WO2019111053A2 - Methods for treating obsessive compulsive disorder - Google Patents

Methods for treating obsessive compulsive disorder Download PDF

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WO2019111053A2
WO2019111053A2 PCT/IB2018/001519 IB2018001519W WO2019111053A2 WO 2019111053 A2 WO2019111053 A2 WO 2019111053A2 IB 2018001519 W IB2018001519 W IB 2018001519W WO 2019111053 A2 WO2019111053 A2 WO 2019111053A2
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treatment
dtms
group
weeks
subject
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WO2019111053A3 (en
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Abraham Zangen
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Brainsway Ltd.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N2/00—Magnetotherapy
    • A61N2/004—Magnetotherapy specially adapted for a specific therapy
    • A61N2/006—Magnetotherapy specially adapted for a specific therapy for magnetic stimulation of nerve tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
    • A61B5/316—Modalities, i.e. specific diagnostic methods
    • A61B5/369—Electroencephalography [EEG]
    • A61B5/372—Analysis of electroencephalograms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N2/00—Magnetotherapy
    • A61N2/02—Magnetotherapy using magnetic fields produced by coils, including single turn loops or electromagnets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/02—Detecting, measuring or recording pulse, heart rate, blood pressure or blood flow; Combined pulse/heart-rate/blood pressure determination; Evaluating a cardiovascular condition not otherwise provided for, e.g. using combinations of techniques provided for in this group with electrocardiography or electroauscultation; Heart catheters for measuring blood pressure
    • A61B5/021—Measuring pressure in heart or blood vessels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/16—Devices for psychotechnics; Testing reaction times ; Devices for evaluating the psychological state
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
    • A61B5/316—Modalities, i.e. specific diagnostic methods
    • A61B5/369—Electroencephalography [EEG]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/40—Detecting, measuring or recording for evaluating the nervous system
    • A61B5/4076—Diagnosing or monitoring particular conditions of the nervous system
    • A61B5/4082—Diagnosing or monitoring movement diseases, e.g. Parkinson, Huntington or Tourette
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/40—Detecting, measuring or recording for evaluating the nervous system
    • A61B5/4076—Diagnosing or monitoring particular conditions of the nervous system
    • A61B5/4088—Diagnosing of monitoring cognitive diseases, e.g. Alzheimer, prion diseases or dementia

Definitions

  • the subject is a mammal.
  • the mammal is primate, and, more particularly, a human.
  • Obsessive-compulsive disorder is a highly debilitating condition with a lifetime prevalence of 2%- 3%, and a notable percentage of patients (40-60%) who have a partial or no response to medications.
  • obsessions are repetitive, intrusive, and distressing thoughts, ideas, images, or urges that often are experienced as meaningless, inappropriate, and irrelevant, and persist despite efforts to suppress, resist, or ignore them.
  • Compulsions are repetitive, stereotyped behaviors and/or mental acts that are used to diminish the anxiety and distress associated with the obsessions.
  • the first is an executive dysfunction model, implicating the dorsolateral prefrontal cortex (DLPFC), caudate nucleus, striatum, and thalamus, and proposes that the main dysfunction occurs impulse control and inhibition of behaviors.
  • DLPFC dorsolateral prefrontal cortex
  • the second is a modulatory control model, implicating the orbitofrontal cortex (OFC), medial prefrontal cortex (mPFC), and cingulate gyrus, in which the dysfunction may be one of inability to regulate socially appropriate behaviors.
  • OFC orbitofrontal cortex
  • mPFC medial prefrontal cortex
  • cingulate gyrus in which the dysfunction may be one of inability to regulate socially appropriate behaviors.
  • a Food and Drug Administration (FDA) regulated, prospective, double-blind, placebo controlled multicenter study demonstrates that high-frequency deep transcranial magnetic stimulation (dTMS) treatment over the mPFC and the anterior cingulate cortex (ACC), when applied following exposure to OCD symptom provocation, is safe, tolerable and effective in reducing OCD symptoms.
  • FDA Food and Drug Administration
  • dTMS deep transcranial magnetic stimulation
  • ACC anterior cingulate cortex
  • a method for treating a subject afflicted with obsessive compulsive disorder comprising:
  • dTMS deep transcranial magnetic stimulation
  • the stimulation is applied immediately after the inducing the personalized provocation; up to 5 minutes after the inducing the personalized provocation; or up to 30 minutes after the inducing the personalized provocation.
  • the stimulation is applied immediately after the inducing the personalized provocation; up to 5 minutes after the inducing the personalized provocation; or up to 30 minutes after the inducing the personalized provocation.
  • the stimulation is applied 3-5 minutes after the inducing the personalized provocation.
  • the provocation is designed to achieve a score of between 4 to 7 on a 1 to 10 visual analog scale (VAS) self-report and wherein the stimulation is given after a score of 4 to 7 is achieved.
  • VAS visual analog scale
  • the subject is instructed to focus his/her thoughts on the provocation during the stimulation session.
  • the high frequency ranges from 5-25Hz. In a more particular embodiment thereof, the high frequency ranges from l8-22Hz. In a more particular embodiment thereof, the high frequency is about 20Hz or is 20Hz.
  • the stimulating is effectuated at a stimulation intensity between 80% and 120% of the leg resting motor threshold (RMT).
  • the stimulating is effectuated at a stimulation intensity of 100% of the leg resting motor threshold (RMT).
  • the high frequency is 20Hz dTMS at a stimulation intensity of 100% of leg resting motor threshold (RMT) at a frequency of 2 second pulse trains and 20 second inter-train intervals for a total of 50 trains and 2000 pulses per session.
  • the stimulating of brain structures in at least one of the ACC or the mPF C is sufficient to stimulate interconnecting fibers of the at least one of the ACC or the mPF C of the subj ect’ s brain.
  • the stimulating of brain structures in at least one of the ACC or the mPFC is sufficient to stimulate brain structures in the at least one of the ACC or the mPFC, without a significant increase of electrical fields induced in superficial cortical regions of the subject’s brain.
  • the deep TMS is delivered to each subject’s skull position relative to a location on each subject’s skull identified as corresponding to a stimulation point that stimulates a muscle of the subject’s leg at leg resting motor threshold (RMT).
  • RMT leg resting motor threshold
  • the deep TMS is delivered to each subject’s skull 2 cm to 7 cm anterior to the stimulation point that stimulates the muscle of the subject’s leg.
  • the deep TMS is delivered to each subject’s skull 4 cm anterior to the stimulation point that stimulates the muscle of the subject’s leg.
  • the muscle is the tibialis muscle.
  • the stimulation intensity is 100% of the leg resting motor threshold (RMT) the deep TMS stimulates approximately 70 cm 3 of target neuronal volume above neuronal activation threshold.
  • RMT leg resting motor threshold
  • the subject afflicted with obsessive compulsive disorder is selected based on the subject’s baseline amplitude of theta frequency band during and/or following a Stroop task.
  • the baseline amplitude of the theta frequency band ranges from 4-8 Hz.
  • the subject afflicted with obsessive compulsive disorder is selected based on the subject’s lack of responsiveness to at least one of serotonin reuptake inhibitors or cognitive behavioral therapy.
  • the stimulation is given in 29 sessions over a six week period of time.
  • the stimulation is given in a range of 20 to 30 sessions over a four week to six week period of time.
  • a device for treating a subject afflicted with obsessive compulsive disorder wherein the device is as set forth in Figure 33 and wherein the device is configured to deliver deep transcranial magnetic stimulation (dTMS) to the subject’s skull such that brain structures in at least one of the ACC or the mPFC of the subject’s brain are stimulated and wherein the dTMS is delivered repetitively and at a high frequency comprising at least 5Hz.
  • the device is implement on a subject afflicted with obsessive compulsive disorder wherein the subject has undergone induction of a personalized provocation related to at least one of obsessions or compulsions of the subject.
  • FIG. 1 An illustration of the HAC-Coil Deep IMS System
  • FIG. 2 Kaplan Meier Curve of The Time To Drop-Out Up To 6 Weeks (ITT). Log-Rank p-value: 0.6109
  • FIG. 3 Total YBOCS Score Over Time To 6 Weeks And 10 Weeks Visit (mlTT)
  • FIG. 4 YBOCS Change From Baseline Over Time To 6 Weeks And 10 Weeks Visit (mlTT)
  • FIG. 5 Total CGI-I Score over Time to 6 Weeks and 10 Weeks Visit (mlTT)
  • FIG. 6 Total CGI-S Score over Time to 6 Weeks and 10 Weeks Visit (mlTT)
  • FIG. 7 CGI-S Change from Baseline over Time to 6 Weeks and 10 Weeks Visit (mlTT)
  • FIG. 8 Total SDS Score over Time to 6 Weeks and 10 Weeks Visit (mlTT)
  • FIG. 9 SDS Change from Baseline over Time to 6 Weeks and 10 Weeks Visit (mlTT)
  • FIG. 10 Total HDRS-21 Score over Time to 6 Weeks and 10 Weeks Visit (mlTT)
  • FIG. 11 HDRS-21 Change from Baseline over Time to 6 Weeks and 10 Weeks Visit (mlTT)
  • FIG. 12 Total YBOCS Score Over Time To 6 Weeks And 10 Weeks Visit (PP)
  • FIG. 13 YBOCS Change From Baseline Over Time To 6 Weeks And 10 Weeks Visit (PP)
  • FIG. 14 Total CGI-I Score Over Time To 6 Weeks And 10 Weeks Visit (PP)
  • FIG. 15 Total CGI-S Score Over Time To 6 Weeks And 10 Weeks Visit (PP)
  • FIG. 16 CGI-S Change From Baseline Over Time To 6 Weeks And 10 Weeks Visit (PP)
  • FIG. 17 Total SDS Score Over Time To 6 Weeks And 10 Weeks Visit (PP)
  • FIG. 18 SDS Change From Baseline Over Time To 6 Weeks And 10 Weeks Visit (PP)
  • FIG. 19 Total HDRS-21 Score Over Time To 6 Weeks And 10 Weeks Visit (PP)
  • FIG. 20 HDRS-21 Change From Baseline Over Time To 6 Weeks And 10 Weeks Visit (PP)
  • FIG. 21A-D Clinical effect of the treatment.
  • Panel A presents mean J SEM changes in YBOCS scores from baseline along the study, for the HF and sham groups.
  • Panel B presents the number and percentage of participants who responded to treatment (i.e. 30% reduction in symptoms at week 5) in each group.
  • Panel C and Panel D present changes from baseline in CGI-I scores and the percentage of participants that benefit from the treatment, in each group. *p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.001.
  • FIG. 22 Electrophysiological effect of the treatment. Grand averages of pre- and post-treatment EEG measurements during correct and mistake responses in the Stroop task, as recorded from the Cz electrode in theta band (4e8 Hz), are presented. Time point 0 is set at the motor response.
  • FIG. 23A-D Treatment effect on theta power during the Stroop task.
  • Panels A and C present wavelet expression of pre- and post-treatment activity, respectively.
  • Time point 0 represents motor response.
  • Panels B and D present mean J SEM theta power following correct and mistake responses, pre- and post-treatment, respectively, as detailed in the text. **p ⁇ 0.01.
  • FIG. 24 Correlation between the clinical and the electrophysiological changes. Correlation between changes in YBOCS scores and ERN amplitudes (Pre-minus post-treatment) are presented for the HF and sham groups. Analysis revealed a significant positive correlation between the two measurements only in the HF group (r % 0.63, p ⁇ 0.01).
  • FIG. 25 Consort Chart *see interim analysis for differences in sample size.
  • FIG. 26 Interim analysis for the clinical effect of the treatment. Mean + SEM changes in YBOCS scores from baseline along the study, for the LF, HF and sham groups.
  • FIG. 27 Response to treatment by gender. The number of female and male responders within the HF stimulated group. *p ⁇ 0.05
  • FIG. 28 Colored field maps for the H7 coil.
  • the H7 coil consists of 16 windings arranged in two groups (8 in each group). The windings are flexible and designed conform to the human head.
  • the maps indicate the electric field absolute magnitude in each pixel at 100% of the average leg motor threshold which was set to 100 V/m, for 14 coronal slices 1 cm apart. Red pixels indicate regions with field intensity above the threshold for neuronal activation.
  • FIG. 29 Consort diagram of the study design and allocations.
  • FIG. 30 Change in Y-BOCS scores (Mean +/- SE) from baseline throughout the study, for the high- frequency and Sham groups.
  • FIG. 31A-B Percentage of full response ( ⁇ 30% decrease) (A) and individual distribution of responders and non responders (B) in Y-BOCS scores at the week 6 visit in both treatment groups.
  • FIG. 32 Percentage of patients reported as‘moderate’ to‘very much improved’ in CGI-I in both groups.
  • FIG. 33 Perspective illustration of a coil, which is an example of a central base coil in accordance with embodiments of the present invention.
  • FIG. 33 presents a perspective illustration of a coil 1010.
  • Coil 1010 includes a base portion 12 having a base portion right side 16 and a base portion left side 18 on the two sides of central axis 14.
  • Base portion right side 16 and base portion left side 18 are substantially horizontal and parallel to central axis 14.
  • Base portion right side 16 includes multiple right side stimulating elements 20, which are spaced apart from one another by a distance D1 of approximately 0.3 cm.
  • Base portion left side 18 includes multiple left side stimulating elements 22, which are spaced apart from one another by a distance D2 of approximately 0.3 cm.
  • Right side stimulating elements 20 and left side stimulating elements 22 are configured such that when coil 1010 is placed on the head, the stimulating elements 20 and 22 lie along a top of a medial portion of the head.
  • the distance D10 between base portion left side 18 and base portion right side 16 is between 4 and 8 cm.
  • 10 is a central base coil
  • Coil 1010 further includes a return portion 32 including a return portion right side 36 and a return portion left side 38.
  • Return portion right side 36 includes right side return elements 40 which are contacting return elements 50 since they are configured to contact a skull when coil 1010 is in place.
  • Return portion left side 38 includes left side return elements 42 which are also contacting return elements 50.
  • Connecting elements 44 connect right side stimulating elements 20 to right side return elements 40 and connect left side stimulating elements 22 to left side return elements 42.
  • Connecting elements 44 and right and left side return elements 40 and 42 are curved such that right side stimu- lating elements 20, connecting elements 44 and right side return elements 40 form substantially a circular shape, and left side stimulating elements 22, connecting elements 44 and left side return elements 42 form substantially a circular shape.
  • Each of the circular shapes are configured to lie on a top and side portion of a head.
  • the distance D5 between base portion right side 16 and return portion right side 36 is approximately 6 cm.
  • the distance D6 between base portion left side 18 and return portion left side 38 is approximately 6 cm.
  • Coil 1010 is configured to be placed on medial frontal cortex regions such as medial prefrontal cortex or medial motor cortex, and is used to stimulate the medial cortex regions including motor cortex regions and, as described herein, is useful for treating OCD.
  • devices for use in treating OCD and methods for treating subjects afflicted with OCD are described herein.
  • Evidence of the utility and efficacy of such devices and methods are presented in a study relating to a prospective, double blind, randomized, sham controlled, multi-center clinical trial in outpatients recruited in both academic and private research centers.
  • the purpose of the study was to explore the safety and efficacy of Deep TMS for the treatment of Obsessive Compulsive Disorder.
  • the study was conducted at 11 study sites around the globe.
  • Patients were screened based on the inclusion/exclusion criteria described in the study protocol after a written informed consent was obtained from the patient.
  • subjects were randomly assigned to either active DTMS or Sham treatment (1 : 1 ratio) using an IWRS system. Subjects were stratified per center.
  • TMS sessions were performed daily for 6 weeks (29 DTMS sessions). Treatment was administered according to a predefined treatment protocol (20 Hz, 100% stimulation intensity of the measured MT, 2 sec pulse trains, 20 sec inter-train intervals, 50 trains, 2000 pulses per session).
  • Hie primary psychiatric assessment conducted during the study to evaluate efficacy was the Yale-Brown Obsessive Compulsive Scale (YBOCS). Additionally, other psychiatric assessments were performed during tire study, including the Sheehan Disability Scale (SDS) and the Clinical Global impression (Severity and Improvement; CGI-S and CGI -I).
  • SDS Sheehan Disability Scale
  • CGI-S and CGI -I Clinical Global impression
  • SSI Scale for Suicide Ideations
  • Safety assessments also included cognitive changes evaluations performed throughout the study, including the Mini-Mental Status.
