number of PEC responders (patients who achieve a ^40% decrease from Baseline in PEC total score) at or before 2 hours after drug administration. 2. Change in PEC score from Baseline as compared with placebo over time measured from 30 minutes through 8 hours following drug administration. 3. Change in CGI-I scores from Baseline at 2 hours after drug administration. 4. The number of CGI-I responders (patients who achieve a CGI-I score of 1 or 2) at 2 hours after drug administration 5. Change in mCGI-S scores from Baseline as assessed at 2 hours after drug administration. 6. The number of mCGI-S responders (patients who achieve a mCGI-S score of 0 or 1) at 2 hours after drug administration. 7. Change in ACES scores from Baseline at 2, 4, and 8 hours after drug administration. 8. The safety profile of dexmedetomidine sublingual film will be measured by frequency of TEAEs, vital signs measurements, ECGs, and clinical laboratory results. 9. The overall tolerability of oral film will be measured by frequency of TEAEs reports and incidence of local site (oral/sublingual) tolerability. [0536] Part 2: 1. Incidence of interactions with emergency services related to agitation. 2. Incidence of overall adverse events and AEs leading to discontinuation. 3. Proportion of patients who report somnolence (ACES score ^8 reported by Informant) pre-dose to post-dose. 4. Proportion of patients who report somnolence (Karolinska Sleepiness Scale [KSS] score ^7 reported by patient) pre-dose to post-dose. 5. Proportion of patients who report improvement in agitation (Yes/No) post-dose for the first treated episode compared with placebo. 6. Proportion of mCGI-S responders (patients who achieve a mCGI-S score of 0 or 1) following drug administration for the first treated episode. 126 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 7. Proportion of patients who report a 1-point improvement in mCGI-S score following drug administration for the first treated episode. 8. Proportion of CGI-C responders (patients who achieve a CGI-C score of 1 or 2) following drug administration for the first treated episode. 9. Change in mCGI-S scores from pre-dose to post-dose for the first treated episode. 10. CGI-C scores following drug administration for the first treated episode. 11. Time to end of an agitation episode from dosing for the first treated episode. 12. Proportion of patients who report improvement in agitation (Yes/No) post-dose for all treated episodes compared with placebo. 13. Proportion of mCGI-S responders following drug administration for the last treated episode and all treated episodes. 14. Proportion of patients who report a 1-point improvement in mCGI-S score following drug administration for the last treated episode and all treated episodes. 15. Proportion of CGI-C responders following drug administration for the last treated episode and all treated episodes. 16. Change in mCGI-S scores from pre-dose to post-dose following drug administration for the last treated episode and all treated episodes. 17. CGI-C scores following drug administration for the last treated episode and all treated episodes. 18. The frequency of treated agitation episodes compared with placebo. 19. Time to end of an agitation episode from dosing for the last treated episode and across all treated episodes. 20. Change in agitation behaviors scale following drug administration. 21. Change in Goal Attainment Scale (GAS) from Baseline to end of study. 22. Proportion of patients who receive rescue medication compared with placebo. 23. Time to use of rescue medication for patients receiving dexmedetomidine sublingual film compared with placebo. [0537] Exploratory endpoints: [0538] Part 1: 127 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 1. Patients’ opinion on taste, acceptability, and likability of study treatment will be assessed with a likability questionnaire. 2. Patient satisfaction with dexmedetomidine sublingual film in the treatment of episodes of agitation will be assessed with the TSQM. 3. Time to rescue medication during the 8-hour post-treatment evaluation period for subjects receiving dexmedetomidine sublingual film compared to placebo. 4. Proportion of subjects per treatment group who received rescue medication during the 8-hour post-treatment evaluation period for subjects receiving dexmedetomidine sublingual film compared to placebo. 5. Correlation between PEC and the mCGI-S at Baseline and 2 hours. [0539] Part 2: 1. Patient satisfaction with the treatment of episodes of agitation will be assessed with the TSQM. 2. Correlation between Informant and patient ratings on the mCGI-S and CGI-C scales pre-dose and after drug administration. [0540] Study Design: [0541] This is a randomized, double-blind, placebo-controlled, 2-part, Phase 3 study to assess the efficacy, safety, and tolerability of a 60 mcg or 80 mcg dose of dexmedetomidine sublingual film in adult (18-75 years old) males and females with agitation episodes associated with a primary diagnosis of bipolar I disorder, bipolar II disorder, schizophrenia, schizoaffective disorder, or schizophreniform disorder. Part 1 of the study is an 8-hour, in- clinic treatment, and post-treatment observation period with patients experiencing an acute episode of agitation. Part 2 of the study is a 12-week study