Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/22—Hormones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/22—Hormones
  • A61K38/25—Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • 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
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • 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
  • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
  • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms

Definitions

• This disclosure is directed to methods for treating sustained mild traumatic brain injuries which injuries include, by way of example, concussions, and other such neurological disorders.
• the methods employ an effective amount of a composition comprising ghrelin or a ghrelin variant.
• This disclosure is also directed to a kit of parts comprising multiple doses of ghrelin or a variant thereof.
• Mild traumatic brain injuries typically including concussions, having “your bell rung,” and the like, describe an insult to the brain that, in turn, can cause long term injury to the brain. It most often occurs from direct contact to the head, but can also result from indirect injury (e.g., whiplash injury or violent shaking of the head). Individuals who have suffered one brain injury are more at risk for a second brain injury and more susceptible for subsequent injuries. The damage from successive mTBIs is cumulative. (Cantu, R.C., Second- impact syndrome, Clinics in Sports Medicine, 17(I):37-44, 1998).
• the long term damage arising from mTBI include cognitive and motor skill deterioration such as psychomotor slowing, poor concentration and attention retrieval resulting in increased variability of performance, and overall executive dysfunction, as well as sleep dysfunction, and emotional/behavioral changes (Stuns, et ah, ‘Adult Clinical Neuropsychology: Lessons from Studies of the Frontal Lobes’, Annual Review of Psychology , 53, 401-433 (2003)).
• cognitive and motor skill deterioration such as psychomotor slowing, poor concentration and attention retrieval resulting in increased variability of performance, and overall executive dysfunction, as well as sleep dysfunction, and emotional/behavioral changes
• Common examples of long term effects of mTBI are found in soldiers, boxers, soccer players, and the like.
• individuals who, long after the occurrence of the mTBI(s) begin to manifest the cumulative damage to the brain by loss of one or more cognitive skills and/or motor skills.
• mTBI is caused by one or more injuries as opposed to an underlying disease modality. That is, the injuries to the brain cannot be attributed to an underlying pathology but, rather are the results of the injuries.
• Short-term symptoms of mTBI include, among others, headaches, loss of clarity or confusion, difficulty in focusing, double vision, blurry vision, sleep dysfunction, emotional/behavioral changes, emotional outbursts, and loss of memory. Described herein are improvements in treating mTBI, including mTBI that is sustained or poorly resolved. Summary
• PCS post concussion syndrome
• ghrelin Treatment of mTBI with ghrelin or a variant thereof has been described, for example, in U.S. Patent Application Publication No. 2017/0281732 which is incorporated herein by reference in its entirety.
• ghrelin can be administered within 72 hours after the occurrence of the injury.
• ghrelin treatment mitigates one or more symptoms of mTBI in a subject with a sustained mTBI, even several days to weeks after the initial injury.
• This disclosure is directed in part to methods for mitigating one or more debilitating symptoms of a mTBI for a patient diagnosed with a sustained mTBI.
• this disclosure involves the administration of ghrelin or a variant thereof over one or multiple consecutive days after the diagnosis of a sustained mTBI.
• the present disclosure also relates to treatment of mTBI with multiple doses of ghrelin or variant thereof. That is, in one embodiment, mTBI (acute, sustained, and/or PCS) may be treated by administering ghrelin or a variant thereof two or more times a day for at least one day. In one embodiment, mTBI (acute, sustained, and/or PCS) may be treated by administering ghrelin or a variant thereof one or more times per day for at least 2 days.
• ghrelin administration is continued until the patient’s symptoms are resolved. In one embodiment, ghrelin administration is continued until the patient is able to resume normal activities. In one embodiment, ghrelin administration is continued until the patient is cleared by a clinician to resume normal activities. “Normal activities” may be any activities that were interrupted by the mTBI. For example, the patient may have been instructed (e.g., by a clinician) not to perform certain tasks, not to return to work, school, sport activities, or some other activity due to the mTBI. Alternatively, the patient may have been unable to perform the task, and/or the task may have been uncomfortable or otherwise undesireable, due to the mTBI.
• a method for mitigating one or more debilitating symptoms of mTBI for a patient diagnosed with a sustained mTBI which method includes administering to the patient an effective amount of ghrelin or a variant thereof over multiple consecutive days after the diagnosis of a sustained mTBI.
• the methods can include selection or identification of a patient exhibiting one or more symptoms of a sustained mTBI.