  • MMSE Buschke Selective Reminding Test
  • AMI-SF Autobiographical Memory' Interview' --- Short Form
  • the Intent-to-treat (ITT) analysis set includes 99 randomized patients, as one subject withdrew consent (patient did not tolerate the stimulation used to measure the motor threshold). The subject withdrew' consent after randomization, but before receiving even one active/sham treatment. Thus, the subject is not included m the ITT analysis set. 48 subjects were randomized to receive active treatment (DTMS) and 51 to receive Sham treatment. Baseline demographic information and safety and tolerability ' results are presented for the Intent-to-treat (ITT) analysis set.
  • Efficacy results are presented for the modified ITT (mITT) analysis set, which included 94 subjects who met the study eligibility criteria. The subjects excluded from this analysis set were those subjects that did not meet the inclusion/exclusion criteria for the study and did not receive at least one treatment session.
  • mITT modified ITT
  • Hie baseline demographic data, general medical and psychiatric history, concomitant medications, baseline assessment scores and physical and neurological examination data were analyzed to assess if there were any basic differences between the treatment groups prior to commencement of the clinical study (Tables 9- 18).
  • the baseline demographic information, including age, gender and the medical and psychiatric history' data did not show' any significant differences in the data between the treatment groups, except for age of onset of OCD. Although, the age at which professional help was first sought was not statistically different between the groups, therefore, this data does not seem to affect the study outcome.
  • the baseline assessment scores were very similar between the treatment groups, with no significant differences. This was true of the physical and neurological examination data, as well . The above data demonstrated that there were no significant differences between the study treatment groups.
  • the primary' efficacy end-point was the change from baseline in YBOCS scores to the 6 week visit.
  • the primary' efficacy analysis was conducted on all evaluable subject data, in the mITT analysis set.
  • the change from baseline m the YBOCS score (Table 21) demonstrates that the YBOCS score decreased by 6.7 points in the DTMS group and by 3.6 points in the Sham group at the 6 week visit.
  • the effect size of the study is 0.69 (Cohen's D). According to widely accepted guidelines, in which 0.2 is defined as a small effect, 0.5 as a medium effect, and 0.8 as a large effect, the DTMS multicenter study may be considered to have a greater than medium to large effect size.
  • the DTMS has a positive treatment outcome and has demonstrated a beneficial effect in reducing OCD symptoms in moderate to severe OCD patients.
  • the reduction in the YBOCS of 6.0 points is clinically meaningful and statistically significant compared to the sham and the effect size of 0.69 demonstrates a difference between the two groups, which is large enough and consistent enough to be clinically important.
  • the positive treatment outcome was demonstrated immediately (as soon as 2 weeks) after treatment commence and was stable and even enhanced during treatment.
  • the primary efficacy endpoint of the study was substantiated by the success of the secondary endpoints including the change from baseline in the YBOCS score at 10 weeks.
  • the change from baseline in the YBOCS score at the 10 week visit (Table 21) demonstrates that the YBOCS score decreased by 7.6 points in the DTMS group and by 4.7 points in the Sham group.
  • the adjusted YBOCS score decreased by 6.5 points (95% Cl) in the DTMS group versus 4.1 points (95% Cl) in the Sham group, these decreases were both statistically significant (Table 34).
  • the difference between the treatment groups is also statistically significant (p-value: 0.0380) and clinically meaningful.
  • the effect size of the study is 0.62 (Cohen's D).
  • the DTMS multicenter study may he considered to have a greater than medium to large effect size.
  • the treatment effect is maintained for at least 4 weeks after completion of all treatment sessions, at 10 weeks.
  • the Paxil (Paroxetine) study (Study 1) (with baseline YBOCS score of 23-26) reported a decrease of 4 to 7 points in die YBOCS score in the drug group (depending on dosage 20-60mg), versus 3 points in the placebo group, a difference of 1- 4 points, at 12 weeks.
  • the Zoloft (Sertraline) study (with baseline YBOCS score of 23-25) reported a decrease of 4 points m the YBOCS score in the drug group, versus 2 points in the placebo group, a difference of 2 points at 8 weeks.
  • the DTMS treatment outcome is similar to FDA approved, OCD medications both in the decrease in YBOCS score in the treatment group and with a similar difference in YBOCS score between the treatment and sham/placebo group.
  • the DTMS positive treatment outcome in terms of supplemental assessment scores also demonstrates similar positive results to those reported in the FDA approved SSRI NDAs.
  • the DTMS treatment does not entail the complexity of the metabolism of these drugs or the complications of long-term usage, and the warnings and precautions regarding potential side effects are much less than those reported for drags.
  • the DTMS treatment achieves the same reduction in OCD symptoms as expressed by the reduction in YBOCS and a significantly‘Improved” clinical state based on the CGI Improvement scale in half the time as medications, i.e., 6 weeks vs 12 weeks.
  • prognostic factor analysis including age, gender, treatment question, age of disease onset, duration of disease and CBT treatment (lifetime) at baseline were presented (Table 23). There were no statistically significant differences found between the study groups for any of the prognostic factors. It is important to note that the results of the treatment question did not affect the study results.
  • the Response rate (defined as a reduction from baseline of at least 30% in YBOCS score) at the 6 week visit m the DTMS group is 38.1% versus 11.1% in the Sham group (Table 33).
  • the responder results are not only statistically significant but also clinically meaningful, as demonstrated by the effect size expressed in terms of Number Needed to Treat (NNT).
  • NNT Number Needed to Treat
  • the number needed to treat (NNT) for OCD patients treated with SSRI monotherapy at standard (antidepressant) doses is approximately 5, meaning that if 5 patients are treated with an SSRI, one can be expected to respond who would not have responded to placebo.
  • the NNT for a dose escalation from a medium dose to the higher doses is 13— 15 28 Therefore, the results of this study demonstrate a much greater effect size than conventional SSRI treatments for OCD.
  • the effect size as obtained by the Number Needed to Treat (NNT) was 3.64, which still means that for every 4 patients treated with the Deep TMS System, 1 subject will have a response due to the device. Consequently, the effect size remains larger than for SSRI treatment for OCD at 10 weeks.
  • the positive effect of the DTMS treatment described herein was supported by the secondary assessment scales measuring improvement and severity in subjects’ clinical status using the CGI Improvement (CGI-I) and CGI Severity (CGI-S) scales.
  • the DTMS treatment achieves a significantly“Improved” clinical state based on the CGI Improvement scale, which is similar to the highest dosage of both SSRJs, in half the time as these medications, i.e., 6 weeks vs 12-13 weeks, with far less complications and side effects than drug usage.
  • CGI-S CGI Severity
  • the exploratory' efficacy end-points were the response and remission rates at 10 weeks and the change from baseline in HDRS-21 scores to 6 and 10 weeks.
  • the adverse events are reported in the study according to system organ class and preferred term according to the medDRA adverse event classification, for each of the study group (Tables 54-56). 35 subjects (73%) reported adverse events in the DTMS group versus 35 (69%) subjects in the Sham group. The incidence of adverse event reporting w'as not statistically significant (chi-square p-vaiue: 0.6393).
  • the adverse events reported in the study are typical side effects reported previously with the Deep TMS system and with other marketed TMS devices.
  • the most frequent AE was headache reported by 37.5% of the subjects who received the DTMS treatment and by 35.3% of the subjects who received the Sham treatment. Reporting of headaches was not statistically significantly different between the treatment groups.
  • OCD Obsessive-compulsive disorder
  • the FDA approved SSRIs are Fluoxetine (Prozac), Fluvoxamine (Luvox), Sertraline (Zoloft) and Paroxetine (Paxil) These medications are considered to be equally effective, although some may work for some people and not for others. A notable percentage of patients (40-60%) have a partial or no response to medications. The onset of improvement in OCD symptoms may take weeks to months after starting a medication. Combining medications, such as antidepressants and antipsychotic medications may he effective in controlling OCD symptoms, although all psychiatric medications have side effects, such as stomach upset, sleep disturbance, sweating and reduced interest in sexual activity.
  • adherence to anti-psychotic drugs is about 50% in the first year, and decreases to about 25% in the second year due to intolerable safety issues with low benefit over time.
  • the above reported results of the multicenter DTMS study have demonstrated that the DTMS treatment can be as effective, or better than conventional SSRI medications in treating OCD.
  • the adverse events reported in this study for DTMS treatment are known and well tolerated by OCD subjects.
  • the DTMS treatment enables patient compliance with the treatment during a 6 week treatment period.
  • the safety profile of the DTMS treatment is better than that reported for SSRI medications.
  • the overwhelming clinical benefits enabled by the DTMS treatment including high efficacy expressed in terms of a statistically significant reduction in YBOCS symptoms score, large effect size and low NNT, statistically significant response rates and improvement in CGI-I and CGI-S, outweigh the minimal risks involved with the administration of the treatment.
  • the DTMS treatment provides clinically meaningful efficacy in a relatively short time of 6 weeks with a proven safety profile, high tolerability and extremely high treatment compliance by the OCD patient population compared to currently available medicinal treatments in the market.
  • Transcranial magnetic stimulation is a noninvasive technique used to apply magnetic pulses to the brain.
  • the device currently in use in research and clinical settings is a metallic coil shaped like a figure 8 (figure-8-coil). This device has been found to be capable of stimulating only superficial brain areas, primarily the cerebral cortex, at depths of 1-2 cm below the scalp.
  • the pulses are administered by passing currents through the coil placed upon the patient’s scalp, inducing electrical activity in the underlying cortical tissue that can result in neuronal depolarization.
  • the stimulation method is referred to as“repetitive TMS” (rTMS). rTMS does not involve anesthesia administration and has tolerable side effects.
  • SRIs serotonin reuptake inhibitors
  • SRIs serotonin reuptake inhibitors
  • SSRIs selective serotonin reuptake inhibitors
  • the FDA approved SSRIs are Fluoxetine (Prozac), Fluvoxamine (Luvox), Sertraline (Zoloft) and Paroxetine (Paxil).
  • Clomipramine Anafranil
  • Clomipramine may be slightly more effective than the SSRIs, however, it is known to have a more complicated set of side-effects than the newer SSRIs.
  • the onset of improvement in OCD symptoms may take weeks to months after starting a medication.
  • Combining medications, such as antidepressants and antipsychotic medications may be effective in controlling OCD symptoms.
  • Ail psychiatric medications have side effects, such as stomach upset, sleep disturbance, sweating and reduced interest in sexual activity. 40-60% of patients do not respond to medications for OCD.
  • the main anatomical targets for ablation include the fiber tracts that connect the cortex to thalamic nuclei, the anterior limb of the internal capsule and the cingulate gyrus.
  • the main anatomical targets for ablation include the fiber tracts that connect the cortex to thalamic nuclei, the anterior limb of the internal capsule and the cingulate gyrus.
  • DBS Invasive Implantable Deep brain stimulation
  • DBS causes a functional lesion by inhibiting the brain core which is stimulated. This inhibition can be caused by a depolarization blockage of the neurons, by synaptic depression (exhaustion) or by synaptic inhibition via “neuronal jamming,” inducing a meaningless activation pattern.
  • DBS activates the neuronal network connected to the brain core which is stimulated. Dien stimulation leads to a modulation of the pathological activity in the neuronal network. It is most likely that the therapeutic effects of DBS are caused by a combination of direct and indirect effects dependent on the specific cytoarchitecture of the stimulated brain area. Because the field intensity of the electrode decreases exponentially with distance, neurons are influenced in various ways. The neuronal cell body is probably inhibited in the center of the stimulation area, and the axonal terminals are stimulated on the edge of the stimulation area.
  • Positron emission tomography has demonstrated increased regional blood flow and metabolic activity within the OFC, anterior cingulate gyms, and caudate nucleus during symptom provocation in obsessive- compulsive disorder; and decreased activity in the DLPFC.
  • behavior therapy responders had significant bilateral decreases in caudate glucose metabolic rates that were greater than those in poor responders. Furthermore, the pretreatment correlations of brain activity between the orbital gyri and both the head of the caudate nucleus and the right thalamus decreased significantly after effective treatment.
  • OCD patients revealed higher activation relative to controls in a predominantly fronto- cingulate network including the dorsal anterior cingulate cortex (ACC) and right dorsolateral prefrontal cortex (DLPFC).
  • ACC dorsal anterior cingulate cortex
  • DLPFC right dorsolateral prefrontal cortex
  • the left DLPFC to dorsal ACC connectivity was lower as the severity' of obsessive and compulsive symptoms increased. The results are consistent with an overactive, but intact, error control system in OCD patients.
  • Deep Transcranial Magnetic Stimulation is a relatively new form of TMS, winch allows direct stimulation of deeper neuronal pathways than standard TMS.
  • This form of TMS makes use of novel H-coils w'hich are designed to allow deeper brain stimulation related to the control of motivation , reward and pleasure, specifically, fibers connecting the cingulate or prefrontal cortex with the nucleus accumbens and ventral tegmental area, without a significant increase of electric fields induced in superficial cortical regions, as tested on a phantom brain in order to optimize the cod design for maximizing the percentage of stimulation in depth relative to the cortical regions.
  • the DTMS induces an effective field at a depth of approximately 3 cm below the skull, compared to less than 1.5 cm for the standard TMS figure-8 coil.
  • the safety and efficacy of the DTMS device was evaluated in a multicenter, randomized, controlled study on subjects suffering from OCD.
  • the HAC-Coil Deep TMS treatment is provided with the HAC-Coil IMS System that is composed of the following four main components:
  • the HAC-Coil Deep TMS System is illustrated in FIG. 1.
  • the HAC-Coii is designed to stimulate neuronal pathways related to the control of motivation, reward and pleasure, specifically, the prefrontal cortex and fibers connecting the cingulate or prefrontal cortex with the nucleus accumhens and ventral tegmental area.
  • the HAC-Coil is made of insulated copper wires. The total length is about 500 cm, winded into 14 windings, connected in series. The windings are connected to a special power cable and a connector. This connector can be connected to the Magstim Rapid or Rapid 2 stimulator. In addition, a temperature sensor is included with an appropriate cable.
  • the HAC Coil is designed to stimulate neuronal pathways m the medial prefrontal cortex or motor cortex, including the anterior cingulated cortex.
  • the effective part of the coil, in contact with the patient’s head has a shape of half a donut.
  • the frame of the inner rim of the half donut is flexible in order to fit the variability in human skull shape.
  • the electromagnetic coil is contained in a helmet, which is connected by an adaptor to a positioning device.
  • the coil is connected to the neurostimulator cable and a connector. This connector can be connected to the neurostimulator.
  • a temperature sensor is included with an appropriate cable.
  • a commercial TMS neurostimulator such as the Magstim Rapid, Rapid 2 or Super Rapid 2 is used to deliver electrical stimulation to the brain, enabling a controlled output, frequency, pulse duration and indication of coil temperature.
  • the Magstim stimulators were cleared by FDA (K992911 and K051864) for peripheral nerve stimulation. The detailed technical specifications of the Magstim Stimulator are available on the Magstim Ltd. website.
  • the positioning system includes a helmet that comprises the coils, an adjustable arm connected to the helmet and a device enabling rotation of the helmet around three orthogonal rotation axes.
  • the positioning device enables accurate and comfortable displacement and positioning of the coil over the patient'shead.
  • the Cooling System is designed to maintain ambient temperature in the coils during repetitive operation.
  • the Cooling System consists of an external unit and and an air hose streaming the cooled air into the helmet.
  • the air flow cools tire coils during pulse trains and maintains them at ambient temperature.
  • Hie TMS stimulator and the cooling system are placed in a mobile cart (ITD, Germany).
  • the adjustable arm is connected to the cart.
  • a personal cap is provided for each patient.
  • the cap is made from a biocompatible material (Fabrifoam).
  • a flexible ruler is attached along the cap midline, with the 0 mark positioned at the patient’s nasion.
  • the cap is used for accurate positioning of the coil on the patient’s head, by moving the coil from the area above the motor cortex to the treatment location at the prefrontal cortex.
  • the cap guarantees hygienic treatment conditions.
  • the system used in the Multicenter OCD Study contained the active HAC-Coil and a sham coil both contained within the device helmet.
  • the system used in the clinical study also contained a card reader unit which enabled activation of the either the HAC-coil or the sham coil.
  • the card reader activated tire real HAC-coil or the sham coil using a magnetic, pre programmed, randomization treatment card.