to evaluate the safety and efficacy of 80 mcg dexmedetomidine sublingual film when used in an at-home setting when treating episodes of agitation in patients. [0542] All patients enrolled in Part 1 will be individuals who have never previously received a dose of dexmedetomidine sublingual film or prescription IGALMI™. Patients in Part 2 of the study should not have been treated with prescription IGALMI™ and may have participated in Part 1 of the study or other double-blind dexmedetomidine sublingual film trial. [0543] Part 1: In-Clinic Period Setting Conduct: 128 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 [0544] The in-clinic study period randomizes patients 1:1 to receive 60 mcg of dexmedetomidine sublingual film or a matching placebo. Eligible patients may be identified in outpatient clinics, mental health centers, psychiatric or medical emergency services, including medical/psychiatric observation units, or as newly admitted patients in a hospital setting for acute agitation or already hospitalized for their underlying, primary psychiatric disorder. Patients will be domiciled in a clinical research setting or hospitalized to remain under medical supervision while undergoing Screening procedures to assess eligibility, during treatment, and during the post-treatment observation period of at least 8 hours. [0545] While randomization is not formally stratified, the randomization scheme is designed so that no more than 70% of the patients in this part of the study have a primary diagnosis of bipolar disorder (bipolar I or bipolar II) or schizophrenia (including schizoaffective and schizophreniform disorder). [0546] Upon confirmation of eligibility, patients will be randomized to receive either 60 mcg dexmedetomidine sublingual film or a matching placebo. When dosing, patients will be instructed on how to take the study treatment sublingually and that they should retain it in the sublingual cavity until dissolved. The patient self-administers under the supervision of a trained clinic staff member. If the patient cannot self-administer, the event is recorded, and the patient’s participation in the study will conclude. Patients are also evaluated for local irritation in the film’s placement area. Efficacy and safety assessments are conducted periodically before and after dosing. All efforts should be made to have all the protocol-defined assessments completed for the patient. [0547] If the patient’s status warrants (as determined by the Investigator), a rescue medication can be administered. The rescue medication can be either a benzodiazepine (lorazepam maximum dose of 4 milligram [mg] or oxazepam maximum dose of 60 mg) or any antipsychotic except clozapine, pimozide, or prochlorperazine, with a maximum dose approximately equivalent to 300 mg of chlorpromazine as specified by BioXcel and as chosen by the Investigator. [0548] The patient must remain in the clinic for a minimum of 8 hours of observation following administration of study treatment. [0549] Efficacy, safety, tolerability, and pharmacokinetics (PK) are assessed throughout the treatment period at various times. (Table 22: Part 1 Schedule of Events for details) [0550] Part 2: Community (At-home) Setting Conduct: 129 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 [0551] Part 2 is a randomized, double-blind, placebo-controlled, Phase 3, 12-week study in the at-home community setting to assess the safety and efficacy of an 80 mcg dose of dexmedetomidine sublingual film. [0552] Eligible patients will be individuals receiving stable treatment for their underlying primary diagnosis for at least 3 months and who experience periodic episodes of agitation. Eligible patients may be enrolled individually or with a reliable Informant who can participate in the study conduct when an episode of agitation is treated with the study medication and who can attend the monthly clinic visits. Patients who will be enrolled individually should have a point-of-contact who can help with outreach and follow-up with the patient if the site staff is unable to reach the patient for more than 1 week. Upon confirmation of eligibility, the patient or patient/Informant dyads will be randomized 1:1 to administer 80 mcg dexmedetomidine sublingual film or matching placebo film when an episode of agitation occurs at home. [0553] At the Baseline visit, patient or patient/Informant dyads will be trained on their responsibilities during the study, including how to recognize agitation signs and symptoms using the agitation behaviors scale and goal attainment scale, managing agitation episode with non-pharmacological methods (if appropriate), when to administer study treatment or rescue medication, how to take study medications and how to complete the Agitation Episode Diary and when to contact site staff. A study reference guide will be provided to patient or patient/Informant dyads with these instructions. When an agitation episode occurs, the patient or patient/Informant dyad should complete an Agitation Episode Diary for each episode and contact the site staff as soon as possible (within a maximum of 48 hours after the episode has occurred). It should be noted that episodes of agitation in the at-home environment are likely associated with an even greater risk of harm to the patient