• administration of ghrelin or a variant takes the form of a continuous release patch or transdermal device which is optionally replaced during treatment.
• ghrelin or a variant is administered orally, e.g., sublingually.
• ghrelin or a variant is administered by injection.
• ghrelin administration takes the form of one or more administration(s).
• the administration can be one or more administrations for 1-2 days.
• the administration can be one or more administrations per day for a period of at least 3 days and preferably at least 5 days and more preferably at least 7 days after diagnosis of a sustained mTBI.
• only a single administration per day is employed and administration is done on a daily basis.
• administration takes the form of a medicament loaded syringe.
• kits of parts comprising a plurality of single dose compositions of ghrelin each composition marked, labeled or otherwise identified for administration on a treatment schedule.
• concentration for each single dose composition of ghrelin is tapered from an initial dose to a final dose over a period of at least 3 days, preferably at least 5 days and more preferably at least 7 days.
• concentration of ghrelin is reduced from the first dose to the final dose such that the last dose has a ghrelin concentration that is no more than 50% of the initial dose.
• compositions and methods are intended to mean that the compositions and methods include the recited elements, but not excluding others.
• compositions and methods shall mean excluding other elements of any essential significance to the comTBInation for the stated purpose.
• a composition consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed disclosure.
• Consisting of shall mean excluding more than trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this disclosure.
• ghrelin refers to the naturally occurring peptide comprising 28 amino acids that include an N-octanoyl group at the 3-position of serine.
• the amino acid sequence of ghrelin is known.
• ghrelin variant refers to peptides that include a C-terminal alkyl ester (- COOR) where R is Ci-Ce alkyl, Cb-Cb alkenyl or Cb-Cb alkynyl; a N-terminal amide (R 1 C(0)NH-) where R 1 is Ci-Cb alkyl, C2-C6 alkenyl or C2-C6 alkynyl; a comTBInation of a C-terminal alkyl ester and a N-terminal amide both as defined above; and/or a ghrelin variant as described in U.S. Patent Application Publication No. 2017/0281732, which is incorporated herein by reference in its entirety, including for all compositions, formulations, and methods taught therein.
• administration refers to dosing a patient with an effective amount of a composition comprising ghrelin (or variant) wherein the dosing can be a single administration, continuous or intermittent or by several subdoses that in the aggregate provide for a single dose.
• dosing may be continued throughout the course of treatment that may be as short as 1-2 days, 3 days or as long as 7 or more days such as 10 days, 12 days or 14 days, wherein treatment is initiated after diagnosis of a sustained mTBI.
• the route of administration is selected by the attending clinician and is based on factors such as the age, weight and general health of the patient as well as the severity of the condition. Suitable routes include parenteral, intravenous, transdermal, vaginal, nasal, sublingual, pulmonary, and the like.
• asymptomatic means that the patient reports that s/he has no remaining debilitating symptoms of the sustained mTBI. While some mild symptoms may persist, debilitating symptoms such as, by way of example only and without limitation, debilitating headaches, double vision, blurred vision, nausea, migranes, and confusion have abated. In some cases, the patients is able to resume most if not all of his/her day-to-day or normal activities.
• traumatic brain injury can be rated as mild, moderate or severe based on TBI variables that include duration of loss of consciousness (LOC), Glasgow Coma Score (GCS) and post traumatic stress amnesia (see, e.g., Levin et al, "The Galveston Orientation and Amnesia Test: a practical scale to assess cognition after head injury," J Nervous Mental Dis 167: 675-84 (1979); Holm et al.,” J.
• a brain injury can be classified as a mild brain injury when a patient has a GCS score of 13-15, post-traumatic amnesia of less than 1 day, and/or a LOC of between 0 to 30 minutes.
• sustained mTBI (sometimes referred to as a “poorly resolved mTBI”) means that one or more symptoms of a mTBI are not resolved after several days to weeks after the initial injury such that the patient remains debilitated. In one embodiment, one or more of the symptoms of the mTBI persist for at least 7 days after the injury. However, a sustained mTBI is not to be confused with a PCS which requires a much prolonged duration of symptoms (typically about 30 days or more) than that of a sustained mTBI.