  • Transcranial magnetic stimulation is a non-invasive technique often used for treating Major Depressive Disorder by stimulating the brain.
  • the standard FIG.-8 coils have been shown to have a major effect mostly confined to the superficial cortical regions under the windings of the coil.
  • the intensity of the electric field decreases rapidly deeper in the brain.
  • a very high intensity is needed.
  • Such intensity cannot be reached by the magnetic stimulators available today, using standard circular or FIG.-8 coils.
  • the intensity needed to effectively stimulate deeper brain regions would over-stimulate cortical regions leading to undesirable side effects.
  • the Deep TMS System was developed and intended for deeper brain stimulation targeting the anterior cingulate for the treatment of Obsessive Compulsive Disorder (OCD).
  • OCD Obsessive Compulsive Disorder
  • the Deep TMS device is intended to safely deliver high-frequency (20Hz) repetitive transcranial magnetic pulses (2 second trains) to induce electric field of sufficient magnitude, i.e., 100% of resting Motor Threshold (rMT) of the foot, for the treatment of Obsessive Compulsive Disorder (QCD), using a flexible coil conforming to the shape of the head.
  • rMT resting Motor Threshold
  • Hie Deep TMS System is indicated for use in adult patients with Obsessive Compulsive Disorder (OCD). Patients already on OCD treatments (psychotropic medications and or psychotherapy) should be maintained at their current dosages during the Deep TMS treatment.
  • OCD Obsessive Compulsive Disorder
  • the DTMS device technology is based on applying deep brain TMS by means of repetitive pulse trains at a determined frequency
  • a pre-selected treatment protocol is assumed to activate deep brain regions and their interconnecting fibers. This, in turn, may affect the mechanisms involved in the pathophysiology of OCD on one hand, as well as the rewarding circuits, motivation and pleasure on the other hand.
  • the system employs and executes the rTMS method that is based on creating alternating magnetic fields of between 1 and 10 KHz in the brain.
  • a Magstim Rapid or Rapid 2 magnetic neurostimulator sends electrical pulses to the non-invasive stimulating coil placed adjacent to the patient's head.
  • Hie stimulating coil that is held and aligned by the Positioning System helmet, is placed near the intended site of stimulation, and the stimulator initiates brief magnetic pulses that induce electrical currents in the tissue thereby producing a localized axonal depolarization .
  • Hie Cooling System maintains ambient temperature in the coils during repetitive operation.
  • the treatment protocol began with localization of the optimal spot on the scalp for stimulation of tire tibialis muscle and determination of the individual motor threshold. The coil was then be placed 4 cm anterior to the motor spot. Subjects in the treatment group received prefrontal rTMS (20 Hz at 100%, 2 s on 20 s off, 50 trains, over an 18 minute period, i.e., 2000 stimuli per session).
  • the Deep TMS study was designed as a prospective, double blind, randomized , sham -controlled multi-center study.
  • Subjects were excluded from the study if they suffered from any other Axis I diagnosis as the primary diagnosis or if they were diagnosed with severe Personality Disorder (excluding Obsessive Compulsive Personality Disorder). Additional exclusion criteria included any significant neurological injury, disorder or insult; increased risk of seizure for any reason, including familial or personal history of epilepsy; prior treatment with rTMS (because they could not be blinded); history of significant hearing loss; history of substance abuse; pregnancy; presence of intracranial implants or any other metal object within or near the head excluding the mouth that cannot be safely removed. Additionally, subjects were excluded if they were assessed with a present risk of suicide or if they had a history of suicide attempt in tire last 3 years (because we did not want to assign them to sham).
  • the study consisted of three phases, including the Screening phase (approximately 2-3 weeks, with no treatment), followed by a 6 weeks of daily treatments with Deep TMS or sham treatments. Additionally, subjects wore followed up at 10 weeks (4 weeks after the last treatment).
  • OCD symptoms Prior to initiation of each treatment, OCD symptoms were provoked for each subject in an individual manner for up to 5 minutes. The symptom provocation had to induce a stress level between 4-7 on a visual analog scale (VAS) in order to proceed with DTMS treatment.
  • VAS visual analog scale
  • Each DTMS treatment (for active and sham groups) was conducted as follow's. Before starting each treatment, the subject was instructed to insert earplugs to lessen any possible adverse effect on hearing. The patient’s motor threshold was measured at the beginning of each w'eek by delivering single stimulations over the leg area of the motor cortex. The anterior cingulate gyrus was chosen as the treatment location which was determined by locating the coil 4 cm anterior to the leg MT location using the ruler on the head cap.
  • the treatment location was recorded in the operator case report forms.
  • Subjects received treatment at a power output of 100% of the measured MT.
  • the treatment group received DTMS at 20 Hz and 100% stimulation intensity of the measured MT.
  • Each DTMS repetition included 2 second pulse trains and 20 second inter-train intervals.
  • Subjects received 50 trains in each treatment session, for a total of 2000 pulses per session. Each session lasted about 30 minutes of which the DTMS session lasted approximately 20 minutes.
  • the control group received sham (placebo) treatment with identical parameters. Subjects were told that facial and hand twitching may occur due to either sham or active treatment.
  • the aim of the study was to evaluate the safety and efficacy of the Deep TMS Treatment in subjects with Obsessive Compulsive Disorder (OCD).
  • OCD Obsessive Compulsive Disorder
  • the primary objective of the study was to compare the change in Y BOCS scores from baseline to the 6 week (post-randomization) visit, between the two treatments groups.
  • MMSE Mini Mental State Exam
  • BSRT Buschke Selective Reminding Test
  • AMI-S Autobiographical Memory Interview - Short Form
  • AE Adverse Events
  • Subjects was diagnosed as suffering from OCD according to the DSM-iV-TR.
  • Subjects were maintained on SSRT medications (with or without additional antidepressant or psychotropic augmentation for treatment of OCD), at a stable therapeutic dosage for at least 2 months prior to study entry and for the duration of the trial and/or subjects were maintained on psychotherapeutic behavioral intervention therapy (subjects undergoing CBT treatment must be in the maintenance stage (i.e., not during the assessment or skills acquisition or training stages).
  • TSS Transcraniai Magnetic Stimulation Safety Screening questionnaire
  • Subject was capable and willing to provide informed consent. Subject was able to adhere to the treatment schedule.
  • Subjects was diagnosed according to the SCID I as suffering from any other Axis I diagnosis as the primary diagnosis. Subjects was diagnosed according to the SCID II as suffering from severe Personality Disorder (excluding Obsessive Compulsive Personality Disorder) or hospitalized due to exacerbation related to borderline personality disorder. Present suicidal risk as assessed by the investigator using the Seale for Suicide Ideation (SSI), brief mental status exam and psychiatric interview or significant suicide risk based on HDRS-21 item 3 score of 3 or 4 or a history of attempted suicide in the past year.
  • SSI Seale for Suicide Ideation
  • Subjects had a history of significant hearing loss. Subjects had a significant neurological disorder or insult including, but not limited to:
  • Subject had a history of substance abuse including alcoholism within the past 6 months (except nicotine and caffeine). Inadequate communication with the patient. Subject w'as participating in another clinical study or enrolled in another clinical study within 30 days prior to this study. Subjects who suffered from an unstable physical, systemic and metabolic disorder such as unstabilized blood pressure or acute, unstable cardiac disease. Subject was on high doses of antidepressant or psychotropic medications, which are known to lower the seizure threshold. Subject was currently on Clomipramine. Subject had previous treatment with TMS Women wlio were breast-feeding Women who were pregnant or with suspected pregnancy Women of childbearing potential and not using a medically accepted form of contraception when engaging in sexual intercourse
  • Subject was considered to have completed the study if he or she completed all required assessments at w3 ⁇ 4ek 6 of the treatment trial period
  • Randomization and Blindin Subjects were randomized into the study by center. After subjects met the eligibility criteria, they were equally allocated (with a 1 : i ratio) to one of the 2 treatment groups (Sham vs. Active TMS) stratified by center, based on a stratified randomization scheme using the SAS (version 9.1) random number generator. The study statistician prepared the randomization scheme. The block size was random and study personnel were blinded to the randomization block size.
  • IWRS Interactive Web-Based Randomization System
  • the unique subject randomization code matched one of the pre-programmed treatment cards maintained at the clinical site. The operator was then asked to take the treatment card with the same randomization code from the box of pre programmed treatment cards and to complete the subject ID on the card label and place the treatment card inside the subject's Operator Binder
  • the operator sw ped the patient’s treatment card by the card reader in the DTMS System.
  • the card reader activated either active or sham treatment mode according to the treatment group to which the patient had been randomized.
  • the study personnel did not have any knowledge of whether the active mode or sham mode was activated by the patient’s treatment card. Thus, all study personnel, including the operator, the independent rater and study subjects were blinded to the treatment administered. The study patients were asked whether they believe they had received active or sham stimulation after the first treatment session.
  • the system operator determined the motor threshold (MT) and administered the treatments. Each operator underwent extensive training including hands-on training regarding the procedures related to the administration of the treatment prior to treating study subjects.
  • OCD symptoms were provoked for each subject in an individual manner to activate the relevant brain circuitry.
  • the provocations consisted of text or props (e.g., photo, video, objects, etc.) tailored towards the subject’s specific obsessions and compulsions, which provoked or induced typical OCD symptoms in the subject.
  • the subject was exposed to the provocation during a period of up to 5 minutes. Tire provocation had to induce a stress level between 4-7 on a visual analog scale (VAS) in order to proceed with DTMS treatment.
  • VAS visual analog scale
  • the patient’s MT was measured by placing the H-coil above the leg area of the motor cortex.
  • Tire MT was measured by gradually increasing the stimulation intensity by using the single pulse mode and applying one pulse ever ⁇ ' 5 sec, i.e. 0.2 Hertz.
  • the Threshold is defined as the lowest intensity of stimulation producing motor evoked potentials of at least 50pV in 5 of 10 trials.
  • Both study groups received stimulations (real or sham) over tire anterior cingulate cortex.
  • Tire coil was repositioned 4 cm anterior to the location of the MT for stimulation of the leg using the ruler on the patient’s cap, and a DTMS session was performed at 100% of the motorthreshold.
  • Each treatment session last 20 to 30 minutes (of which, the DTMS session takes approximately 20 minutes).
  • the treatment group received the following dose of DTMS: 20 Hz, at 100% MT, 2 sec pulse train, 20 second inter-train interval, 50 trains, i.e. a total of 2000 pulses per session.
  • Tire control group received inactive/ sham treatment with identical parameters. Patients were told that facial and hand twitching may occur due to either sham or active treatment.
  • the operator observed the subject closely for any sign of imminent seizure activity or muscle twitching. Presence of a physician or nurse trained in seizure management, emergency equipment (oxygen, suction, blood pressure monitor, and CPR equipment) and antiepileptic medications were readily available in the immediate vicinity of the treatment room. Before starting each treatment, subjects were instructed to insert earplugs to mitigate any possible adverse effect on hearing. Subjects were informed of the risk of perm anent hearing loss if an earplug should become detached or fall out and were asked to immediately report any loosening or detachment of an earplug during treatment. In case of coil overheating, a warning was displayed and the operator removed the coil from the patient.
  • the coil cooled down within several minutes and then treatment was resumed. Any events of coil overheating, removal and treatment resumption were recorded. Patients were asked not to meet or discuss the study treatment with other subjects before, during and after assessment or treatments in order to maintain study blinding.
  • HDRS Hamilton Depression Rating Scale
  • Tire HDRS was published more than 40 years ago for the purpose of “quantifying the results of an interview’” (Hamilton, 1960). Although not designed for use in treatment studies, Hamilton anticipated that the scale would have value in evaluating the impact of treatment. During the past 40 years the HDRS has been the most widely used outcome measure in antidepressant efficacy trials (Prien et al., 1991).
  • CGI-S Clinical Global Impression-Severity score
  • Subjects were assessed for the severity of illnesses at the baseline visit, at the weekly assessment visits during the treatment period and at the 10 week follow-up visit .
  • the CGI-S is a commonly used tool for assessing the overall severity of patient's illness. It uses 7 levels, ranging from normal to severely ill.
  • Tire Global Improvement item requires the clinician to rate how much the patient's illness has improved or worsened relative to a baseline state.
  • Sheehan Disability Scale was developed to assess functional impairment in three inter-related domains; work/school, social and family life. It is used by researchers and practicing clinicians (Rush, 2000). The SDS is a brief self-report tool. Hie subject rates the extent to which work/school, social life and home life or family responsibilities are impaired by his or her symptoms on a 10 point visual analog scale. This 10 point visual analog scale uses spatiovisua!, numeric and verbal descriptive anchors simultaneously to assess disability. This range of anchor options addresses the various ways that individuals approach rating a continuum. The change-over- time score is of interest to clinicians in monitoring response to treatment.
  • TSS Transcranial Magnetic Stimulation Adult Safety Screen
  • TMS Transcranial Magnetic Stimulation Adult Safety Screen
  • the Scale for Suicide Ideation (SSI) is a 21-item interviewer -administered rating scale that measures the current intensity of patients' specific atitude, behaviors, and plans to commit suicide on the day of the interview.
  • MMSE Mini-Mental State Exam
  • MMSE mini-mental state examination
  • the BSRT test was performed at the baseline visit, at 6 week assessment visit and at the 10 week follow- up visit or at the time of discontinuation.
  • the test is used to provide a traditional measure of verbal learning and memory using l2-word lists, 6 trials, and 30 minutes delayed free recall, followed by reacquisition of the list (6 trials) (3 alternate forms). Since subjects are only reminded of words not recalled on the previous trial, this task provides more information on encoding and retention than other list learning tasks. This task is especially sensitive to anterograde amnestic effects of ECT and other interventions (41). The primary' dependent measure will be total words correctly reported at the second administration (reacquisition).
  • AMI-SF Autobiographical Memory Interview - Short Form
  • the AMI-S test was performed at the baseline visit, at the 6 week assessment visit and at the 10 week follow up visit or at the time of discontinuation.
  • the test assesses memory for events in the past and the development of retrograde amnesia. This common side effect of ECT is not expected to be manifest with DTMS and a single task will be used for this purpose.
  • the short form involves inquiries about the details of 6 events. Five questions are asked about each event, yielding 30 items. Following each phase patients are only asked about items for which they produced a response at baseline. Inconsistency in responses relative to baseline (including "don't know" responses) is the measure of retrograde amnesia.
  • the study was planned as a randomized two-arm sham controlled, 10 week, double blind, multi-center trial in outpatients recruited in both academic and private research centers.
  • the aim of the study was to evaluate the efficacy and safety of Deep TMS de vice (with the HAC-coil) in subjects with OCD.
  • the mean change in YBOCS score from baseline to 6 weeks in the DTMS group is equal to the mean change in YBOCS score from baseline to 6 weeks in the sham group.
  • Hie mean change in YBOCS score from baseline to 6 weeks in the DTMS group is not equal to the mean change in YBOCS score from baseline to 6 weeks in the sham group.
  • the minimum sample size was increased to 49 subjects per arm to account for potential drop-outs, for a total of 98 subjects.
  • Subjects who met the eligibility criteria were equally allocated (with a 1 : 1 ratio) to one of the two treatment groups, DTMS or sham, based on a randomization scheme with blocks stratified by site.
  • the randomization scheme was prepared by the study statistician using the SAS (version 9.3.) random number generator.
  • the intent-to-treat (ITT) analysis set includes all patients randomized to the study who have received at least one active/ sham treatment. According to the ITT principle, all subjects are analyzed in the treatment group as assigned by randomization.
  • Hie modified intent-to-treat (mITT) analysis set includes all patients randomized to the study who have received at least one active/ sham treatment and met the study Eligibility Criteria.
  • mITT set ail subjects are analyzed in the treatment group as treated. That is, the mITT set was analyzed in the pre-defined treatment assignment as provided in the original randomization list, as none of the study subjects received different treatment by mistake.
  • the per-protocol (PP) analysis set consists of all subjects included in the mITT analysis set who in addition have no major protocol deviation. Potential protocol deviations were defined and classified as minor or major before opening the randomization codes. The list of protocol deviation was documented in the “Clinical Study Guidelines for Data Review and Statistical Analysis” plan prepared prior to randomization code unblinding.
  • Safety assessments are performed on the ITT analysis set.
  • the mITT data analysis set serves as the principal data analysis set for the primary and exploratory efficacy statistical inference.