than those treated in a clinical environment. Additionally, 50% of patients will receive placebo as their study treatment. The patient or patient/Informant dyads will be trained on safety precautions, the assessment of risk when an agitation episode occurs and when to seek emergency services. [0554] After randomization at the Baseline visit, the patient or patient/Informant dyads will be dispensed 3 packages, each containing one 80 mcg strip of dexmedetomidine sublingual film or matching placebo. If all packages are used before the next scheduled clinic visit, the patient or Informant (if part of patient/Informant dyad) will need to return to the clinic to return the used packages and obtain 3 additional doses of study treatment. In this case, the Investigator should carefully consider the adequacy of the patient’s antipsychotic and/or mood stabilization treatment and review the patient’s adherence with that treatment. At Visits 1 and 2, additional 130 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 packages may be dispensed, if needed, but at no time should a patient have more than a total of 3 packages of study drug. [0555] The patient or patient/ Informant dyads will also be instructed on how the patient is to take the study treatment sublingually and retain the study treatment in the sublingual cavity until dissolved. [0556] At the Baseline visit, the Investigator will provide the patient or patient/Informant dyad with a prescription for a rescue medication of the Investigator’s choosing. The patients will be guided to administer the study drug first for an agitation episode. Ideally, the patient should not take the rescue medication until 2 hours after study treatment. If rescue medication is taken to treat that episode of agitation, then study drug may not be used to treat that episode of agitation subsequently. If symptoms persist or escalate, then patients or patient/Informants should be advised to contact site staff and/or seek medical care. [0557] The training for patients or patient/Informant dyads will include how to identify signs and symptoms of agitation in the patient using the agitation behaviors scale and goal attainment scale. Patients will be trained on when they can take study treatment or rescue medication on their own recognizance and on the circumstances when the Informant can recommend that the patient self-administer a dose of study treatment or rescue medication. The patients should be advised to administer the study drug at home and whenever possible throughout the study. For patient/Informant dyads, the Informant should be present when the patient is starting dosing with the study medication and whenever possible throughout the study. This is important to collect the study data. Once the patient becomes familiar with dosing and the subsequent effects of the study medication, they can dose without the Informant being present, but it is always preferable that the Informant is present with the patient. If the patient records an agitation episode independently, the Informant (as soon as feasible) and site should be informed (within 48 hours) to follow-up. [0558] If the patient is unable to self-administer study medication during their first episode of agitation where treatment is attempted, the event will be recorded as a missed agitation episode along with the reason, and the Investigator should determine if the patient is able to continue participation in the study. If it is found, in Part 2, that a patient is unable to consistently self- administer treatment during subsequent episodes of agitation, the Investigator should determine if the patient is able to continue participation in the study. Such patients may be replaced. 131 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 [0559] Study site staff will contact patient or patient/Informant dyads via phone 2 times per week from Day 0 through Day 84 or early termination (ET) to inquire about agitation episodes since the last contact. If an agitation episode had occurred, then site will solicit responses to all questions in the Agitation Episode Diary based on an interview with the patient. For patient/Informant dyads, information from patients and Informants should be recorded separately during the interview. During subsequent clinic visits, the site staff should review any Agitation Episode Diary completed by the patient or patient/Informant dyads, reconcile, and update the corresponding electronic case report form (eCRF) as appropriate. If an agitation episode occurred that was treated with study medication, an assessment of suicidal ideation behaviors should be done using the Columbia-Suicide Severity Rating Scale (C-SSRS) during the phone interview. [0560] In addition, the patient or patient/Informant dyads will return to the clinic for follow- up visits one month and two months (28 and 56 days) after the Baseline visit, as well as for a final study visit at the end of the 3-month (84 days) study period (Table 23: Part 2 Schedule of Events). [0561] Independent Data Monitoring Committee: Part 2 of the study will be monitored under the supervision of a Data Monitoring Committee (DMC) which is independent from the sponsor. [0562] Number of Subjects (planned): In Part 1 of the study, approximately 200 patients will be enrolled at up to approximately 20 study sites in the United States (US). In Part 2, approximately 250 patient-Informant dyads will be enrolled at up to 30 study sites in the US. The same sites may participate in Part 1 and Part 2. Patients in Part 1 of the study should not have previously been treated with dexmedetomidine sublingual film or prescription IGALMI™. Patients in Part 2 of the study should not have been treated with prescription IGALMI™ and may have participated in Part 1 of the study or other double-blind dexmedetomidine sublingual film trial. [0563] Diagnosis and Main Criteria for Eligibility: [0564] Patient Inclusion Criteria (Parts 1 and 2) 1. Male and female patients 18 to 75 years old, inclusive. 