• the methods described herein treat patients who are diagnosed as having a sustained mTBI. Such a diagnosis and selection or identification of such patients may be made based on the continuation of debilitating symptoms for mTBI, for example at least 3, 4, 5, 6, or 7 days after the insult arising from the mTBI, without a diagnosis of PCS. Many patients who suffer from mTBI do not seek immediate medical treatment and only do so when the debilitating symptoms of that mTBI do not resolve in a timely manner.
• the methods described herein further relate to treatment of patients having mTBI with ghrelin or variant thereof by administering multiple doses (administrations) and/or for multiple days.
• the mTBI is acute mTBI.
• the mTBI is sustained mTBI.
• the mTBI is PCS.
• the mTBI is not acute mTBI.
• the mTBI is not PCS.
• ghrelin or a variant thereof is administered as a one day treatment, and/or daily ghrelin administration for multiple consecutive days after diagnosis.
• such treatment may be initiated at least 3 days after the mTBI.
• treatment with ghrelin or variant is initiated at least 4 days after the mTBI.
• treatment with ghrelin or variant is initiated at least 5 days after the mTBI.
• treatment with ghrelin or variant is initiated at least 6 days after the mTBI.
• treatment with ghrelin or variant is initiated at least 7 days after the mTBI.
• treatment with ghrelin or variant is initiated at least 8 days after the mTBI. In embodiments, treatment with ghrelin or variant is initiated at least 9 days after the mTBI. In embodiments, treatment with ghrelin or variant is initiated at least 10 days after the mTBI. In embodiments, treatment with ghrelin or variant is initiated at least 2 weeks after the mTBI. In embodiments, treatment with ghrelin or variant is initiated at least 4 weeks after the mTBI. In embodiments, treatment with ghrelin or variant is initiated between about 3 days and about 30 days after the mTBI. In embodiments, treatment with ghrelin or variant is initiated between more than 3 days and about 30 days after the mTBI.
• treatment with ghrelin or variant is initiated between about 4 days and about 30 days after the mTBI. In embodiments, treatment with ghrelin or variant is initiated between about 7 days and about 30 days after the mTBI. In embodiments, treatment with ghrelin or variant is initiated between about 7 days and about 28 days after the mTBI. In embodiments, treatment with ghrelin or variant is initiated between about 7 days and about 21 days after the mTBI. The number of days may be any value or subrange within the recited ranges, including endpoints. [0034] In embodiments, ghrelin or a composition comprising ghrelin is administered.
• a ghrelin variant or a composition comprising a ghrelin variant is administered.
• Ghrelin or a variant can be administered in single adminstration or multiple administrations for a day or for multiple days.
• the ghrelin or variant can be administered each day for at least 1 day.
• the ghrelin or variant can be administered each day for at least 2 days.
• the ghrelin or variant can be administered each day for at least 3 days.
• the ghrelin or variant can be administered each day for at least 4 days.
• the ghrelin or variant can be administered each day for at least 5 days.
• the ghrelin or variant can be administered each day for at least 6 days. In one embodiment, the ghrelin or variant can be administered each day for at least 7 days. In one embodiment, the ghrelin or variant can be administered each day for at least 8 days. In one embodiment, the ghrelin or variant can be administered each day for at least 9 days. In one embodiment, the ghrelin or variant can be administered each day for at least 10 days. In one embodiment, the ghrelin or variant can be administered each day for at least 11 days. In one embodiment, the ghrelin or variant can be administered each day for at least 12 days. In one embodiment, the ghrelin or variant can be administered each day for at least 13 days.
• the ghrelin or variant can be administered each day for at least 14 days. In some cases, daily ghrelin or variant administration is continued up to 14 days. In an embodiment, ghrelin or variant can be administered daily for between 1 and 14 days. In an embodiment, ghrelin or variant can be administered for more than 14 days. In an embodiment, ghrelin or variant can be administered until one or more symptoms of the mTBI (or sustained mTBI or PCS) is resolved. In an embodiment, the ghrelin or variant can be administered continuously (e.g., using a transdermal patch) for between 1 and 14 days or more.
• ghrelin or variant can be administered at least once per day. In one embodiment, ghrelin or variant can be administered at least twice per day. In one embodiment, ghrelin or variant can be administered at least 3 times per day. In one embodiment, ghrelin or variant can be administered at least 4 times per day. In one embodiment, ghrelin or variant can be administered at least 5 times per day. In one embodiment, ghrelin or variant can be administered once per day. In one embodiment, ghrelin or variant can be administered twice per day. In one embodiment, ghrelin or variant can be administered 3 times per day. In one embodiment, ghrelin or variant can be administered 4 times per day.