  • the primary efficacy assessment is also performed on per protocol (PP) analysis sets and on the ITT analysis set, by assigning treatment groups as randomized instead of as treated, as sensitivity analyses.
  • PP per protocol
  • the hierarchy approach is adopted for the primary ' and secondary' endpoints to control the ty'pe I error due to multiple endpoint testing.
  • the primary ' endpoint is first analyzed and only if p ⁇ 0.05, will the secondary' endpoints be analyzed.
  • the order of the secondary' endpoints appears herein above (ordered i, ii, and iii). This approach is maintaining the overall study type 1 error by continuing to analyze the next end-point in the hierarchy' only if the previous endpoint analysis is found significant.
  • the exploratory ' end-points are not part of the hierarchy as descriptive statistics are mainly planned. Nevertheless, nominal p-values are presented for all statistical comparisons.
  • baseline data The data collected at the last recorded visit prior to study treatment initiation are considered as baseline data. Generally, these are the data recorded at the baseline visit.
  • the standard summary statistics for continuous variables are: N, mean, standard deviation, median, minimum and maximum .
  • Tire standard summary ' statistics for categorical variables are: count and proportion .
  • Demographic and baseline condition related characteristics are tabulated and compared between the study groups. Continuous variables will be summarized by a mean, standard deviation, minimum, median and maximum, and categorical variables by a count and percentage.
  • This data includes:
  • the principal statistical analysis is performed using a Repeated Measures Analysis (RMA) of covariance model (SAS® MIXED procedure).
  • RMA Repeated Measures Analysis
  • SAS® MIXED procedure The analysis, which aims to compare the YBOCS slopes of change from baseline between study aims, includes the following fixed effects: time from randomization, treatment group, time by treatment interaction, use of SSRIs and any other antidepressant or psychotropic medications, and/or psychotherapeutic behavioral interventions at enrollment, center and baseline YBOCS score.
  • Baseline YBOCS scores are entered as continuous variables so that the potential for co-linearity problems will be minimized.
  • the individual subject intercept and the time effects are also included m the model as random effects (random intercept and slope model).
  • the principal statistical analysis is a comparison between the treatments groups' slopes, derived from the time by treatment interaction term from the RMA model described above.
  • the covariance structures that were used initially are unstructured, compound symmetry, Toepelitz or autoregressive (whichever model has the lower AIC statistic), although other structures may be evaluated as well in the model selection process.
  • the adjusted mean changes from baseline in YBOCS scores to 6 weeks post randomization are estimated from the model (LS Means) for each group as well as the difference between the adjusted means and presented together with 95% confidence intervals.
  • Binary efficacy and other categorical measures are compared between the study groups at the week 6 and week 10 with a chi-squared test or Fisher’s exact test.
  • Adjustment for other covariates such as demographics or other baseline patient characteristics or the forced choice questionnaire regarding treatment received may be performed by adding these variables to the above described models.
  • the -2 log likelihood ratio test for nested models is used to test the contribution of the "general relation” beyond the "linear relation”.
  • the criterion to reject linearity is used if the p-value of the chi-square statistic with the appropriate degrees of freedom is less than 0.05.
  • Patients who drop out after one or more treatments and have data available for the analysis (i.e., at least one post baseline assessment) of continuous variables are analyzed with a repeated measures analysis of variance model using PROC mixed in S AS which can handle missing data at random.
  • Subgroup analysis of the primary efficacy endpoint by center will be used to evaluate the poolability of the results.
  • the significance of center-to-center variability in treatment effect will be evaluated by including an interaction temi of treatment by center in the regression model.
  • the reasons for differential treatment effect such as patient and clinical characteristics, will be investigated and reported.
  • Safety assessment performed for the ITT analysis set, includes the following:
  • AE incidence tables, in general and by severity, by relationship to treatment and by baseline parameters are presented.
  • OCD Obsessive Compulsive Disorder
  • Table 1 presents the overall subject accountability for each data analysis set.
  • Table 2 presents subject accountability by study treatment group for each data analysis set. Of 131 subjects screened, a total number of 100 subjects were randomized to the study. Eligible and consenting subjects were randomized to either the active treatment group or the sham control group (Sham).
  • the Intent-to-treat (ITT) analysis set includes 99 randomized patients, as one subject withdrew consent while the motor threshold was being measured. The patient did not tolerate the stimulation used to measure the motor threshold. The subject withdrew consent after randomization, but before receiving even one active/sham treatment. Thus, the subject is not included in the ITT analysis set. 48 subjects were randomized to receive active treatment (DTMS) and 51 to receive Sham treatment.
  • DTMS active treatment
  • the rrilTT analysis set includes 94 subjects who met the study eligibility criteria.
  • the per-protocol (PP) analysis set includes 93 subjects who completed the study without any major protocol violations.
  • the number of patients and reasons for their exclusion are shown in Table 3 and 4.
  • Table 5 presents the distribution of patients among the 11 participating study centers, 7 centers enrolled fewer than 10 subjects and the remainder between 10 and 21. There were 9 US centers, 1 Israeli, and 1 Canadian site.
  • Table 6 presents the distribution of patients in US centers and QUS centers.
  • One subject was excluded from the ITT analysis set who withdrew consent while the motor threshold was being measured. The patient did not tolerate the stimulation used to measure the motor threshold. The subject withdrew consent after randomization, but before receiving even one active/ sham treatment. Thus, the subject is not included in the ITT analysis set.
  • Treatment dose a stimulation intensity that is 100% of the patient s measured Motor Threshold. This stimulation intensity is considered an adequate dose of DIMS treatment so that the treatment will be effective in treating QCD.
  • treatment according to the study protocol was defined as an average stimulation intensity of at least > 90% of the patient’s measured Motor Threshold in treatment sessions 1 through 29. There was 1 subject who did not receive an adequate treatment dose and was considered a major protocol violation.
  • Table 7 shows the number and percentage of subjects withdrawn or dropped out up to 6 weeks and 10 weeks.
  • Table 8 summarizes the reasons for drop-out / withdrawal.
  • FIG. 2. portrays the drop out pattern via Kaplan- Meier curves of time to drop-out in each group for the 6 week end-point. From Table 6 we see that only 10% of the subjects dropped out before the 6 week end-point in both of the study groups, thus demonstrating an extremely low drop-out rate in this study. Furthermore, FIG. 2 demonstrates that the“survival” pattern, i.e. the time to drop-out, in the two groups is very ' similar. Additionally, the log-rank test, which compares the survival curves of the two groups is not significant, P value: 0.6109.
  • Table 7 Number Of Subjects Withdrawn or Dropped Out Up To 6 Week And 10 Week (ITT)
  • the demographic and baseline characteristics are provided in this section for the ITT analysis set.
  • the OCD patient population recruited in this study are typical of the US OCD patient population enrolled in OCD clinical trials, as demonstrated in the demographic and baseline characteristics tables reported in this section.
  • Demographic data are presented in Table 9.
  • the age range of the subjects in both groups was 23/22 to 68/66, approximately 41% were female and 58% were male.
  • the large majority of both groups were of ethnic origin “Not Hispanic or Latino” and“Write” race. No statistically significant differences were found between the study groups with respect to age, gender, race, ethnicity, marital status or education.
  • Table 10 shows the distribution of baseline values of all assessment scale data represented in the efficacy analyses, including the Yale-Brown OCD Scale (YBOCS), the Sheehan Disability Scale (SDS), the Clinical Global Impression - Severity scale (CG1-S), the Clinical Global Impression - Improvement scale (CGI-I) and the Hamilton Depression Rating Scale (HDRS-21) scores.
  • YBOCS Yale-Brown OCD Scale
  • SDS Clinical Global Impression - Severity scale
  • CGI-I Clinical Global Impression - Improvement scale
  • HDRS-21 Hamilton Depression Rating Scale
  • Table 11 presents the patient’s medical history by body system. No statistically significant differences were found between the study groups with respect to percent of abnormalities. The full listing of abnormalities by body system per group is detailed herein.
  • Table 11 Medical History by Body System (ITT)
  • Table 12 shows the patients’ psychiatric history according to treatment group.
  • the mean age of OCD onset was 14.4 years in the DIMS group and 11.7 years in the Sham group.
  • the age at which professional help was first sought was not different between the groups.
  • 93.8% of the subjects in the DTMS group and 98% of the subjects in the Sham group indicated that their OCD symptoms affected their function at school or work.
  • CBT Cognitive Behavioral Therapy
  • Table 12 Psychiatric History (ITT)
  • Tables 13 presents the number (and percentage) of subjects treated with SSRJ, antidepressant and other psychiatric medications at baseline by study group and Table 14 presents the number (and percentage) of subjects treated with other concomitant medications at baseline by study group.
  • Table 13 SSRI, Antidepressant and Other Psychiatric Medications Taken at Baseline (ITT)
  • Table 15 presents the results of the physical examination performed at screening by body system for each study group. There were no statistically significant differences found between the study groups with respect to percent of abnormalities.
  • Table 16 presents the results of the neurological examination performed at screening by test for each study group. There were no statistically significant differences found between the study groups with respect to percent of neurological examination abnormalities.
  • Table 16 Neurological examination at screening visit (ITT)
  • Table 17 presents the subjects’ baseline height and weight in each study group. There were no statistically significant differences found between the study groups with respect to height as screening and weight at baseline. The average height in both groups was approximately 172-173 meters and the BMI was approximately 26.
  • Table 18 shows the temperature, pulse rate, and blood pressure at screening visits and at baseline in both study groups, we see that the groups have similar values for all vital signs.
  • the QCD patient population recruited in this study are typical of the US QCD patient population enrolled in OCD clinical trials, as demonstrated in the demographic and baseline characteristics tables reported in this section
  • Table 19 presents the number of subjects who attended each visit per study group.
  • Table 20 shows the number of treatments received at each treatment visit (from treatment 1 to treatment 29 ⁇ for all subjects in each study group. Note that the protocol allowed subjects to miss up to 3 treatments out of the 29 treatment sessions.
  • Table 20 Number of Subjects at each Treatment Visit (ITT)
  • the primary efficacy end-point as dictated in the study protocol was the change from baseline in YBOCS scores to the 6 week visit.
  • the primary efficacy analysis is conducted on all evaluable subject data, in the mITT analysis set.
  • Table 21 show's the unadjusted total YBOCS score and change in score from baseline.
  • FIGs. 3 and 4 are graphical representations of the table and present the mean ( ⁇ SE) of the YBOCS scores and changes from baseline, respectively. We see from these representations that in both study groups there was a reduction over time in YBOCS scores.
  • Table 21 Distribution of YBOCS Score and Change from Baseline to 6 and 10 Week Visits (mITT)
  • the change front baseline in the Y BOCS score extracted from Table 19 demonstrates that the YBOCS score decreased by 6 7 points in the DTMS group and by 3.6 points in the Sham group at the 6 week visit.
  • Table 22 presents the adjusted means extracted from the model at the 6-week visit.
  • the YBOCS score decreased by 6.0 points (95% Cl) in the DTMS group and by 3.3 points (95% Cl) in the Sham control group, these decreases were both statistically significant.
  • the difference between the slopes of 2.8 points across 6 weeks between the treatment arms is also statistically significant (p-value: 0.0127).
  • Table 22 Adjusted Means of the Change from Baseline to 6 Weeks in YBOCS (mITT)
  • the YBOCS primary efficacy analysis at the 6 visit was also conducted on all evaluable subject data, in the PP cohort and the ITT cohort and are presented herein.
  • the effect size of the study is 0.69.
  • the DTMS multicenter study may be considered to have a greater than medium to large effect size.
  • the DTMS has a positive treatment outcome and has demonstrated a beneficial effect in reducing OCD symptoms in moderate to severe OCD patients.
  • the reduction the YBOCS of 6.0 points is clinically meaningful and statistically significant compared to the sham and the effect size of 0.69 demonstrates a difference between the two groups, which is large enough and consistent enough to be clinically important.
  • the positive treatment outcome was demonstrated immediately (as soon as 2 weeks) after treatment commence and was stable and even enhanced during treatment. Hie DTMS treatment effect was also confirmed at week 10 (4 weeks after treatment completion) .
  • Tire primary efficacy endpoint of the study was substantiated by the success of the secondary endpoints including the change from baseline in the YBOCS score at 10 weeks.
  • the change from baseline in the unadjusted YBOCS score at the 10 week visit extracted from Table 21 demonstrates that the YBOCS score decreased by 7.6 points in the DTMS group and by 4.7 points in the Sham group.
  • Table 34 presents the adjusted means extracted from the model at the 10-week visit.
  • the YBOCS score decreased by 6.5 points (95% Cl) in the DTMS group versus 4.1 points (95% Cl) in the Sham group, these decreases were both statistically significant.
  • the difference between the treatment groups is also statistically significant (p-value: 0.0380).
  • the effect size of the study is 0.62.
  • the DTMS multicenter study may be considered to have a greater than medium to large effect size.
  • the treatment effect is maintained for at least 4 weeks after completion of all treatment sessions, at 10 weeks.
  • the positive effect was corroborated by responder analysis, thus supporting the robustness of the clinical effect.
  • NNT (1/difference in response rates)
  • the number needed to treat (NNT) for OCD patients treated with SSRI monotherapy at standard (antidepressant) doses is approximately 5, meaning that if 5 patients are treated with an SSRI, one can be expected to respond who would not have responded to placebo.
  • the NNT for a dose escalation from a medium dose to the higher doses is 13—15.
  • CGI-I CGI Improvement
  • CGI-S CGI Severity
  • CGI-S CGI Severity
  • the DTMS benefit is also reported by the excellent safety profile for the DTMS device, with similar known side effects of conventional TMS treatments and no reported differences in adverse events between the DTMS and Sham treatments.
  • the DTMS treatment described herein has been demonstrated as effective for the treatment of OCD as reported by the primary efficacy analysis and as supported by the secondary efficacy analyses and is a safe treatment as demonstrated by the known side effects and lack of adverse events.
  • Table 23 presents the results of the prognostic factor analysis including age, gender, treatment questi on, age of onset, duration of disease and CBT treatment (lifetime) Tire Type III p-value is the statistical significance of the factor in the model.
  • the adjusted slope per group and the difference between the slopes are presented in the table together with level of significance and 95% CL According to Table 23, none of the variables were found to be related to the change from baseline in YBOCS score.
  • CGI Improvement CGI-I
  • CGI Severity CGI-S
  • SDS Sheehan Disability Scale
  • Table 24 presents the CGI-I score distribution with the percent of subjects m each treatment group according to the outcome classification on the CGI Improvement Scale. Improvement Scale
  • the CGI-I scores were categorized into the following two categories:
  • Table 25 presents the distribution of the CGI-I scores per visit and treatment arm along with the p-value of the Fisher’s exact test per visit.
  • Table 25 Comparison of CGI-I Outcome Categories (mITT)
  • the CGI Improvement results are maintained 4 weeks after treatment at the 10 week visit. That is, 72% of the DTMS subjects maintained some clinical improvement. Although, those subjects reporting a moderate to very much‘Improved” clinical state remained much higher in the DTMS group (49% of DTMS subjects versus only 27 5% in the Sham group), this was not statistically significant at 10 weeks.
  • the DTMS treatment achieves a significantly“Improved” clinical state based on the CGI Improvement scale, which is similar to the highest dosage of both SSRIs, in half the time as these medications, i.e., 6 weeks vs 12-13 weeks, with far less complications and side effects than drug usage .
  • the CGI Improvement score is also presented as a continuous variable. Table 26 presents descriptive statistics of the unadjusted CGI-I score at each visit and the change from baseline to week 6 and
  • FIG. 5 presents the mean ( ⁇ SE) of the CGI-I scores and changes from baseline, respectively.
  • Table 26 Distribution of CGI-I Score and Change from Baseline to 6 and 10 Weeks Visit (mlTT)
  • Table 27 presents the adjusted means extracted from the model at the 6-week visit.
  • the CGI-I score at the 6 weeks visit was 3.8 points (95% Cl) in the DTMS group and by 4.2 points (95% Cl) in the Sham group.
  • the difference between the treatment arms is not statistically significant (p-value: 0.0985)
  • Table 28 presents the CGI-S score distribution with the percent of subjects in each treatment group according to the outcome classification on the CGI Seventy Scale.
  • Table 35 presents the distribution of the changes in CGI-S scores per visit and treatment ann along with the p ⁇ value of the Fisher’s exact test per visit.