2. Patients who can read, understand, and provide written informed consent. 132 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 3. Patients who meet the Diagnostic and Statistical Manual of Mental Disorders, v5, Text Revision (DSM-5/5-TR) criteria for a primary diagnosis of bipolar I or bipolar II disorder, schizophrenia, schizoaffective, or schizophreniform disorder. 4. Patients who, in the opinion of the Principal Investigator, are in good general health before study participation based on a detailed medical history, a physical examination, a 12-lead ECG, a blood chemistry profile, hematology, and urinalysis. 5. Female participants, if of childbearing potential and sexually active, and male participants, if sexually active with a partner of childbearing potential, agree to use a medically acceptable and effective birth control method throughout the study and for one month following the end of the study. Medically acceptable methods of contraception used by the participant and/or their partner include abstinence, birth control pills or patches, diaphragm with spermicide, intrauterine device (IUD), condom with foam, or spermicide, vaginal spermicidal suppository, surgical sterilization, and progestin implant or injection. Prohibited methods include the rhythm method, withdrawal, condoms alone, or diaphragm alone. [0565] Additional Inclusion Criteria for patients to be enrolled in Part 1: 1. Patients who are judged to be clinically agitated at Screening and Baseline with a total score of ^14 on the 5 items (poor impulse control, tension, hostility, uncooperativeness, and excitement) comprising the PEC. 2. Patients with a score of ^4 on at least 1 of the 5 items on the PEC at Baseline. [0566] Additional Inclusion Criteria for patients to be enrolled in Part 2: The patients may be enrolled by themselves or as part of a patient/Informant dyad with an Informant (see Informant Inclusion Criteria). 1. Based on history, in the past 2 months, patients have had at least one clinical presentation of agitation requiring an intervention (e.g., receipt of as needed [PRN] medication for the episode, clinic visit, emergency room visit, emergency medical services intervention, law enforcement intervention). 2. Patients who are receiving stable treatment for the last 3 months for the underlying primary diagnosis. 3. The patient can understand and follow the study procedures, including completing the Agitation Episode Diary. 133 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 [0567] Patient Exclusion Criteria (Parts 1 and 2) 1. Patients with serious or unstable medical illnesses. These include current hepatic (moderate-severe hepatic impairment), renal, gastroenterological, respiratory, cardiovascular (including ischemic heart disease, congestive heart failure), endocrinologic, or hematologic disease. 2. Psychiatric comorbidities are generally allowed; however, substance use disorders (SUD) (within the past two years) are exclusionary if the substance involved is other than nicotine or caffeine. Note: marijuana/cannabis use is not an exclusion based on positive urine drug screen (UDS) or patient admission of use, provided its use meets the following criteria: a) marijuana is prescribed for medical use (medical marijuana); b) marijuana is not the sole focus of treatment; c) severity of a cannabis-related SUD is not greater than mild (as defined by the DSM-5 Substance Use Disorder criteria); 4) illicit or recreational use is not escalating to recover from the effects of cannabis or withdrawal symptoms related to its use (even agitation). 3. The Investigator believes the patient has a history of agitation episodes due to substance use. 4. A diagnosis of antisocial personality disorder, borderline personality disorder, or narcissistic personality disorder that predated the diagnosis of schizophrenia or bipolar disorder, or in the opinion of the Investigator, is independent of the signs and symptoms of the schizophrenia or bipolar disorder. 5. Suicidality as assessed with the Columbia Suicide Severity Rating Scale (C-SSRS). A score of ^4 on the Ideational Component in the last year is exclusionary. Clinically significant risk of suicide based on the Investigator’s clinical opinion or a history of an actual suicide attempt in the last year are also exclusionary. 6. Self-injurious behavior that is active. 7. Female patients who have a positive pregnancy test at Screening or Baseline or are breastfeeding. 8. Patients currently treated with alpha-1 noradrenergic blockers (terazosin, doxazosin, tamsulosin, alfuzosin, or prazosin), alpha-2 adrenergic agonists, or other prohibited medications. 