• ghrelin or variant can be administered 5 times per day.
• patients with acute mTBI are sent home once a clinician has determined that the mTBI does not pose an immediate risk.
• sustained mTBI e.g., unresolved symptoms that last days, weeks, or months after the intial injury
• a treatment for sustained mTBI e.g. treatment that is significantly later in time than the acute injury and where the underlying adverse events in the brain have gone on unabated.
• These methods may be predicated on a dosing schedule that requires daily ghrelin administration over the course of one or several days so as to both mitigate the debilitating symptoms of the mTBI and to address the adverse condition of the brain.
• a patient having sustained mTBI is selected for treatment.
• a patient having one or more symptoms (e.g., debilitating symptoms) of mTBI at least 3 days after injury is selected.
• a patient having one or more symptoms (e.g., debilitating symptoms) of mTBI at least 4 days after injury is selected.
• a patient having one or more symptoms (e.g., debilitating symptoms) of mTBI at least 5 days after injury is selected.
• a patient having one or more symptoms (e.g., debilitating symptoms) of mTBI at least 6 days after injury is selected.
• a patient having one or more symptoms (e.g., debilitating symptoms) of mTBI at least 7 days after injury is selected.
• a patient having acute mTBI is selected.
• a patient who does not have acute mTBI e.g., at least 3, at least 7, e.g. days after injury
• a patient having PCS is selected.
• a patient who has not been diagnosed as having PCS is selected.
• kits of parts comprising a plurality of single dose compositions of ghrelin each composition marked, labeled or otherwise identified for administration on a treatment schedule.
• concentration for each single dose composition of ghrelin is the same throughout the treatment period.
• concentration of ghrelin is reduced or tapered from an initial first dose to a final dose over a period of at least 1, 2, or 3 days, preferably at least 5 days and more preferably at least 7 days.
• the concentration of ghrelin is reduced from the first dose to the last dose such that the last dose has a ghrelin concentration that is no more than about 50% of the first dose.
• the ghrelin concentration changes at least twice during the treatment period.
• Example ghrelin concentration changes are provided in Table 1. Table 1
• mTBI is diagnosed using one or more diagnostic devices or protocols.
• the methods provided herein are used in conjunction with one or more recovery protocols.
• a potential brain injury can be diagnosed and/or monitored utilizing the BTrackSTM System (balancetrackingsystems.com/; Balance Tracking Systems Inc.), utilizing the NFL Concussion Tool, “sports concussion assessment tool” (“SCAT-2;” static.nfl.com/static/content/public/photo/2014/02/20/0ap2000000327062.pdf, which is incorporated herein by reference in its entirety) or other similar tools utilized by the NHL, the NBA, FIFA, rugby leagues and unions, boxing organizations, etc.
• GFAP Glial Fibrilliary Acid Protein
• a subject administered ghrelin or variant as described herein may show improvement on one or more assessment tools, when evaluated before, during, and/or after the administration. Any suitable tool may be used, as would be recognized by one of skill in the art.
• the subj ect shows improvement in number of symptoms and/or severity in sub-acute concussion.
• the subj ect shows improvement on the Post-Concussion Symptom Score questionnaire (PCSS) (available at: hawaiiconcussion.com/downloads/Post-Concussion-Symptom-Scale.pdf, which is incorporated by reference herein in its entirety).
• PCSS Post-Concussion Symptom Score questionnaire
• the PCSS may be used as an overall measure of symptom burden.
• the subject shows improvement in quality of life.
• the subject shows improvement on the Quality of Life after Brain Injury scale (QOLIBRI) (Qolibri. Quality of Life Assessment for TBI. Available from: qolibrinet.com, which is incorporated herein by reference in its entirety).
• QOLIBRI Quality of Life after Brain Injury scale
• the QOLIBRI is a 37 item instrument specifically developed to assess health-related quality of life (HRQoL) of individuals after traumatic brain injury.
• the subject shows improvement on the Patient Global Assessment of Status (PGAS).
• This tool may utilize a visual analog scale (VAS) to simply assess the patient’s global assessment of their symptoms via the question “How would you rate the effect of your symptoms on how you feel or function today?”
• VAS visual analog scale
• the subject shows improved cognitive function.