  • the CGI Severity results are maintained 4 weeks after completion of the DTMS treatment at the 10 week visit. That is, 64% of the DTMS subjects maintained an“Improvement” in their CGI-S scores compared to 61% at 6 weeks. Although, those subjects reporting an“Improved” clinical status remained much higher in the DTMS group (64% of DTMS subjects versus only 45% in the Sham group), this was not statistically significant at 10 weeks.
  • CGI-S is also presented as a continuous variable.
  • Table 29 presents descriptive statistics of the CGI-S score at each visit and the change from baseline to week 6 and 10.
  • FIGs 6 and 7 present the mean ( ⁇ SE) of the CGI-S scores and changes from baseline, respectively. In general, we see a reduction in CGI-S score over time in both groups.
  • Table 30 presents the adjusted means of the change from baseline extracted from the model at the 6-week visit.
  • the CGI-S decreased by 0.71 points (95% Cl) in the DTMS group and by 0.40 points (95% Cl) in the Sham group.
  • Table 36 presented below presents the adjusted means of the change from baseline extracted from the model at the 10-week visit.
  • the CGI-S decreased by 0.94 points (95% Cl) in the DTMS group and by 0.66 points (95% Cl) in the Sham group, these decreases were both statistically significant.
  • the difference between the treatment groups is not statistically significant (p-value: 0.2343).
  • FIG. 8 and 9 present the mean ( ⁇ SE) of the SDS scores and change from baseline respectively.
  • Table 31 Distribution of SDS Score and Change from Baseline to 6 and 10 Week Visits (mITT)
  • Table 32 presents the adjusted means of the change from baseline extracted from the model at the 6-week visit. SDS decreased by 3.8 points (95% Cl) in the DTMS group and by 3.0 points (95% Cl) in the Sham group, at 6 week visit these decreases were both statistically significant. Although, there is a trend towards better improvement in SDS scores in the DTMS group compared to the Sham group, the difference between the treatment groups is not statistically significant (p-value: 0.4786).
  • Table 32 Adjusted Means of the Change from Baseline to 6 Weeks in SDS (mITT)
  • Table 37 presented below presents the adjusted means of the change from basehne extracted from the model at the 10-week visit.
  • the SDS decreased by 2.6 points (95% Cl) in the DIMS group and by 3.3 points (95% Cl) in the Sham group.
  • the difference between the treatment groups w3 ⁇ 4s not found statistically significant (p-value: 0.5519).
  • the improvement in these parameters may be more latent and not yet apparent at 6 or 10 weeks.
  • the Sheehan Disability Scale is not commonly used as a study endpoint in evaluating SSRI medications in FDA approved NDAs and therefore, the clinical significance of this finding is limited.
  • the primary endpoint of the DTMS Study (change in YBOCS score) was further supported by the first secondary endpoint in which we found a statistically significant difference between the DTMS treatment and the Sham treatment with regards to CGI Improvement and CGI Severity.
  • the hierarchy approach was followed in performing the statistical analyses of the secondary efficacy endpoints.
  • the first secondary endpoint CGI-I and CGI-S scores at 6 weeks
  • the subsequent secondary' endpoint i.e., Response Rate was analyzed.
  • the next secondary endpoint based on Response Rates of subjects to the DIMS treatment demonstrated a further positive treatment outcome and further supported the primary' efficacy endpoint of the study with statistically significant results as presented in the next section.
  • the Response rate and Partial Response rate at the 6 week visit are presented in Table 33.
  • Response is defined as a reduction from baseline of at least 30% in the YBOCS score.
  • Partial Response is defined as a reduction from baseline of at least 20% in the YBOC score.
  • Remission rate is defined as a YBOCS score less than ( ⁇ ) 10.
  • the Partial Response rate at the 6 week visit in the DTMS group is 54.8% versus 26.7% in the Sham group. This difference is also statistically significant p 0.0076 (chi-squared test).
  • the effect size as obtained by the Number Needed to Treat is 3 7, which means that for every 4 patients treated with the Deep TMS System, 1 subject will have a response due to the device.
  • the number needed to treat (NNT) for OCD patients treated with SSR1 monotherapy at standard (antidepressant) doses is approximately 5, meaning that if 5 patients are treated with an SSR1, one can be expected to respond who would not have responded to placebo.
  • the NNT for a dose escalation from a medium dose to the higher doses is 13-15 28 . Therefore, the results of tins study demonstrate a much greater effect size than conventional SSRJ treatments for OCD.
  • the Response rate (as presented in Table 41 and below) at the 10 week visit was 45.2% in the DTMS group compared to 17 8% in the Sham group.
  • the subsequent secondary endpoint i.e., Change from Baseline in YBOCS score at 10 weeks
  • the next secondary endpoint based on YBOCS score at 10 weeks demonstrated a further positive treatment outcome and further supported the primary efficacy endpoint of the study with statistically significant results as presented in the next section.
  • Table 34 presents tire adjusted means extracted from the model at the 10-week visit.
  • the YBOCS score decreased by 6.5 points (95% Cl) in the DTMS group versus 4.1 points (95% Cl) in the Sham group, these decreases were both statistically significant.
  • the difference between the treatment groups is also statistically significant (p-value: 0.0380).
  • the treatment effect is maintained for at least 4 weeks after completion of all treatment sessions, at 10 weeks.
  • the effect size of the study is 0.62.
  • the DTMS multicenter study- may be considered to have a greater than medium to large effect size.
  • Table 35 presents the adjusted means extracted from the model at the 10-week visit.
  • the CGI-I score at the 10 week visit was 3.6 points (95% Cl) in the DTMS arm and 3.9 points (95% Cl) in the control arm. Tire difference between the treatment arms is not statistically significant (p-value: 0.3339).
  • Table 36 presents the adjusted means extracted from the model at the 10-week visit.
  • the CGI-S decreased by 0.94 points (95% Cl) in the DTMS group and by 0.66 points (95% Cl) in the Sham group, these decreases were both statistically significant.
  • the difference between the treatment groups is not statistically significant (p-value: 0.2343)
  • Table 37 presents the adjusted means extracted from the model at the 10-week visit.
  • the SDS decreased by 2.6 points (95% Cl) in the DTMS group and by 3.3 points (95% Cl) in the Sham group.
  • the difference between the treatment groups was not found statistically significant (p ⁇ value: 0.5530).
  • Remission Rate at the 6 week visit are presented in Table 38. Remission rate was defined as a YBOCS score of less than ( ⁇ ) 10.
  • the secondary efficacy analyses for Remission rates were also conducted on all evaluable subject data, in the PP cohort and the ITT cohort.
  • the exploratory end-points are not part of the hierarchy approach as descriptive statistics are mainly planned
  • the exploratory efficacy end-point as dictated in tire study protocol was the change from baseline in HDRS- 21 scores to 6 and 10 weeks.
  • Table 39 shows the unadjusted HDRS-21 scores at each visit along with the change from baseline in HDRS-21 scores.
  • FIGs. 10 and 1 1 present the mean ( ⁇ SE) of the HDRS-21 scores and changes from baseline, respectively.
  • Table 40 presents the adjusted means extracted from the model at the 6 and 10 week visits for the mITT analysis sets. The differences within the treatment arms and between the treatment arms were not statistically significant. As the majority of the study subjects did not suffer from co-morbid Major Depressive Disorder (MDD) (mean HDRS-21 score at baseline in both treatment groups was 10), we do not expect any significant changes or improvements in HDRS-21 score due to the treatment in non-MDD patients. Furthermore, we can infer that the improvement in OCD was not as a result of an improvement in depression.
  • MDD co-morbid Major Depressive Disorder
  • the HDRS-21 exploratory efficacy analysis at 10 week visit was also conducted on ail evaluable subject data, in the PP cohort and the ITT cohort and is presented herein.
  • Remission rate at the 6 week visit, where remission is defined as YBOCS score ⁇ 8 was defined in the study protocol as an exploratory endpoint .
  • the results of the Remission Rates defined as YBOCS ⁇ 10 did not show results that justified performing this statistical analysis.
  • the Response rate, Partial Response rate and Remission rate at the 10 week visit, are presented in Table 41.
  • Response, Partial Response and Remission rate are as defined herein.
  • Table 41 Response, Partial Response and Remission Rates at 10 Week Visit (mITT)
  • Table 42 presents the responses to the treatment question presented to tire study subjects, according to treatment group.
  • Time points range from baseline to week 6 and week 10
  • “early termination” time point which refers to the assessment visit at or after the last treatment in the study in case of early termination from the study is provided, as relevant.
  • Table 43 presents the vital signs in both study groups as measured at baseline, and during the course of the study up to 6 weeks and 10 weeks. Vital signs include weight, body temperature, pulse and blood pressure (systolic and diastolic BP). No notable differences were observed between the study groups overtime in all vital signs.
  • Table 43 Vital Sigsas over Time (ITT) ge eline
  • Table 44 shows the results of the physical examinations performed throughout the study with respect to the percent abnormal in each of the study groups by body area. No notable differences in the percentage of normal tests are observed between the study groups at each of the time points.
  • Tables 45 shows the results of the neurological examinations performed throughout the study with respect to the percent abnormal in each of the study groups by test type. No notable differences in the percentage of normal tests are observed between the study groups at each of the time points.
  • Table 46 presents descriptive statistics of the SSI at each visit along with the change from baseline.
  • Table 46 SSI Score and Change From Baseline in Score (ITT)
  • Table 47 presents descriptive statistics of the MMSE at each visit along with the change from baseline. No statistically significant differences were found between the groups at the 6 week or at the 10 weeks visit.
  • Table 47 MMSE Score and Change from Baseline (ITT)
  • Tables 48 to 51 present descriptive statistics of the unadjusted components of BSRT Score components, LTS, CLTR, Total Number of Intrusions, and Total Number of Recalls at Delayed Recall, along with the change from baseline to week 10, respectively.
  • Long Term Storage is defined as any word that is spontaneously, recalled, i.e. without reminding, and is identified by 2 consecutive recalls of the word.
  • a vOrd is considered to be in LTS on all subsequent trials regardless of whether the word is recalled. If a word in LTS is consistently recalled on all subsequent trials (but not just the last trial), then it is scored as in Consistent Long Term Retrieval (CLTR).
  • Table 50 BSRT Total Number of Intrusions Score and Change from Baseline (ITT)
  • Table 51 BSRT Total Number of Recalls at Delayed Recall Score and Change from Baseline (ITT)
  • Table 52 presents descripti ve statistics of the unadjusted AMI-SF Score and the change from baseline to week 10
  • Table 52 AMI-SF Score and Change from Baseline (ITT)
  • Table 54 presents details of the adverse event by system organ class and preferred term according to the medDRA adverse event classification, in each of the study groups. As can be seen from Table 54, there are no statistically significant differences in any of the Adverse Events between the DTMS and Sham treatment groups.
  • Table 55 presents details of the adverse event by system organ class and preferred term by Causality, in each of the study groups.
  • Table 56 presents details of the adverse event by system organ class and preferred term by Severity , in each of the study groups.
  • the adverse events reported in the study are typical side effects reported previously with the Deep TMS system and with other marketed TMS devices.
  • the most frequent AE was headache reported by 37.5% of the subjects who received the DTMS treatment and by 35.3% ofthe subjects who received the Sham treatment. Reporting of headaches was not statistically significantly different between the treatment groups.
  • Most other forms of pain and discomfort (administration/application site pain/discomfort, pain in jaw, facial pain, muscle pain/spasm/twitching, neck pain, etc.) were reported as either mild or moderate and mostly resolved after treatment with or without analgesic medications (e.g. Paracetamol, Ibuprofen). In most of the subjects, the discomfort or pain disappeared once the subject became accustomed to the treatment.
  • Tins event was reported as mild and was considered as probably not related to the DTMS treatment. There were no events of hypoacusis reported in the study.
  • Gastrointestinal Signs and Symptoms
  • Facial pain is a common adverse event reported with TMS treatment.
  • TMS treatment There were 2 subjects (4%) reported in the Deep TMS treatment group with facial pain. The e vents were mild and were spontaneously resolved. Fatigue was more common in the Sham group, with 5 subjects (10%) compared to 1 subject (2%) in the Deep TMS treatment group. All events were mild and were spontaneously resolved or resolved following treatment with medications. Fatigue was reported as not related to the DTMS treatment.
  • One (i) subject (2%) reported a sensation of pressure in the Deep TMS treatment group. The event was mild and reported as not related to the treatment.
  • One (1) subject (2%) reported discomfort during the treatment in the DTMS treatment group, compare to none in the Sham group. Although reported as moderate, the subject withdrew his/her participation in the study due to this adverse event after two treatment sessions.
  • Adverse events related to musculoskeletal disorders include pain in different body areas, such as back, knee, muscle, neck, etc and muscle pain/spasm/strain/twitching and myalgia.
  • Neck pain was reported as mild or moderate in the Deep TMS treatment group and was resolved following treatment with medications. There were few cases of muscle pain/spasm/strain/twitching and myalgia, 3 subjects (6%) in the DTMS group and 6 subjects (12.5%) in the Sham group. Only 2 events were reported as possibly related to the DTMS treatment and all cases were reported as mild, except for one case in the Sham group which was reported as moderate.
  • Headache (and pain in head), eye pain, dizziness, tremor and night terrors were reported under nervous system disorder. Hie most frequently reported Adverse Event was Headache, which was reported by 18 subjects (37.5%) who received the DTMS treatment and also by 18 subjects (35.3%) who received the Sham treatment. Most events were mild or moderate and only 3 events in the DTMS group were reported as severe and 1 event in the Sham group. Most headache events resolved following treatment with medications. In any case, there was no statistically significant difference between the treatment groups with regard to reporting of headaches. There was one subject (2%) who reported eye pain in the Sham group. This event was reported as mild and possibly related. Dizziness was reported in 1 subject (2%) in the DTMS group and 2 subjects (4%) in the Sham group. The event was reported as mild or moderate and possibly related to treatment in both groups. Both the tremor and the night terrors w'ere each reported in one subject (2%) in the DTMS group as mild and not related to the treatment.
  • Table 57 presents the number of treatments interrupted per group and overall by treatment number and reason.
  • Table 57 Number of Treatments Interrupted and Reason for Interruption (ITT)
  • the Intent-to- treat (ITT) analysis set includes 99 randomized patients, as one subject withdrew consent (patient did not tolerate the stimulation used to measure the motor threshold). The subject withdrew consent after randomization, but before receiving even one active/sham treatment. Tims, the subject is not included in the ITT analysis set. 48 subjects were randomized to receive active treatment (DTMS) and 51 to receive Sham treatment. Baseline demographic information and safety and tolerability results are presented for the Intent- to-treat (ITT) analysis set. Efficacy results are presented for the modified ITT (mITT) analysis set, which included 94 subjects who met the study eligibility criteria, as pre- defined in the Study Protocol, Statistical Considerations - Analysis Sets.
  • the baseline demographic data, general medical and psy chiatric history, concomitant medications, baseline assessment scores and physical and neurological examination data were analyzed to assess if there were any basic differences between the treatment groups prior to commencement of the clinical study (Tables 9-18).
  • the baseline demographic information, including age, gender and the medical and psychiatric history' data did not show' any significant differences in the data between the treatment groups, except for age of onset of QCD. Although, the age at which professional help was first sought was not statistically different bet een the groups, therefore, this data does not seem to affect the study outcome.
  • the baseline assessment scores w'ere very similar between the treatment groups, with no significant differences. This was true of the physical and neurological examination data, as well. The above data demonstrated that there were no significant differences between the study treatment groups.
  • the primary efficacy end-point was the change from baseline in YBOCS scores to the 6 week visit.
  • the primary' efficacy analysis was conducted on all evaluable subject data, in the inlTT analysis set.
  • the change from baseline in the YBOCS score (Table 21) demonstrates that the YBOCS score decreased by 6 7 points in the DTMS group and by 3 6 points in the Sham group at the 6 week visit.
  • the effect size of the study is 0.69 (Cohen's D). According to widely accepted guidelines, in which 0.2 is defined as a small effect, 0.5 as a medium effect, and 0.8 as a large effect, the DTMS multicenter study may be considered to have a greater than medium to large effect size.
  • the DTMS has a positive treatment outcome and has demonstrated a beneficial effect in reducing OCD symptoms in moderate to severe QCD patients.