134 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 9. Patients with hydrocephalus, seizure disorder, or history of significant head trauma, stroke, transient ischemic attack, subarachnoid bleeding, brain tumor, encephalopathy, meningitis, Parkinson’s disease, or focal neurological findings. 10. History of syncope or other syncopal attacks, current evidence of hypovolemia, orthostatic hypotension, a decrease in systolic blood pressure (SBP) of ^20 millimeters of mercury (mmHg) or a decrease in diastolic blood pressure (DBP) of ^10 mmHg at 1 or 3 minutes after standing from 5 minutes of supine rest, a Screening and Baseline heart rate of <55 beats per minutes or SBP <100 mmHg or DBP <60 mmHg. 11. Patients with laboratory or ECG abnormalities considered clinically significant by the Investigator or qualified designee (advanced heart block [second-degree or above atrioventricular block without pacemaker], diagnosis of sick sinus syndrome) with clinical implications for the patient’s participation in the study. 12. Patients with known personal or family history of genetic long QT syndrome. 13. Patients who have received an investigational drug within 30 days before the study start (30 days before the initial dose in Part 1; 30 days before Day 0 in Part 2). 14. Patients who have previously received dexmedetomidine sublingual film via prescription (under the trade name IGALMI™) or received dexmedetomidine sublingual film in an open-label clinical trial. 15. Patients considered by the Investigator to be unsuitable candidates for receiving dexmedetomidine (e.g., patients with a history of allergic reactions to dexmedetomidine) or considered to be unsuitable for participating in the study for any reason. [0568] Additional Exclusion Criteria for patients to be enrolled in Part 1: 16. Patients with agitation caused by acute intoxication, including identification of alcohol by breathalyzer or drugs of abuse (except for THC) during urine screening. 17. Use of benzodiazepines or other hypnotics or antipsychotic drugs in the 4 hours before study treatment. 18. Patients who have previously received dexmedetomidine sublingual film in a clinical trial. 135 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 [0569] Informant Inclusion Criteria (Part 2 only) 1. At least 18 years of age at the time of screening. 2. Is a spouse, significant other, family member, friend, house manager or home health aide of an adult patient who is determined to be eligible for the study per the patient inclusion/exclusion criteria. 3. Has known the patient for at least 12 months cumulatively. 4. Currently living with or routinely contacting the patient at least five days a week. 5. Does not plan to discontinue seeing or caring for the patient during the study period. 6. Willing and able to provide written informed consent. 7. Willing and able to follow the study procedures, including completing the Agitation Episode Diary and other study procedures during the study. 8. Willing and able to accompany patient and remain present at the clinical site during the clinic visits and be interviewed by the Investigator. [0570] Study Treatment [0571] Randomization [0572] Upon confirmation of eligibility, patients will be randomized as follows: Part 1: 1:1 to receive 60 mcg of dexmedetomidine sublingual film or matching placebo. Part 2: 1:1 to receive 80 mcg of dexmedetomidine sublingual film or matching placebo. [0573] Study randomization will be computer generated. Test Product, Dose, and Mode of Administration: [0574] The product is a thin film formulation of dexmedetomidine for sublingual or buccal administration. Dosing delivers 60 mcg of dexmedetomidine in Part 1 and 80 mcg of dexmedetomidine in Part 2. The product is a small, solid-dose film formulation, approximately 286 millimeters squared (mm2) in area and 0.7 millimeters (mm) thick, designed to completely dissolve in the sublingual space within 1-3 minutes. Patients will receive a single film strip for sublingual placement in the oral cavity. 136 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 [0575] Reference Therapy, Dosage and Mode of Administration: Matching placebo films to be taken sublingually as described above. [0576] Duration of Treatment: Part 1: 8 hours. Part 2: 12 weeks. [0577] Study Treatment Administration: [0578] Patients will be instructed on how to take the study treatment sublingually, and that they should retain the study treatment in the sublingual cavity until dissolved; although the study treatment can be taken sublingually or buccally, all patients in this study will only take the study treatment sublingually. The patient will self-administer dexmedetomidine sublingual film. If the patient is unable to self-administer in Part 1, the event will be recorded, and the patient’s participation in the study will conclude. [0579] In Part 2, if the patient cannot self-administer during their first episode of agitation where treatment is attempted, the event is recorded, and the Investigator should determine if the patient is able to continue participation in the study. If it is found, in Part 2, that a patient is unable to consistently self-administer treatment during subsequent episodes of agitation, the Investigator should determine if the