• the subject shows improvement on BrainCheck. See, Yang, S., et al., Diagnostic accuracy of tablet-based software for the detection of concussion. PLoS One, 2017. 12(7): p. eO 179352, which is incorporated herein by reference in its entirety.
• the subject shows improvement in one or more of the tests measured by BrainCheck.
• BrainCheck is a validated digital assessment tool to aid in the diagnosis of mild cognitive decline. The tool measures a battery of 7 tests to measure cognition, reaction time, and balance. BrainCheck is a Class II medical device by the FDA.
• BrainCheck assessments include a coordination balance test measuring static and dynamic balance using the Ebbinghaus Illusion, a digit symbol substitution test for general cognitive performance, the Flanker test measuring visual attention, the Stroop Effect measuring reaction time, Trails A&B measuring visual attention and task switching and Recall tests to measure immediate and delayed memory. All scoring algorithms compare test results to a normative age matched dataset.
• the subject shows improvement in any one or more of the assessments of more than about 10%.
• the subj ect shows improvement in any one or more of the assessments of more than about 15%.
• the subject shows improvement in any one or more of the assessments of more than about 20%.
• the subject shows improvement in any one or more of the assessments of more than about 25%.
• the subject shows improvement in any one or more of the assessments of more than about 30%. In one embodiment, the subject shows improvement in any one or more of the assessments of more than about 35%. In one embodiment, the subject shows improvement in any one or more of the assessments of more than about 40%. In one embodiment, the subject shows improvement in any one or more of the assessments of more than about 45%. In one embodiment, the subject shows improvement in any one or more of the assessments of more than about 50%. In one embodiment, the subject shows improvement in any one or more of the assessments of more than about 60%. In one embodiment, the subject shows improvement in any one or more of the assessments of more than about 70%. In one embodiment, the subject shows improvement in any one or more of the assessments of more than about 80%.
• the subject shows improvement in any one or more of the assessments of more than about 90%. In one embodiment, the subject shows improvement in any one or more of the assessments of up to about 100%. The improvement may be between any two time points, e.g., before, during, and/or after administration of ghrelin or variant.
• Ghrelin or a variant thereof will be administered in a therapeutically effective amount by any of the accepted modes of administration suitable for delivery of a peptide.
• the actual amount of ghrelin or a variant thereof is dependent upon numerous factors such as the severity of the symptoms to be treated, the age and otherwise relative health of the subject, the route and form of administration, and other factors well-known to the skilled artisan.
• an effective amount or a therapeutically effective amount or dose of ghrelin or a variant thereof refers to that amount that results in amelioration of debilitating symptoms in a patient.
• Specific dosages may vary within a range depending upon the dosage form employed and/or the route of administration utilized. The exact formulation, route of administration, dosage, and dosage interval should be chosen according to methods known in the art, in view of the specifics of a subject’s condition.
• the effective amount of ghrelin or a variant thereof ranges from about 10 ng/kg to about 10 mg/kg per day. In one embodiment, the effective amount of ghrelin or a variant thereof ranges from about 1 pg/kg to about 10 mg/kg per day. In one embodiment, the effective amount of ghrelin or a variant thereof ranges from about 1 pg/kg to about 1 mg/kg per day. In one embodiment, the effective amount of ghrelin or a variant thereof ranges from about 10 pg/kg to about 1 mg/kg per day. In one embodiment, the effective amount of ghrelin or a variant thereof ranges from about 20 pg/kg to about 1 mg/kg per day.
• the effective amount of ghrelin or a variant thereof ranges from about 30 pg/kg to about 1 mg/kg per day. In one embodiment, the effective amount of ghrelin or a variant thereof ranges from about 40 pg/kg to about 1 mg/kg per day. In one embodiment, the effective amount of ghrelin or a variant thereof ranges from about 50 pg/kg to about 1 mg/kg per day. In one embodiment, the effective amount of ghrelin or a variant thereof ranges from about 60 pg/kg to about 1 mg/kg per day. In one embodiment, the effective amount of ghrelin or a variant thereof ranges from about 70 pg/kg to about 1 mg/kg per day.
• the effective amount of ghrelin or a variant thereof ranges from about 80 pg/kg to about 1 mg/kg per day. In one embodiment, the effective amount of ghrelin or a variant thereof ranges from about 90 pg/kg to about 1 mg/kg per day. In one embodiment, the effective amount of ghrelin or a variant thereof ranges from about 100 pg/kg to about 1 mg/kg per day. In one embodiment, the effective amount of ghrelin or a variant thereof ranges from about 10 pg/kg to about 0.1 mg/kg per day. The effective amount may be any value or subrange within the recited ranges, including endpoints.