  • the reduction in the YBOCS of 6 0 points is clinically meaningful and statistically significant compared to the sham and the effect size of 0.69 demonstrates a difference between the two groups, which is large enough and consistent enough to be clinically important.
  • the positive treatment outcome was demonstrated immediately (as soon as 2 weeks) after treatment commence and was stable and even enhanced during treatment.
  • the primary efficacy endpoint of the study was substantiated by the success of the secondary endpoints including the change from baseline in the YBOCS score at 10 weeks.
  • the change from baseline in the YBOCS score at the 10 week visit (Table 21) demonstrates that the YBOCS score decreased by 7 6 points in the DTMS group and by 4.7 points in the Sham group.
  • the adjusted YBOCS score decreased by 6.5 points (95% Cl) in the DTMS group versus 4.1 points (95% Cl) in the Sham group, these decreases were both statistically significant (Table 34).
  • the difference between the treatment groups is also statistically significant (p- value: 0.0380) and clinically meaningful.
  • the effect size of the study is 0.62 (Cohen's D).
  • the DTMS multicenter study may be considered to have a greater than medium to large effect size.
  • the treatment effect is maintained for at least 4 weeks after completion of all treatment sessions, at 10 weeks.
  • the Zoloft (Sertraline) study (with baseline YBOCS score of 23-25) reported a decrease of 4 points in the YBOCS score in the drag group, versus 2 points in the placebo group, a difference of 2 points at 8 weeks.
  • a decrease of 6 and 7 points in the YBOCS score were reported in the drag group, versus 3 and 4 points in the placebo group, respectively, for a difference of 3 points at 12 weeks.
  • the Prozac, Paxil and Zoloft studies included an OCD patient population with only moderate OCD, wnth a lower average baseline YBOCS score of 22-26
  • the DTMS treatment outcome is similar to FDA approved, OCD medications both in the decrease in YBOCS score in the treatment group and with a similar difference in YBOCS score between the treatment and sham/placebo group.
  • the DTMS positive treatment outcome in terms of supplemental assessment scores also demonstrates similar positive results to those reported in the FDA approved SSRI NDAs.
  • the DTMS treatment does not entail the complexity of the metabolism of these drugs or the complications of long-term usage, and the warnings and precautions regarding potential side effects are much less than those reported for drugs.
  • the DTMS treatment achieves the same reduction in OCD symptoms as expressed by the reduction in YBOCS and a significantly“Improved” clinical state based on the CGI Improvement scale (see further discussion below) ) in half the time as medications, i.e., 6 weeks vs 12 weeks.
  • prognostic factor analysis including age, gender, treatment question, age of disease onset, duration of disease and CBT treatment (lifetime) at baseline were presented (Table 23). There were no statistically significant differences found between the study groups for any of the prognostic factors. It is important to note that the results of the treatment question did not affect the study results.
  • the Response rate (defined as a reduction from baseline of at least 30% in YBOCS score) at the 6 week visit in the DTMS group is 38 1% versus 11.1% in the Sham group (Table 33)
  • the Partial Response rate (defined as a reduction from baseline of at least 20% in YBOCS score) at the 6 week visit in the DTMS group is 54 8% versus 26.7% in the Sham group (Table 33). This difference is also statistically significant p 0 0070.
  • the responder results are not only statistically significant but also clinically meaningful, as demonstrated by the effect size expressed in terms of Number Needed to Treat (NNT).
  • NNT Number Needed to Treat
  • the number needed to treat (NNT) for QCD patients treated with SSRI monotherapy at standard (antidepressant) doses is approximately 5, meaning that if 5 patients are treated with an SSRI, one can be expected to respond who would not have responded to placebo.
  • the NNT for a dose escalation from a medium dose to the higher doses is 13- 15. Therefore, the results of this study demonstrate a much greater effect size than conventional SSRI treatments for GCD.
  • the effect size as obtained by the Number Needed to Treat (NNT) was 3.64, which still means that for every 4 patients treated with the Deep TMS System, 1 subject will have a response due to the device. Consequently, the effect size remains larger than for SSRI treatment for OCD at 10 weeks.
  • CGI-I CGI Improvement
  • CGI-S CGI Severity
  • the DTMS treatment achieves a significantly“Improved” clinical state based on the CGI Improvement scale, which is similar to the highest dosage of both SSRIs, in half the time as these medications, i.e., 6 weeks vs 12-13 weeks, with far less complications and side effects than drug usage.
  • the CGI Improvement results are maintained 4 weeks after treatment at the 10 week visit. That is, 72% of the DTMS subjects maintained some clinical improvement and 49% maintained a moderate to very much “Improved” clinical status. Although, those subjects reporting a moderate to very much“Improved” clinical state remained much higher in the DTMS group (49% of DTMS subjects versus only 27.5% in the Sham group), this was not statistically significant at 10 w3 ⁇ 4eks (Table 24-25).
  • CGI-S CGI Severity
  • the improvement in these parameters may be more latent and not yet apparent at 6 or 10 weeks.
  • the exploratory' efficacy end-points were the response and remission rates at 10 weeks and the change from baseline in HDRS-2I scores to 6 and 10 weeks.
  • Obsessive-compulsive disorder is a highly debilitating condition, although SSR1 medications can help control the obsessions and compulsions of OCD.
  • SSR1 medications can help control the obsessions and compulsions of OCD.
  • the FDA approved SSRIs are Fluoxetine (Prozac), Fluvoxamine (Luvox), Sertraline (Zoloft) and Paroxetine (Paxil). These medications are considered to be equally effective, although some may work for some people and not for others.
  • a notable percentage of patients (40-60%) have a partial or no response to medications.
  • the onset of improvement in OCD symptoms may take weeks to months after starting a medication.
  • Combining medications such as antidepressants and antipsychotic medications may be effective in controlling OCD symptoms, although all psychiatric medications have side effects, such as stomach upset, sleep disturbance, sweating and reduced interest in sexual activity'. Furthermore, adherence to anti-psychotic drugs is about 50% in the first year, and decreases to about 25% in the second year due to intolerable safety issues with low benefit over time.
  • the above reported results of the multicenter DTMS study have demonstrated that the DTMS treatment can be as effective, or better than conventional SSRI medications in treating OCD.
  • the adverse events reported in this study for DTMS treatment are known and well tolerated by OCD subjects. Additionally, the DTMS treatment enables patient compliance with the treatment during a 6 week treatment period. Thus, the safety profile of the DTMS treatment is better than that reported for SSRI medications.
  • the performance data provided in the regulatory' submission further supports the safety of the DTMS device.
  • the overwhelming clinical benefits enabled by the DTMS treatment including high efficacy expressed in terms of a statistically significant reduction in YBOCS symptoms score, large effect size and low NNT, statistically significant response rates and improvement in CGI-1 and CGI-S, outweigh the minimal risks involved with the administration of the treatment.
  • the DTMS treatment provides clinically meaningful efficacy in a relatively short time of 6 weeks with a proven safety profile, high tolerability and extremely high treatment compliance by the OCD patient population compared to currently available medicinal treatments in the market.
  • the primary efficacy end-point as dictated in the study protocol was the change from baseline in YBOCS scores to the 6 week visit.
  • the primary' efficacy analysis is conducted on all evaluable subject data, in the PP analysis set.
  • Table 59 show's the unadjusted total YBOCS score and change in score from baseline.
  • FIGs. 12 and 13 are graphical representations of the table and present the mean ( ⁇ SE) of the YBOCS scores and changes from baseline, respectively. We see from these representations that in both study groups there was a reduction over time in YBOCS scores.
  • Table 59 Distribution Of YBOCS Score And Change From Baseline To 6 and 10 Week Visits (PP)
  • Table 60 presents the adjusted means extracted from the model at the 6-week visit.
  • the YBOCS score decreased by 6.0 points (95% Cl) in the DTMS group and by 3.3 points (95% Cl) in tire Sham control group, these decreases were both statistically significant.
  • the difference between the treatment arms is also statistically significant (p-value: 0.0127).
  • the effect size observed is 0.69.
  • the effect size of the study is 0.69. According to widely accepted guidelines, in which 0.2 is defined as a small effect, 0.5 as a medium effect, and 0.8 as a large effect, the DTMS multicenter study may be considered to have a greater than medium to large effect size based on the PP subject cohort.
  • the DTMS has a positive treatment outcome and has demonstrated a beneficial effect in reducing OCD symptoms in moderate to severe OCD patients.
  • the reduction in the YBOCS of 6.0 points is clinically meaningful and statistically significant compared to the sham and the effect size of 0.69 demonstrates a difference between the two groups, which is large enough and consistent enough to be clinically important.
  • the primary efficacy endpoint of the study was substantiated by the success of the secondary endpoints including the change from baseline in the YBOCS score at 10 weeks.
  • the change from baseline in the unadjusted YBOCS score at the 10 week visit extracted from Table 79 demonstrates that the YBOCS score decreased by 7.6 points in the DTMS group and by 4.7 points in the Sham group " fable 71 presents the adjusted means extracted from the model at the 10-week visit.
  • the YBOCS score decreased by 6.5 points (95% Cl) in the DTMS group versus 4.1 points (95% Cl) in the Sham group, these decreases were both statistically significant.
  • the difference between the treatment groups is also statistically significant (p-value: 0.0380).
  • the effect size of the study is 0.62.
  • the DTMS multicenter study may be considered to have a greater than medium to large effect size.
  • the treatment effect is maintained for at least 4 weeks after completion of all treatment sessions, at 10 weeks.
  • the positive effect was corroborated by responder analysis, thus supporting the robustness of the clinical effect.
  • the effect size as obtained by the Number Needed to Treat is 3.9, which means that for every 4 patients treated with the Deep TMS System, 1 subject will have a response due to the device.
  • the number needed to treat (NNT) for OCD patients treated with SSRI monotherapy at standard (antidepressant) doses is approximately 5, meaning that if 5 patients are treated with an SSRI, one can be expected to respond who would not have responded to placebo.
  • the NNT for a dose escalation from a medium dose to the higher doses is 13-15 27 . Therefore, the results of this study demonstrate a much greater effect size than conventional SSRI treatments forGCD.
  • CGI-I CGI Improvement
  • CGI-S CGI Severity
  • CGI-S CGI Severity
  • the DTMS benefit is also reported by the excellent safety profile reported in the clinical study report for the DTMS de vice, with similar known side effects of conventi onal TMS treatments and no reported differences in adverse events between the DTMS and Sham treatments.
  • the DTMS treatment has been demonstrated as effective for the treatment of OCD as reported by the primary efficacy analysis and as supported by the secondary efficacy analyses and is a safe treatment as demonstrated by the known side effects and lack of adverse events.
  • CGI Improvement CGI -I
  • CGI Severity CGI-S
  • SDS Sheehan Disability Scale
  • Table 61 presents the CGI-I score distribution with the percent of subjects in each treatment group according to the outcome classification on the CGI Improvement Scale. Table 61: Outcome Classification (%) in CGI Improvement Scale (PP)
  • the CGI-I scores were categorized into die following two categories:
  • Table 62 presents the distribution of the CGI-I scores per visit and treatment arm along with the p-value of the Fisher’s exact test per visit. At week 6 more subjects had a CGi-i score improved in the DTMS arm than in the Sham arm (p-value: 0.0112). Table 62: Comparison of CGI-I Outcome Categories (PP)
  • the DTMS treatment achie ves a significantly“Improved” clinical state based on the CGI Improvement scale, which is similar to the highest dosage of both SSRls, in half die time as these medications, i.e., 6 weeks vs 12-13 weeks, with far less complications and side effects than drug usage.
  • Table 63 presents descriptive statistics of the unadjusted CGI-1 score at each visit and the change from baseline to week 6 and 10.
  • FIG. 14 presents the mean ( ⁇ SE) of the CGI-I scores and changes from baseline, respectively. In general, we see a reduction in CGI-I score over time in both groups.
  • Table 63 Distribution Of CGI-I Score And Change From Baseline To 6 and 10 Weeks Visit (PP)
  • Table 64 presents the adjusted means extracted from the model at the 6-week visit.
  • the CGI-I score at the 6 weeks visit was 3 75 points (95% Cl) in the DTMS group and by 4.2 points (95% Cl) in the Sham group.
  • the difference between the treatment arms is not statistically significant (p-value: 0.0985).
  • Table 65 presents the CGI-S score distribution with the percent of subjects in each treatment group according to the outcome classification on the CGI Severity' Scale.
  • Table 65 presents the distribution of the changes in CGI-S scores per visit and treatm ent arm along with the p-value of the Fisher’s exact test per visit. At week 6 more subjects had a CGI- S score improved in the DTMS ami than in the Sham arm (p-value: 0.0221).
  • Table 66 presents descriptive statistics of the CGI-S score at each visit and the change from baseline to week 6 and 10.
  • FIGs. 15 and 16 present the mean ( ⁇ SE) of the CGI-S scores and changes from baseline, respectively . In general, we see a reduction in CGI-S score over time in both groups.
  • Table 66 Distribution Of CGI-S Score And Change From Baseline To 6 & 10 Week Visits (PP)
  • Table 67 presents the adjusted means extracted from the model at the 6-week visit.
  • the CGI- S decreased by 0.71 points (95% Cl) in the DTMS group and by 0.40 points (95% Cl) in the Sham group.
  • FIG. 17 and 18 present the mean ( ⁇ SE) of the SDS scores and change from baseline respectively .
  • Table 69 presents the adjusted means extracted from the model at the 6-week visit. SDS decreased by 3.8 points (95% Cl) in the DTMS group and by 3.0 points (95% Cl) in the Sham group, at 6 week visit these decreases were both statistically significant. Although, there is a trend towards better improvement in SDS scores in the DTMS group compared to the Sham group, the difference between the treatment groups is not statistically significant (p-value: 0.4786).
  • the Response rate and Partial Response rate at the 6 week visit are presented in Table 70.
  • Response is defined as a reduction from baseline of at least 30% in the YBOCS score.
  • Partial Response is defined as a reduction from baseline of at least 20% in the YBOC score.
  • Remission rate is defined as a YBOCS score less than ( ⁇ ) 10.
  • Table 70 Response Rate and Partial Response at the 6 Week Visit (PP)
  • the effect size as obtained by the Number Needed to Treat is 3.9, which means that for every 4 patients treated witlr the Deep 'IMS System, 1 subject will have a response due to the device.
  • the number needed to treat (NNT) for OCD patients treated with SSRI monotherapy at standard (antidepressant) doses is approximately 5, meaning that if 5 patients are treated with an SSRI, one can be expected to respond who would not have responded to placebo.
  • the NNT for a dose escalation from a medium dose to the higher doses is 13-15% Therefore, the results of this study demonstrate a much greater effect size than con ventional SSRI treatments for OCD.
  • the Response rate (as presented in Table 94 below) at the 10 week visit was 44.2% in the DTMS group compared to 22.5% in the Sham group.
  • Table 71 presents the adjusted means extracted from the model at the 10-week visit.
  • the YBOCS score decreased by 6.5 points (95% Cl) in the DTMS group versus 4.1 points (95% Cl) in the Sham group, these decreases were both statistically significant.
  • the difference between the treatment groups is also statistically signifi cant (p- value: 0.0380).
  • p- value 0.0380
  • the effect size of the study is 0.62.
  • the DTMS multicenter study may be considered to have a greater than medium to large effect size, based on the PP patient cohort.
  • the CGI Improvement results are maintained 4 weeks after treatment at the 10 week visit. That is, 72% of the DTMS subjects maintained some clinical improvement. Although, those subjects reporting a moderate to very much“Improved” clinical state remained much higher in the DTMS group (49% of DTMS subjects versus only 27.5% in the Sham group), this was not statistically significant at 10 weeks.
  • Table 72 presents the adjusted means extracted from the model at the 10-week visit.
  • the CGI- 1 score at the 10 weeks visit was 3.6 points (95% Cl) in the DTMS arm and 3.9 points (95% Cl) in the control arm. The difference between the treatment arms is not statistically significant (p-value: 0.3339).
  • the CGI Severity results are maintained 4 weeks after completion of the DTMS treatment at the 10 week visit (Table 65). That is, 64% of the DTMS subjects maintained an“Improvement " in their CGI-S scores compared to 61% at 6 weeks. And although, those subjects reporting an“Impro ved” clinical status remained much higher in the DTMS group (64% of DTMS subjects versus only 45% in the Sham group), this was not statistically significant at 10 weeks.