patient is able to continue participation in the study. [0580] Patients should be restricted from food or water intake for 15 minutes after taking the study treatment. [0581] In Part 1, patients will be evaluated for local irritation around the area where the study treatment has been placed. [0582] Patients and Informants will be advised that patients should avoid activities that require them to be alert, such as driving a car or operating machinery for at least 8 hours after receiving study drug. [0583] STUDY ASSESSMENTS: [0584] Efficacy [0585] The efficacy of study treatment will be evaluated during Part 1 using the validated instruments listed below. Efficacy assessments will be completed in Part 2 using the mCGI-S, CGI-C, GAS, and agitation behaviors scale. i. Positive and Negative Syndrome Scale Excited Component (PEC) ii. Clinical Global Impressions – Improvement Scale (CGI-I) iii. Clinical Global Impressions – Change Scale (CGI-C) : The CGI-C is scale completed by the Informant (CGI-C-INF) and patient (CGI-C-PAT) to measure the 137 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 overall change in the patient’s agitation after administration of the study drug. The CGI-C scores range from 1 to 5: 0=not assessed (missing), 1=much better, 2=a little better, 3=no change, 4=a little worse, 5=much worse The CGI-C will be focused on the severity of agitation rather than the severity of the overall illness of bipolar disorder or schizophrenia and related disorders. iv. Modified Clinical Global Impression – Severity Scale (mCGI-S): The mCGI-S, as rated by the Investigator in Parts 1, and by both the Informant (mCGI-S-INF) and the patient (mCGI-S-PAT) in Part 2, will be used as an assessment of efficacy in Part 2. The Handbook of Psychiatric Measures 2nd Edition (Rush et al., 2008) describes an 8-point CGI-S where a rating of 0 is used when the CGI-S was not assessed, and scores of 1-7 rate increasing severities of the psychiatric disorder or symptom being assessed. For this study, the CGI-S has been modified to a 4-point scale (mCGI-S) where 0 is no agitation, and scores of 1-3 describe increasing severities of agitation (mild, moderate, severe). The mCGI-S is dichotomized into scores of ^1 or ^2. The mCGI-S will be focused on the severity of agitation rather than the severity of the overall illness of bipolar disorder or schizophrenia and the related disorders. v. Agitation Behaviors Scale: The agitation behaviors scale consists of 14 observable agitation behaviors that were identified through literature review and qualitative interviews with caregivers of patients who experience agitation related to bipolar disorder. The agitation behaviors scale items will be each rated by the Informant using a 5-point ordinal scale (0 = None, 1 = Mild, 2 = Moderate, 3 = Severe, 4 = Very Severe) according to the current level of severity of agitation that they observe in the patient. 138 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 These 14 items are: repetitive or obsessive behaviors; impulsive, lack of self- control; rapid speech, ranting; resisting care, uncooperative, stubborn; irritable, short tempered; self-harm such as picking at skin, pulling at hair, cutting self, banging head (not suicide); crying, tearfulness; verbal abuse, screaming; non-verbal anger (gestures or body language); destroying, breaking, throwing, punching, or slamming objects; physical aggression (pushing, throwing, kicking); restlessness, fidgeting, unable to sit still; pacing or wandering and difficulty communicating clearly. vi. Goal Attainment Scaling: The Goal Attainment Scaling is a patient-focused method to score patient’s individual goals (a personalized endpoint) due to an intervention (Kiresuk and Sherman 1968). At Baseline, the patient or patient/Informant dyads and the Investigator identify prespecified number of personal goals (up to 3 goals) related to managing their individual agitation episode. The goal attainment levels (successful outcomes) are defined for each goal on a 5-point scale and scored at each clinic visit. [0586] Pharmacokinetics: [0587] Blood samples (4 milliliters [mL] each) for PK analysis will be collected in Part 1 at 2, 4, 6, and 8 hours post-dose per the Schedule of Events (Table 22). 139 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 Table 22. Part 1 Schedule of Events
Figure imgf000142_0001
140 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377
Figure imgf000143_0001
Notes to Table 22: 1 For females of childbearing potential only. 2 If a urine sample cannot be obtained at the time of Screening for a pregnancy test because the patient is unable to provide one, patient may still be enrolled into the study and this is not exclusionary, nor will it be considered a protocol violation. 3 The UDS (on-site dipstick) must be completed with a negative result before dosing with the study drug. A positive tetrahydrocannabinol (THC) in UDS is not exclusionary. If patients are being prescribed benzodiazepines, stimulants, or opiates, then a positive UDS is not exclusionary. 4 Resting vital signs and collection: pulse oximetry, temperature, heart rate, and blood pressure after resting 5 minutes in the supine position. 