• compositions are not limited to any particular composition or pharmaceutical carrier, as such may vary.
• ghrelin or a variant thereof will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
• parenteral e.g., intramuscular, intravenous or subcutaneous
• administration is parenteral using a dosage regimen that can be adjusted as provided above.
• Other pharmaceutical compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
• compositions of this invention can include one or more physiologically acceptable inactive ingredients that facilitate processing of active molecules into preparations for pharmaceutical use.
• one pharmaceutical composition for use in the methods described herein is a sterile, aqueous composition such as those suitable for intravenous or intramuscular injection.
• such compositions are pre loaded into syringes for use by the clinician or the patient.
• the syringes are loaded into a container and are labeled, marked or otherwise identified as for use on a given day. For example, in a 7 day treatment regimen, the identication for each syringe will indicate that it is for day 1 , or day 2 and so on.
• the pharmaceutical composition can take the form of a transdermal patch that provides for continuous release of ghrelin or a variant thereof in amounts such that the aggregate delivered in a given day is an effective amount as provided above.
• ghrelin has a serum half-life of about 30 minutes, continuous release allows for continuous presence in the serum as well as in the brain.
• ghrelin When administration of ghrelin is via a transdermal patch, a single or multiple number of patches can be used. In a preferred embodiment, the multiple number of patches are used where each patch is identified for use in a given day of treatment. Each patch can contain the same dosing of ghrelin or a variant thereof or the dosing can be tapered as provide previously.
• the patch can be formulated to provide the same dose per day of ghrelin or a variant thereof.
• the patch can be formulated so as to provide for a tapering of the dosing of ghrelin or variant thereof over the treatment period.
• this invention provides for a kit of parts comprising a plurality of single dose compositions of ghrelin each composition marked, labeled or otherwise identified for administration on a treatment schedule.
• the concentration for each single dose composition of ghrelin is tapered from an initial first dose to a final dose over a period of at least 3 days, preferably at least 5 days and more preferably at least 7 days.
• the concentration of ghrelin is reduced from the first dose to the last dose such that the last dose has a ghrelin concentration that is no more than 50% of the first dose.
• the drug product is supplied in a 5 mL clear, borosilicate glass vial with a butyl- rubber closure (fluoro-resin film laminated), as a sterile lyophilized white powder or cake equivalent to 14 mg of OXE-103 as the active ingredient and sucrose (inactive ingredient). Matching placebo and diluent product is used.
• OXE-103 drug product, placebo, and diluent are stored refrigerated between 2°C to 8°C (35.6°F to 46.4°F).
• Reconstituted OXE-103 for SC administration 14 mg (in 5 mL multi use vials) is stable for up to 14 days at 10°C or for up to 3 days when stored at 25°C/1000 Lux.
• the reconstituted drug product (and placebo) is stored refrigerated at 2°C to 8°C (35.6°F to 46.4°F).
• a pilot study to treat sub-acute concussion with ghrelin (OXE-103) is performed.
• a treatment group (OXE-103) is compared to a placebo group in randomized, double blind fashion and compared using self-report symptom scoring, quality of life questionnaires, computerized cognitive testing assessing executive function, memory and processing speed, and accelerometer-based balance scoring.
• the exploratory nature of this study is not powered to yield statistically significant outcomes, but allows detection of trends within subjects and between groups, supports comparison with standard tests of neurocognitive functions, and provides sample size estimates for future studies of people with persistent concussion related symptoms.
• Subjects are both men and women, ages 18-55 years old, with a concussion resulting from a direct or indirect blow, rotation, or whiplash injury to the head or body. They are enrolled within 28 days post injury. Subjects are screened for 7 days to establish stability of their symptoms prior to treatment. Subjects have a symptom severity score of > 20 or higher at the time of randomization (end of screening) in order to reduce the expected degree (number and severity) of spontaneous symptom resolution prior to study completion.
• Subjects are excluded if during screening they demonstrate 1) improvement of symptom severity or number of symptoms on two consecutive screening assessments or 2) they show a > 20% reduction in symptom severity or number of symptoms.
• Subjects with pre-existing neurologic conditions other than mTBI are excluded.