  • Table 73 presented below presents the adjusted means extracted from the model at the 10-week visit.
  • the CGI-S decreased by 0.935 points (95% Cl) in the DTMS group and by 0.66 points (95% Cl) in the Sham group, these decreases were both statistically significant.
  • the difference between the treatment groups is not statistically significant (p-value: 0.2343).
  • Table 74 presents the adjusted means extracted from the model at the 10-week visit.
  • the SDS decreased by 2.6 points (95% Cl) in the DTMS group and by 3.3 points (95% Cl) in the Sham group.
  • the difference between the treatment groups was not found statistically significant (p-value: 0.5519).
  • Remission Rate at the 6 week visit are presented in Table 75. Remission rate was defined as a YBOCS score of less than ⁇ ) 10.
  • the exploratory efficacy end-point as dictated in the study protocol was the change from baseline in HDRS- 21 scores to 6 and 10 weeks.
  • Table 76 shows the unadjusted HDRS-21 scores at each visit along with the change from baseline in HDRS-21 scores.
  • FIGs. 19 and 20 present the mean ( ⁇ SE) of the HDRS-21 scores and changes from baseline, respectively.
  • Table 76 HDRS-21 Score And Change From Baseline (PP)
  • Table 77 presents the adjusted means extracted from the model at the 6 and 10 week visits for the PP analysis sets. The differences within the treatment arms and between the treatment arms were not statistically significant. As the majority of the study subjects did not suffer from co- morbid Major Depressive Disorder (MDD) (mean HDRS-21 score at baseline in both treatment groups was 10), we do not expect any significant changes or improvements in HDRS-21 score due to the treatment in non -MDD patients. Furthermore, we can infer that the improvement in GCD was not as a result of an improvement in depression.
  • MDD co- morbid Major Depressive Disorder
  • Remission rate at the 6 week visit, where remission is defined as YBOCS score ⁇ 8 was defined in the study protocol as an exploratory endpoint.
  • the results of the Remission Rates defined as YBQCS ⁇ 10 did not show results that justified performing this statistical analysis.
  • the primary efficacy end-point as dictated in the study protocol was the change from baseline in YBOCS scores to the 6 week visit.
  • the primary efficacy analysis is conducted on all evaluable subject data, in the ITT analysis set.
  • Table 79 show's the unadjusted total YBOCS score and change in score from baseline. We see from these representations that in both study groups there was a reduction over time in YBOCS scores.
  • Table 80 presents the adjusted means extracted from the model at the 6-week visit.
  • the YBOCS score decreased by 6.0 points (95% Cl) in the DTMS group and by 4.1 points (95% Cl) in the Sham control group, these decreases were both statistically significant.
  • the difference between the treatment groups is not statistically significant (p-value: 0 0988)
  • the effect size observed is 0 48.
  • the Effect Size were clinically significant and showed a medium effect size.
  • the effect size of the study is 0.48. According to the widely accepted guidelines of Cohen 3 , in which 0.2 is defined as a small effect, 0.5 as a medium effect, and 0.8 as a large effect, the DTMS multicenter study may be considered to have a medium effect size based on the ITT subject cohort.
  • the DTMS has a positive treatment outcome and has demonstrated a beneficial effect in reducing OCD symptoms in moderate to severe OCD patients.
  • the reduction in the YBOCS of 6.0 points is clinically meaningful and statistically significant and the effect size of 0.48 demonstrates a large enough and consistent enough treatment outcome to be clinically important.
  • the placebo effect in the ITT patient cohort showed a higher reduction in YBOCS score than in the mITT patient cohort and therefore, statistical significant between the treatment groups was not found.
  • the positive effect was corroborated by responder analysis, thus supporting the robustness of the clinical effect.
  • the effect size as obtained by the Number Needed to Treat is 5.3, which means that for every 5 patients treated with the Deep TMS System, 1 subject will have a response due to the device.
  • the number needed to treat (NNT) for OCD patients treated with SSR1 monotherapy at standard (antidepressant) doses is approximately 5, meaning that if 5 patients are treated with an SSRI, one can be expected to respond who would not have responded to placebo.
  • the NNT for a dose escalation from a medium dose to the higher doses is 13-15. Therefore, the results of this study demonstrate an effect size equal to or better than conventional SSRI treatments for OCD.
  • the DTMS benefit is also reported by the excellent safety profile reported in the Clinical Study Report for the DTMS device, with similar known side effects of conventional TMS treatments and no reported differences in adverse events between tire DTMS and Sham treatments.
  • the DTMS treatment has been demonstrated as effective for the treatment of OCD as reported by the primary efficacy analysis and as supported by some of the secondary efficacy analyses and is a safe treatment as demonstrated by the known side effects and lack of adverse events.
  • CGI improvement CGI-1
  • CGI Severity CGI-S
  • SDS Sheehan Disability Scale
  • Table 81 presents the CGI-I score distribution with the percent of subjects in each treatment group according to the outcome classification on the CGI Improvement Scale Table 81: Outcome Classification (%) in CGI Improvement Scale (ITT)
  • the CGI-I scores were categorized into the following two categories:
  • Table 82 presents the distribution of the CGI-I scores per visit and treatment arm along with the p-vaiue of the Fisher ’ s exact test per visit. At week 6 more subjects had a CGI-I score improved in the DTMS arm than in the Sham arm (p-value: 0.0459). Table 82: Comparison of CGI-I Outcome Categories (ITT)
  • the DTMS treatment achieves a significantly“Improved” clinical state based on the CGI Improvement scale, which is similar to the highest dosage of both SSRIs, inhalfthe time as these medications, i.e., 6 weeks vs 12-13 weeks, with far less complications and side effects than drug usage.
  • Table 83 presents descriptive statistics of the unadjusted CGI -I score at each visit and the change from baseline to week 6 and 10. In general, we see a reduction in CGI-I score over time in both groups. Table 83: Distribution Of CGI-I Score And Change From Baseline To 6 and 10 Weeks Visit (ITT)
  • Table 84 presents the adjusted means extracted from the model at the 6-week visit.
  • the CGI-I score at the 6 weeks visit was 3.7 points (95% Cl) in the DTMS group and by 4.1 points (95% Cl) in the Sham group.
  • the difference between the treatment arms is not statistically significant (p-value: 0.2247).
  • Table 85 presents the CGI-S score distribution with the percent of subjects in each treatment group according to the outcome classification on the CGI Severity Scale
  • Table 85 presents the distribution of the changes in CGI-S scores per visit and treatment arm along with the p-value of the Fisher’s exact test per visit. At week 6 more subjects had a CGI- S score improved in the DTMS arm than in the Sham ami (p-value: 0.0562). Table 85: Comparison of Change from Baseline in CGI-S, Outcome Categories (ITT)
  • CGI-S is also presented as a continuous variable.
  • Table 86 presents descriptive statistics of the CGI-S score at each visit and the change from baseline to week 6 and 10.
  • Table 86 Distribution Of CGI-S Score And Change From Baseline To 6 & 10 Week Visits (ITT)
  • Table 87 presents the adjusted means extracted from the model at the 6-week visit.
  • the CGT-S decreased by 0.73 points (95% Cl) in the DTMS group and by 0.53 points (95% Cl) in the Sham group.
  • Table 88 Distribution Of SDS Score And Change From Baseline To 6 and 10 Week Visits (ITT)
  • Table 89 presents the adjusted means extracted from the model at the 6-week visit. SDS decreased by 3.9 points (95% Cl) in the DTMS group and by 3.3 points (95% Cl) in the Sham group, at 6 week visit these decreases were both statistically significant. The difference between the treatment groups is not statistically significant (p-value: 0.5628)
  • the Response rate and Partial Response rate at the 6 week visit are presented in Table 90.
  • Response is defined as a reduction from baseline of at least 30% in the YBOCS score.
  • Partial Response is defined as a reduction from baseline of at least 20% in the YBOC score.
  • Remission rate is defined as a YBOCS score less than ( ⁇ ) 10.
  • Last Observed Value (LGV) method was used.
  • Table 90 Response Rate and Partial Response at the 6 Week Visit (ITT)
  • the effect size as obtained by the Number Needed to Treat (l/difference in response rates) is 5.3, which means that for every 5 patients treated with the Deep TMS System, i subject will have a response due to the device.
  • the number needed to treat (NNT) for QCD patients treated with SSRI monotherapy at standard (antidepressant) doses is approximately 5, meaning that if 5 patients are treated with an SSRI, one can be expected to respond who would not have responded to placebo.
  • the NNT for a dose escalation from a medium dose to the higher doses is 13-15. Therefore, the results of this study demonstrate an effect size equal to or better than conventional SSRI treatments for QCD.
  • the Response rate (as presented in Table 94) at the 10 week visit was 44.2% in the DTMS group compared to 22.45% in the Sham group.
  • Table 91 presents the adjusted means extracted from the model at the 10-week visit.
  • the YBOCS score decreased by 6 5 points (95% Cl) in the DTMS group versus 4.7 points (95% Cl) in the Sham group, these decreases were both statistically significant.
  • the difference between the treatment groups was not found statistically significant (p-value: 0.1406).
  • the effect size observed is 0.45.
  • the effect size of the study is 0.45.
  • the DTMS multicenter study may be considered to have a medium effect size, based on the ITT patient cohort.
  • the reduction in the YBOCS of 7.4 points is clinically meaningful and statistical significant compared to the sham and the effect size of 0.45 demonstrates a large enough and consistent enough treatment outcome to be clinically important.
  • Table 92 below presents the adjusted means extracted from the model at the 10-week visit.
  • the CGI-I score at the 10 weeks visit was 3.6 points (95% Cl) in the DTMS arm and 3.8 points (95% Cl) in the control arm. The difference between the treatment arms is not statistically significant (p-value: 0.4351).
  • the CGI Se verity results are maintained 4 weeks after completion of the DTMS treatment at the 10 week visit (Table 85). That is, 62.5% of the DTMS subjects maintained an“Improvement” in their CGI-S scores compared to 61% at 6 weeks. And although, those subjects reporting an“Improved” clinical status remained much higher in the DTMS group (62.5% of DTMS subjects versus only 50% in the Sham group), this was not statistically significant at 10 weeks.
  • Table 93 presents the adjusted means extracted from the model at the 10-week visit.
  • the CGI- S decreased by 0.95 points (95% Cl) in the DTMS group and by 0.76 points (95% Cl) in the Sham group, these decreases were both statistically significant.
  • the difference between the treatment groups is not statistically significant (p-value: 0.4251).
  • Table 94 presents the adjusted means extracted from the model at the 10-week visit.
  • the SDS decreased by 2.6 points (95% Cl) in the DTMS group and by 3.5 points (95% Cl) in the Sham group.
  • the difference between the treatment groups was not found statistically significant (p-value: 0.4469).
  • Remission Rate at the 6 week visit are presented in Table 95. Remission rate was defined as a YBOCS score of less than ( ⁇ ) 10.
  • the exploratory efficacy end-point as dictated in the study protocol w3 ⁇ 4s the change from baseline in HDRS- 21 scores to 6 and 10 weeks.
  • Table 96 sho 's the unadjusted HDRS-21 scores at each visit along w'ith the change from baseline in HDRS-21 scores.
  • Table 96 HDRS-21 Score And Change From Baseline (ITT)
  • Table 97 presents the adjusted means extracted from the model at the 6 and 10 week visits for the ITT analysis sets. The differences within the treatment arms and between the treatment arms were not statistically significant. As the majority of the study subjects did not suffer from co- morbid Major Depressive Disorder (MDD) (mean HDRS-21 score at baseline in both treatment groups was 10), we do not expect any significant changes or improvements in HDRS-21 score due to the treatment in non-MDD patients. Furthermore, we can infer that the improvement in OCD was not as a result of an improvement in depression.
  • MDD co- morbid Major Depressive Disorder
  • the Remission Rate at the 10 week visit in the DTMS group is 9.3% versus 6.1% in the Sham group.
  • OCD Obsessive Compulsive Disorder
  • CSTC cortico-striato-thalamo-cortical
  • mPFC medial prefrontal cortex
  • ACC anterior cingulate cortex
  • DTMS deep transcranial magnetic stimulation
  • Methods Treatment resistant OCD participants were treated with either high-frequency (HF; 20 Hz), low- frequency (LF; 1 Hz), or sham DTMS of the mPFC and ACC for five weeks, in a double-blinded manner. All treatments were administered following symptoms provocation, and EEG measurements during a Stroop task were acquired to examine changes in error-related activity. Clinical response to treatment was determined using the Yale-Brown-Obsessive-Compulsive Scale (YBOCS).
  • the experiment included baseline clinical and electrophysiological measurements in 41 OCD patients, a 5- weeks treatment phase, corresponding measurements, and a one month follow-up phase.
  • the study was performed at Chaim Sheba Medical Center, Israel (20l2e20l4), and the protocol was approved by the local Institutional Review Board and the Israeli Ministry of Health.
  • OCD participants who met stage III criteria were recruited via newspapers and internet advertisements, and from the outpatient program at Chaim Sheba Medical Center.
  • the inclusion criteria were: 18-65 years old; current DSM-IV diagnosis of OCD; a score of >20 in the Y-BOCS (20 items); CBT at maintenance phase (if conducted); and stable SSRI medications maintenance for 8 weeks prior to enrollment, and unchanged during treatment.
  • Exclusion criteria included any other Axis-I psychopathology or a current depressive episode. All participants signed a written informed consent form.
  • MINI Mini-International Neuropsychiatric Interview
  • YBOCS Yale-Brown-Obsessive-Compulsive Scale
  • RSPM Raven's Progressive Matrices test
  • HAM-D Hamilton's depression rating scale
  • CGI-S Clinical Global Impressions of severity
  • Participants were randomly assigned to receive 1 Hz stimulation (LF), 20 Hz stimulation (HF), or sham stimulation, using a computer program (Interactive Web Randomization System; Medpace's ClinTrak, USA). All groups were treated five times per week for five weeks (for a total of 25 sessions), and each treatment session began with an exposure to personalized obsessive-compulsive cues.
  • YBOCS the clinical response was defined as a reduction of 30%. This threshold was set in accordance with the literature, taking into account the study population (stage III criteria). Nevertheless, results using the more common threshold of 35% reduction in YBOCS scores are also reported.
  • CGI-I response was defined as a score ⁇ 2 (very much improved or much improved).
  • DTMS offers a non-invasive tool to stimulate deep-located re-gions such as the ACC.
  • DTMS was administered using a Magstim Rapid2 TMS stimulator (The Magstim Co. Ltd., Whitland, Carmarthenshire, United Kingdom) equipped with an H7-coil (specifically designed to stimulate the ACC).
  • HF and LF stimulation trains of pulses were delivered at 100% and 110% of the leg RMT, respectively (different intensities were employed for safety reasons, taking into account patients with augmentation medications such as D2 antagonists and the higher risk for HF stimulation).
  • HF (20 Hz) sessions consisted of 50 trains lasting 2 s each, with an inter-train interval of 20 s (2000 pulses in total), while LF (1 Hz) sessions consisted of 900 consecutive pulses.
  • Sham stimulation (randomized to mimic either HF and LF stimulation), and the determination of the type of stimulation for each individual (HF, LF or sham) were performed as previously described. Participants were told that physical sensations may be induced by both real and sham coils, operators and raters were blind to the type of treatment, and raters were not allowed to be present during treatments. Following the first treatment, participants were asked to guess which treatment they were assigned to (active ⁇ sham) by choosing one of the following answers: 1. 1 do not know, 2. Uncertain that I received active ⁇ sham treatment, 3. Strong feeling that I received active ⁇ sham treatment. 4. Active ⁇ sham group.
  • EEG recordings during a Stroop task were performed at Pre- and Post-treatment time-points.
  • the Stroop task was administered using E-Prime software (Psychology Software Tools, Inc.) on a 17 inch computer screen, as previously described. Participants were instructed to press the key associated with the color of the word while ignoring the word's meaning.
  • EEG was recorded using the ASA lab (A.N.T. Enschede, Netherlands), with a 32 channels cap (Waveguard) and two Electrooculography (EOG) channels. Electrode impedances were kept below 10 KU, and all channels were average referenced. Data were collected at 250 samples per second and digitized with a 24-bit AD converter.
  • EEG data were filtered using 1-100 Hz band-pass and 50 Hz notch, and were segmented into trials that were time-locked to the participants' response.
  • the segmented data were baseline corrected, and noisy segments or channels were removed.