5 Orthostatic vital signs collection (systolic and diastolic blood pressure and heart rate) are collected immediately following the collection of resting vital signs; collected at 1 and 3 minutes after standing. 6 The PCRS must be performed just before the PEC rating. 7 A PK sample may not be collected if the Investigator indicates in source documents that the patient is in a mental state that is not conducive to PK sample collection. Noncompliance or refusal of all or any PK draw is not exclusionary and does not result in early termination, nor will this be considered a protocol deviation. 8 The PEC is to be administered within 15 minutes before the administration of study treatment at the pre-dose time point. 9 The ACES is administered within 30 minutes before the administration of the study treatment at the pre-dose time point. 10 The mCGI-S is to be administered immediately prior to dosing at the pre-dose time point. 11 The window for all assessments at the 30-minute and 1-hour time points is ±5 minutes. 12 The window for all assessments at the 2-hour time point is ± 15 minutes. 13 The ECG conducted at the 2, 4, and 8-hour times are collected before obtaining the PK samples. 14 The resting vital signs and orthostatic vital signs collected at the 2, 4, 6, and 8-hour times are to be collected before obtaining the PK sample. 15 The window for all assessments at the 4 hours, 6 hours, and 8 hours times is ±30 minutes. 16 If the patient is determined to be not ready for discharge at the 8-hour time point, the Likability Questions and TSQM should not be completed. 17 If the patient is not discharged at the 8-hour time point, these procedures should be conducted when re- evaluating the patient for discharge and repeated on each occasion that the patient is re-evaluated for discharge. Abbreviations: ACES = Agitation-Calmness Evaluation Scale; BMI = body mass index; CGI = Clinical Global Impression; C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; hr = hour; mCGI-S = Modified Clinical Global Impression-Severity Scale; MINI = Mini-International Neuropsychiatric Interview; PCRS = Placebo-Control Reminder Script; PEC = Positive and Negative Syndrome Scale Excited Component; PK = pharmacokinetic(s); TSQM = Treatment Satisfaction Questionnaire for Medication; UDS = urine drug screen. 141 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 Table 23. Part 2 Schedule of Events
Figure imgf000144_0001
142 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377
Figure imgf000145_0001
1 Resting vital signs and collection: pulse oximetry, temperature, heart rate, and blood pressure after resting for 5 minutes in the supine position. 2 Orthostatic vital signs collection (systolic and diastolic blood pressure and heart rate) are collected immediately following the collection of resting vital signs; collected at 1 and 3 minutes after standing. 3 ECG triplicate readings (30-90 second intervals) will be conducted. 4 For women of childbearing potential. 5 If a urine sample cannot be obtained at the time of Screening for a pregnancy test because the patient is unable to provide one, patient may still be enrolled into the study and this is not exclusionary, nor will it be considered a protocol violation. 6 The UDS (on-site dipstick) must be completed with a negative result before randomization and dispensing the study drug. In addition, the on-site dipstick UDS result at Visit 1 and Visit 2 must be negative in order for the patient to continue participation in the study. A positive tetrahydrocannabinol (THC) in UDS is not exclusionary. If patients are being prescribed benzodiazepines, stimulants, or opiates, then a positive UDS is not exclusionary. 7 Investigator or trained study staff member will collect, and record AEs and use of concomitant medications based on interview with patients and/or Informants and administer the C-SSRS during the monthly clinic visits, unscheduled visits. C-SSRS should be completed during a phone interview only if an agitation episode occurred since the last contact with the patient. 8 If the results of the Screening assessments are not available within window, the activities that are out of window should be repeated as an Unscheduled visit. 9 On Baseline Day 0, the GAS should be administered before randomization and training. During clinic visits on Days 28, 56 and 84/ET, the GAS should be reviewed after the Agitation Episode Diary. 10 The patient or patient/Informant dyad will be trained by study staff. These instructions should be reviewed as appropriate during phone interviews or clinic visits to ensure that patient or patient/Informant dyad understand the instructions. 11 A 3 packages of study medication will be dispensed at Baseline. After Baseline, additional doses (if needed) may be dispensed to the patient or Informant (if part of a patient/Informant dyad) 12 Prescribed at Baseline, and then again, when needed, throughout the duration of the study 13 Site will review Agitation Episode Diary. Patient or patient/Informant dyads will complete Agitation Episode Diary at home when agitation episode occurs 14 Study site staff will contact patient or patient/Informant dyads via phone 2 times per week from Day 0 through Day 84 or ET to inquire about agitation episodes since the last contact and conduct an interview to document the episode and outcomes. Abbreviations: AE = adverse event(s); C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; ET = early termination; GAP = Goal Attainment Scale; MINI = Mini-International Neuropsychiatric Interview; TSQM = Treatment Satisfaction Questionnaire for Medication; UDS = urine drug screen. 143 290971848 v1