• Subjects who have been treated with Donepezi! (Aricept) and/or memantine (Namenda) after the TBi are excluded.
• Subjects receiving other concomitant medications, physical therapy, or other treatments related to their current TBI are eligible 1) if they meet the inclusion criteria related to lack of improvement during the screening period and 2) if such treatments were initiated at least 7 days prior to enrollment and screening. Subjects who are not able to inject themselves are excluded. Ultimately study subject participation is at the discretion of the study physician.
• Described herein is a randomized, double-blind, placebo-controlled design where 40 subjects will be randomized to either a placebo cohort or a treatment with OXE-103 cohort.
• Subjects receive an 8-day supply of syringes pre-loaded with OXE-103 or placebo. Each cohort receives the 2nd set of syringes with OXE-103 or placebo at the day 7 visit. No therapies other than OXE-103 are administered during the 14-day treatment period to either cohort. After completion of 14 days of either placebo or OXE-103 treatment, starting with the Day 14 visit, other medications and therapies can be initiated for either cohort as needed.
• Subject training [0075] Subjects are provided with instructions for SC self-administration of OXE-103 and placebo. Subjects are trained to inject themselves and need to demonstrate competency by self-administering the first dose of the study drug at the study site.
• a subject is accompanied by a reliable and willing household member, that individual is trained to administer study drug to the subject and will be required to demonstrate competency at the study site. If neither self-administration nor administration by a household member is feasible, the subject will be deemed ineligible to participate.
• Subjects are instructed on storage of the drug/placebo according to the parameters.
• a study team member documents the storage location for each subject enrolled. Subjects are asked to inject the first daily dose in the morning, after eating. The second dose occurs in the evening, again after eating.
• Attrition This is a pilot study and no previous data exists as a basis to estimate attrition for this study. Any study participant who withdraws consent or is removed from the study during the 28-day trial period or does not successfully complete the protocol required 14 days of dosing may be replaced to allow for 40 subjects who complete the protocol.
• Target Duration The target duration of the treatment intervention with OXE-103 is two weeks. The total involvement in the study including screening and follow up assessments are 8 weeks.
• Symptom reduction Our primary goal is to describe the change in number of symptoms and/or severity in sub-acute concussion with treatment with OXE-103 using the PCSS at days 1 and 15. We will also collect data at days 21 and 44 to potentially describe long term changes and potential lasting effect (AIM 4).
• Subjects complete the PCSS at the following timepoints[17]: upon signing consent (score must >20) (day -7), mid-way through the screening period (day -3), prior to assignment of a treatment cohort (score must >20) (day 1), as well as days 4, 8, 11, 15, 21 and 44. Subjects are instructed to record their symptoms at the same time of day for each assessment timepoint. There can be a two-hour window either way. (e.g. 12PM +/- 2 hrs.) The PCSS is recorded via a RedCap survey.
• the PCSS is a self-reported assessment of 22 symptoms using a Likert-type scale ranging from 0-6, with 0 indicating no difficulty with the outlined symptom and ratings of 1 -6 representing mild-to-severe difficulty with the symptom.
• the reliability and validity of the PCSS are well documented [18-20]
• 4MBS most burdensome symptoms
• the 22 symptom PCSS assessment is designed to cover the full spectrum of concussion related symptoms across cognitive, emotional and somatic domains.
• the PCSS is particularly useful for diagnosis and monitoring recovery of patients post injury.
• the number of symptoms across cognitive, emotive and somatic domains due to the number of symptoms across cognitive, emotive and somatic domains, resolution of several mild symptoms may result in a change in the overall symptom score with relatively minor clinical impact on the patient’s well-being.
• Pre-IND feedback already obtained from the FDA has noted that an effective therapy for concussion must impact the way a patient feels or functions.
• 4MBS we are likely to be able to correlate symptom scores with improvement in the quality of life tools also being used in the study.
• the completion of the PCSS will take an estimated 5 minutes.
• Quality of Life A secondary goal is to examine change in quality of life with treatment of sub-acute concussion. Without bewing bound by theory, it is hypothesized that OXE-103 will reduce symptoms when comparing days 1 and 15 and therefore improve quality of life as assessed by 1) Quality of Life after Brain Injury scale (QOLIBRI) and 2) a PGAS.