Claims

ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 CLAIMS 1. A method of treating agitation in a patient having schizophrenia or bipolar disorder, comprising administering oromucosally a dose of about 60 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof to the patient, wherein the patient is in a non-clinical setting. 2. The method of claim 1, wherein the patient has schizophrenia. 3. The method of claim 1, wherein the patient has bipolar disorder. 4. The method of claim 3, wherein the patient has bipolar disorder I. 5. The method of claim 3, wherein the patient has bipolar disorder II. 6. The method of claim 1, wherein the non-clinical setting is at home, a group home, an assisted living facility, a correctional facility, hospice or long-term care facility. 7. The method of claim 1 or 2, wherein the patient is mild to moderately agitated. 8. The method of any one of claims 1-3, wherein the patient has not more than 2 episodes of agitation a week. 9. The method of any one of claims 1-4, wherein the dexmedetomidine or a pharmaceutically acceptable salt thereof is administered to the patient through a caregiver. 10. The method of any one of claims 1-4, wherein the dexmedetomidine is self- administered by the patient. 11. The method of any one of claims 1-6, comprising administering a second dose of dexmedetomidine to the patient at least about 2 hours after a first dose if there is no improvement in PEC score by more than 2 points. 12. The method of claim 11, wherein the second dose is about 60 micrograms, about 70 micrograms, about 80 micrograms, about 90 micrograms, about 100 micrograms, about 110 micrograms, about 120 micrograms, or about 180 micrograms of dexmedetomidine or a pharmaceutically acceptable salt thereof. 13. The method of any one of claims 1-8, wherein administration of dexmedetomidine or a pharmaceutically acceptable salt thereof produces an anti-agitation effect within about 30 minutes after administration without causing significant sedation. 14. The method of any one of claims 1-9, wherein administration of dexmedetomidine or a pharmaceutically acceptable salt thereof produces an anti-agitation effect within about 120 minutes after administration without causing significant sedation. 144 290971848 v1 ATTORNEY DOCKET NO.: BXTI-051/01WO CLIENT NO.: 332712-2377 15. The method of any one of claims 1-10, comprising altering a caregiver or informant of an impending episode of agitation via an Ecological Momentary Assessment (EMA) device or other remote compatible device. 16. The method of any one of claims 1-11, comprising assessing a reduction in agitation using a modified CGI-severity (CGI-S) 4-point (0-3) scale. 17. The method of any one of claims 1-11, comprising assessing a reduction in agitation using a Positive and Negative Syndrome Scale – Excited Component (PEC) change from baseline as compared to placebo. 18. The method of any one of claims 1-13, comprising altering a caregiver of a reduction in agitation via Momentary Assessment (EMA) device or other remote compatible device. 19. The method of any one of claims 1-14, comprising assessing severity of agitation via a wearable device or a sensor in contact with the patient’s body. 20. The method of any one of claims 1-16, comprising administering dexmedetomidine or a pharmaceutically acceptable salt thereof buccally, sublingually, or gingivally to the patient. 21. The method of any one of claims 1-16, wherein the composition is a film, a tablet, film, spray, gel, or drops. 22. The method of any one of claims 1-17, wherein the patient is 18 years or older. 23. The method of any one of claims, wherein the patient has at least one episode of agitation in the past one month. 145 290971848 v1
PCT/US2023/073874 2022-09-11 2023-09-11 Methods for treating agitation in community settings WO2024055042A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110021588A1 (en) * 2009-05-15 2011-01-27 Recro Pharma, Inc. Sublingual dexmeditomidine compositions and methods of use thereof
US20190365715A1 (en) * 2016-12-31 2019-12-05 Bioxcel Therapeutics, Inc. Use of sublingual dexmedetomidine for the treatment of agitation
US20200345635A1 (en) * 2018-06-27 2020-11-05 Bioxcel Therapeutics, Inc. Film formulations containing dexmedetomidine and methods of producing them
WO2021016112A2 (en) * 2019-07-19 2021-01-28 Bioxcel Therapeutics, Inc. Non-sedating dexmedetomidine treatment regimens

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110021588A1 (en) * 2009-05-15 2011-01-27 Recro Pharma, Inc. Sublingual dexmeditomidine compositions and methods of use thereof
US20190365715A1 (en) * 2016-12-31 2019-12-05 Bioxcel Therapeutics, Inc. Use of sublingual dexmedetomidine for the treatment of agitation
US20200345635A1 (en) * 2018-06-27 2020-11-05 Bioxcel Therapeutics, Inc. Film formulations containing dexmedetomidine and methods of producing them
WO2021016112A2 (en) * 2019-07-19 2021-01-28 Bioxcel Therapeutics, Inc. Non-sedating dexmedetomidine treatment regimens

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