• QOLIBRI Quality of Life after Brain Injury scale
• the QOLIBRI is a 37 item instrument specifically developed to assess health-related quality of life (HRQoL) of individuals after traumatic brain injury [21]. This is built into a RedCap Survey that will be completed online. Since it was developed for TBI as a disease or condition-specific HRQoL instrument, it is expected to be more sensitive than generic quality of life tools.
• the QOLIBRI was developed by an international task force in two multi language studies involving over 2000 persons after TBI. Use of a TBI-specific assessment of HRQoL can detect the effects of interventions by measuring physical, psychological, daily life and psychosocial changes typical of TBI. An increase/decrease of 20% in QOLIBRI is judged to represent an improvement. [0084] In addition, a PGAS is used in this study.
• the tool utilizes a visual analog scale (VAS) to simply assess the patient’s global assessment of their symptoms via the question “How would you rate the effect of your symptoms on how you feel or function today?”. Patients are instructed to use a slider tool within RedCap to rate the effects of their symptoms from 0 to 10 (with 0 being no effect and 10 being worst effect). An increase/decrease of 20% in PGAS is considered to indicate improvement.
• VAS visual analog scale
• Cognitive testing (AIM 5): A secondary outcome measure is to summarize change in cognitive function in the 2 groups. Without being bound by theory, it is hypothesized that the mechanism of action of OXE-103 will allow an improvement in cognitive function.
• BrainCheck is a validated digital assessment tool to aid in the diagnosis of mild cognitive decline. The tool measures a battery of 7 tests to measure cognition, reaction time, and balance. BrainCheck is a Class II medical device by the FDA. BrainCheck assessments include a coordination balance test measuring static and dynamic balance using the Ebbinghaus Illusion, a digit symbol substitution test for general cognitive performance, the Flanker test measuring visual attention, the Stroop Effect measuring reaction time, Trails A&B measuring visual attention and task switching and Recall tests to measure immediate and delayed memory. All scoring algorithms compare test results to a normative age matched dataset. All these tests are simple video games that require no special skills and are expected to cause no distress.
• the total time to complete the battery of tests is estimated to be 15 minutes.
• BrainCheck will be conducted in clinic on days 1, 7, 14, and 45; and are conducted by the subject at home on days 3, 10, and 21.
• the iPads are given to the subjects at the completion of all study procedures as compensation for their time. If a subject withdraws from the study, they will be asked to return the iPad to the study team.
• Electronic PHI data is kept on HIPAA compliant servers.
• the computers are all password protected. Server access is limited to study team and IT representatives. Access to study specific data and communications relating to the study is limited to the PI and Pi's staff, study personnel, responsible individuals from the study sponsor and appropriate regulatory agencies.
• the research data are be added to the subject's medical records.
• AWS Amazon work servers
• CISO AWS Chief Information Security Officer
• AWS meets criteria for security, availability, and confidentiality in the American Institute of Certified Public Accountants (AICPA) TSP Section 100, Trust Services Principles and Criteria for security, availability, processing, integrity, confidentiality, and privacy.
• BrainCheck uses AWS HIPAA compliant services and holds third-party validations certifying that:
• - AWS complies with the ISO 27018 implementation guidance of controls applicable to public cloud personally identifiable information (PII) protection that supplement the ISO 27002 guidance and the ISO 27001 standard.
• PII public cloud personally identifiable information
• Information that will be transmitted from the app is limited to subject code, survey responses, and timestamps of survey responses. No location data will be transmitted. The vendor will not be permitted to attempt to re-identify subjects.
• the primary objective is to determine the proportion of subjects (responders) who experience a clinically meaningful benefit as defined by a reduction of 20% in both the number and severity of concussion related symptoms.
• Concussion related symptoms are measured using the 22 symptom PCSS. Severity of each of the 22 symptoms is graded by the patient on a 7-point Likert Scale. This scale has been used extensively to assess patients with concussion/mTBI[18, 19].
• Signed consent forms and data forms are stored in a designated file cabinet belonging to a member of the study team with limited access. Outcomes data are entered into the aforementioned REDCap database and access restricted to staff members with approval. All analyzed data are de-identified before submitting to the sponsor or scientific journals, etc. per HIPAA guidelines. Each participant will be assigned a unique study number to allow tracking of information over time. Personally-identifying information is removed from initial data once a study number has been assigned, and from subsequent data once new data has been matched to an existing study number. The identity of participants and their associated study numbers are housed in the Velos system, which will only be accessible by study team members who have authorization to access.

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