  • Data were then gathered according to conditions (congruent/incongruent), divided by response type (correct/mistake) and filtered to the theta band (4-8 Hz). Since most of the mistakes (93%) were made within the incongruent trials, analysis was carried out solely for this condition.
  • the amplitudes following responses (0-120 ms) were computed using an adaptive mean measure.
  • EEG amplitude and power were analyzed using a mixed-model measure ANOVA with Group (HF and sham), Time (Pre- and Post-treatment), and Response type (correct and mistake) as independent variables, and with theta band dB mean power (0-120 ms post response) as the dependent variable. Significant results were further analyzed using Tukey post-hoc. All data are presented as mean ⁇ SEM.
  • the three groups did not differ in their baseline characteristics of gender, age, IQ, concomitant medication, depression, or OCD severity (Table 99). No severe adverse events were recorded, and the treatment was well- tolerated by most participants. Side-effects that included headaches and fatigue were reported by four participants (three from the HF group and 1 from the sham group). Three participants dropped out during treatment - one due to conflicting schedule (sham group) and two due to inconvenience with the treatment (HF group). Thus, the final analysis consisted of 38 participants (out of 41 randomized) that completed the treatment (see Consort chart in Figure 25).
  • the final ERN analysis included 13 participants from the HF group and 9 participants from the sham group, with no differences in behavioral mistake percentage at baseline (13 ⁇ 3.4% and 8 ⁇ 2.3%, respectively), or following treatment (14 ⁇ 2% and 12 ⁇ 2.5%, respectively).
  • the ERN response expressed in the theta band (0-120 ms post response) was similar in both groups at baseline, but there was a shift towards increased ERN in the HF group, and decreased ERN in the sham group following treatment ( Figure 22).
  • the present study is the first to explore the safety, tolerability, and efficacy of multiple sessions of DTMS in the treatment of OCD.
  • the results indicate that HF stimulation over the mPFC and ACC is a safe and effective intervention for the alleviation of OCD symptoms in participants who failed to receive sufficient benefit from previous treatments.
  • the response rate following HF treatment was significantly higher for up to one month, and that the reduction in symptoms severity was related to the magnitude of changes in the ERN response.
  • One mechanism that can explain the observed results is that neuromodulations induced by HF stimulation in the mPFC and ACC reinforced participants' ability to exert inhibitory control over their compulsive behavior.
  • An additional factor that may contribute to the effect of stimulation is the state of the relevant neuronal circuit.
  • the DTMS procedure that was applied here may interfere with the dysfunctional information flow in the frontal-basal ganglia circuit, which is mediated by the ACC and was suggested to be a core pathology of OCD.
  • initiation of behavioral sequences that are stored in the PFC results in motivational distress that is only relieved upon completion of the sequences.
  • hyperactivation of the ACC retards the feeling of completion and generates the compulsive behavior.
  • the protocol described herein may disrupt circuits associated with the feeling of incompleteness and may alter the dysfunctional monitoring activity. Consistent with this hypothesis, our results imply that the beneficial effect of the treatment was associated with modified theta activation over the mPFC and the ACC, which is considered to be the generator and the locus of the ERN response. Particularly, the HF treatment resulted with increased ERN theta activity that was correlated with reduction of symptom's severity. To the best of our knowledge, no TMS protocols or pharmacological interventions have shown such a change in ERN signal in OCD patients. Here again, the finding is somewhat counterintuitive considering that enhanced ERN is generally elicited in OCD participants in comparison to control, and that general hyper-activation of the ACC is commonly found in OCD participants. Patients treatment history
  • Sham stimulation (randomized to mimic either HF and LF stimulation) was performed using a sham coil that is placed within the same helmet as the real coil, but induces only negligible electric fields in the brain. Participant were told that physical sensations may be induced by both real and sham coils. In addition, operators were blind to the type of treatment, which was determined by a magnetic card that was individually assigned following randomization using a computer program (Interactive Web Randomization System; Medpace's ClinTrak, USA)
  • the Stroop task was administered using E-Prime software (Psychology Software Tools, Inc.) on a 17 inch computer screen, and included a response pad with four keys.
  • E-Prime software Psychology Software Tools, Inc.
  • the words‘red’,‘green’,’yellow’ and‘blue’ were presented with their respective color (congruent condition), or in one of the three other colors (incongruent condition), in a balanced manner (50- 50 chance). Participants were instructed to press the key associated with the color of the word while ignoring the word’s meaning.
  • Continuous EEG data were filtered using 1 - 100 Hz band-pass and 50 Hz notch, and were segmented into trials that were time-locked to the participants' response (2 seconds epochs, 1 second before and 1 second after the participant response).
  • the segmented data were baseline corrected (at -300 ms to -70 ms before the event), and noisy segments or were manually inspected and removed. Subsequently, the data were decomposed using Independent Component Analysis (ICA), in which eye blinks and horizontal eye movements were excluded. A second manual inspection was then performed and residual artifacts were removed. Excluded channels were replaced with spherical interpolation of the neighboring channels values.
  • ICA Independent Component Analysis
  • This example details an FDA-regulated multi-center double-blind randomized controlled study, wherein 99 participants received 29 daily sessions of repetitive high-frequency or sham stimulation using a unique deep TMS coil which is designed to stimulate the medial prefrontal and the anterior cingulate cortices.
  • all stimulation sessions were conducted following a tailored and personalized symptoms provocation.
  • Our experiment demonstrates that, compare to sham, real stimulation greatly reduces symptom severity by the end of the treatment, with response rates that remained significantly different for at least an additional month.
  • We discuss several potential mechanisms involving TMS-induced neuroadaptation which could account for these significant therapeutic effects.
  • OCD Obsessive Compulsive Disorder
  • Pre 3-week screening phase
  • Post consisted of five weeks of daily treatments and 4 treatments during the six th week to a total of 29 treatments
  • FU 4-weeks follow-up phase
  • Eligibility criteria included: 22-68 years old, DSM-IV confirmed diagnosis of OCD, treated in an outpatient setting, and Y-BOCS score >20.
  • Serotonin reuptake inhibitors (SRIs), anti-depressants, and D2 or D2-5HT2 antagonist medications were allowed, but doses could not be changed for at least 2 months prior to enrollment and throughout the study.
  • the main exclusion criteria included any primary Axis I diagnosis other than OCD, severe neurological impairment, and increased risk of seizures. All patients provided written informed consent after receiving a complete description of the study.
  • Eligible Subjects were randomized into the study by center. After subjects met the eligibility criteria, they were equally allocated (with a 1 : 1 ratio) to one of the 2 treatment groups (Sham or Active dTMS), based on a stratified randomization scheme using the SAS (version 9.4) random number generator.
  • SAS version 9.4 random number generator.
  • a central Interactive Web-Based Randomization System (IWRS) was developed for the current study and was validated according to the IEEE Standard for Software Development and Test Documentation. Site users entered the IWRS by using their user identification (ID) and password provided by the CRO. The system recognized the user site automatically by the unique user identification. Users were then asked to enter the requested subject details (eligibility code, subject's initials, subject's ID, Date of birth and Motor Threshold level).
  • the IWRS assigned a unique subject randomization code, which determined the treatment assignment for the subject.
  • the unique subject randomization code matched one of the pre-programmed treatment cards maintained at the clinical site. The operator was then asked to take the treatment card with the same randomization code from the box of pre-programmed treatment cards and to complete the subject ID on the card label and place the treatment card inside the subject's Operator Binder.
  • Clinical severity rating scales included the Y-BOCS, Hamilton Depression Rating Scale (HDRS-21), Sheehan Disability Scale (SDS), Clinical Global Impression - Severity (CGI-S), and CGI - Improvement (CGI-I).
  • Safety evaluations included monitoring of adverse events, vital signs assessment, physical and neurological examinations, urine pregnancy tests, and the Scale for Suicidal Ideation (SSI). All raters underwent a uniform training program and certification for the administration of the rating scales.
  • the provocations were designed in a multi-step process to ensure they were tailored for every patient in a similar fashion. They were created in a ninety -minute session by the certified Y-BOCS rater(varing degrees) and site PI (psychiatrist) for each patient during the first assessment meeting, based on the main obsessions and compulsions the patient described during that meeting and submitted to the central expert rater for prior to randomization.
  • the steps were as follows: Detailed Y- BOCS symptom checklist, draft symptom list, complete Y-BOCS severity measure, create hierarchy, develop internal provocations, develop external provocations, and review with the dTMS operators.
  • the patient’s OCD symptomology was collected using the detailed Y -BOCS symptom checklist.
  • the main current OCD symptoms were annotated during the interview to focus on during YBOCS scoring and for creation of provocations.
  • the obsession (such as did I cause harm?) and compulsion (reviewing or checking) that cause the most symptoms, are focused on in detailed fashion to create provocations in an individualized hierarchal fashion, using the most troubling symptoms.
  • ten provocations are designed, five internal and five external.
  • the series of five internal provocations are meant to have escalating difficulty relevant to the individual, generating doubt in the patient by asking questions such as: Is it possible that... ? How can you be sure?
  • VAS visual analog scale
  • the tailored provocation was administered prior to each treatment session, after the coil was in the treatment position and lasted between 3-5 minutes.
  • the provocations were delivered by the TMS operators (BA or BS), who were trained about OCD (so as not to give reassurance and strengthen compulsions) and about the patients specific symptomology.
  • the operators had a list of ten provocations to use as a guide, not to be read verbatim. Additionally, they were not to use themselves as a target of the provocation which could ruin the therapeutic alliance.
  • the operator would start with the lowest provocation on the hierarchy, and ask the VAS. If it was too low, they would go to a higher provocation.
  • the provocations used for each treatment, and the outcome self- reported distress score on a 1 to 10 visual analog scale (VAS) were recorded on the case report forms (CRFs).
  • dTMS was administered using a Magstim Rapid2 TMS (The Magstim Co. Ltd., Whitland, Carmarthenshire, United Kingdom) stimulator equipped with a unique H shaped coil design.
  • the H-coil version used in this study was the H7 (HAC) (Brainsway LTD, Jerusalem, Israel).
  • H7 H7
  • RMT leg resting motor threshold
  • Approximately 70 cm 3 of the neuronal volume are stimulated above neuronal activation threshold (100 V/m).
  • Maps of the H7 coil field distribution are shown in Figure 28.
  • the subjects’ RMT was determined prior to the first treatment and at the beginning of each week by ascertaining the coil position that elicited the minimal involuntary contractions of the feet.
  • the motor threshold was determined visually, but EMG could be used as well.
  • the resting MT was defined as the minimum stimulator output resulting in either foot or toe movement for 3/6 trials.
  • the Active treatment group received 20 Hz dTMS at 100% of RMT, with 2 second pulse trains and 20 second inter-train intervals for a total of 50 trains and 2000 pulses per session.
  • the Sham group received treatment with identical technical parameters, that induced scalp sensations but without penetration of the electric field into the brain, as previously described. Subjects were told that face or hand twitching might occur during applications of protocols of either Sham or Active treatments.

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Abstract

Devices for treating obsessive compulsive disorder and methods for treating subjects afflicted with obsessive compulsive disorder are presented herein. In a particular aspect, the devices described herein are used to treat obsessive compulsive disorder in a subject in which personalized provocation related to at least one of obsessions or compulsions of the subject has been induced. In another aspect, methods for treating subjects afflicted with obsessive compulsive disorder are used to treat a subject in which personalized provocation related to at least one of obsessions or compulsions of the subject has been induced.

Description

METHODS FOR TREATING OBSESSIVE COMPULSIVE DISORDER
RELATED APPLICATIONS
This application claims priority of U.S. Provisional Application No. 62/594,246, filed December 4, 2017, the entirety of which is incorporated herein by reference for all purposes.
FIELD OF THE INVENTION
Methods and systems for treating a subject afflicted with obsessive compulsive disorder (OCD) are described herein. In a particular embodiment thereof, the subject is a mammal. In a more particular embodiment thereof, the mammal is primate, and, more particularly, a human.
Figure imgf000002_0001
Obsessive-compulsive disorder (OCD) is a highly debilitating condition with a lifetime prevalence of 2%- 3%, and a notable percentage of patients (40-60%) who have a partial or no response to medications.
According to the DSM-IV-TR, obsessions are repetitive, intrusive, and distressing thoughts, ideas, images, or urges that often are experienced as meaningless, inappropriate, and irrelevant, and persist despite efforts to suppress, resist, or ignore them. Compulsions are repetitive, stereotyped behaviors and/or mental acts that are used to diminish the anxiety and distress associated with the obsessions.
Two models have been suggested to explain the neurobiology of OCD. The first is an executive dysfunction model, implicating the dorsolateral prefrontal cortex (DLPFC), caudate nucleus, striatum, and thalamus, and proposes that the main dysfunction occurs impulse control and inhibition of behaviors.
The second is a modulatory control model, implicating the orbitofrontal cortex (OFC), medial prefrontal cortex (mPFC), and cingulate gyrus, in which the dysfunction may be one of inability to regulate socially appropriate behaviors.
SUMMARY
As described herein, a Food and Drug Administration (FDA) regulated, prospective, double-blind, placebo controlled multicenter study demonstrates that high-frequency deep transcranial magnetic stimulation (dTMS) treatment over the mPFC and the anterior cingulate cortex (ACC), when applied following exposure to OCD symptom provocation, is safe, tolerable and effective in reducing OCD symptoms. As such, these results represent a novel intervention for the treatment of OCD.
In an aspect, a method for treating a subject afflicted with obsessive compulsive disorder is presented herein, the method comprising:
(i) inducing a personalized provocation related to at least one of obsessions or compulsions of the subject and
(ii) stimulating brain structures in at least one of an anterior cingulate cortex (ACC) or a medial prefrontal cortex (mPFC) of the subject’s brain after the inducing, wherein the stimulating bilaterally stimulates brain structures in at least one of the ACC or the mPFC of the subject’s brain, wherein the stimulating comprises applying deep transcranial magnetic stimulation (dTMS) to the subject’s skull such that brain structures in at least one of the ACC or the mPFC of the subject’s brain is stimulated, wherein the dTMS is delivered repetitively and at a high frequency comprising at least 5Hz.
In a particular embodiment of the method, the stimulation is applied immediately after the inducing the personalized provocation; up to 5 minutes after the inducing the personalized provocation; or up to 30 minutes after the inducing the personalized provocation. In a more particular embodiment thereof, the
the stimulation is applied 3-5 minutes after the inducing the personalized provocation.
In a particular embodiment of the method, the provocation is designed to achieve a score of between 4 to 7 on a 1 to 10 visual analog scale (VAS) self-report and wherein the stimulation is given after a score of 4 to 7 is achieved.
In a particular embodiment of the method, the subject is instructed to focus his/her thoughts on the provocation during the stimulation session.
In a particular embodiment of the method, the high frequency ranges from 5-25Hz. In a more particular embodiment thereof, the high frequency ranges from l8-22Hz. In a more particular embodiment thereof, the high frequency is about 20Hz or is 20Hz.
In a particular embodiment of the method, the stimulating is effectuated at a stimulation intensity between 80% and 120% of the leg resting motor threshold (RMT). In a more particular embodiment thereof, the stimulating is effectuated at a stimulation intensity of 100% of the leg resting motor threshold (RMT). In a still more particular embodiment thereof, the high frequency is 20Hz dTMS at a stimulation intensity of 100% of leg resting motor threshold (RMT) at a frequency of 2 second pulse trains and 20 second inter-train intervals for a total of 50 trains and 2000 pulses per session.
In a particular embodiment of the method, the stimulating of brain structures in at least one of the ACC or the mPF C is sufficient to stimulate interconnecting fibers of the at least one of the ACC or the mPF C of the subj ect’ s brain. In a more particular embodiment thereof, the stimulating of brain structures in at least one of the ACC or the mPFC is sufficient to stimulate brain structures in the at least one of the ACC or the mPFC, without a significant increase of electrical fields induced in superficial cortical regions of the subject’s brain.
In a particular embodiment of the method, the deep TMS is delivered to each subject’s skull position relative to a location on each subject’s skull identified as corresponding to a stimulation point that stimulates a muscle of the subject’s leg at leg resting motor threshold (RMT). In a more particular embodiment thereof, the deep TMS is delivered to each subject’s skull 2 cm to 7 cm anterior to the stimulation point that stimulates the muscle of the subject’s leg. In a still more particular embodiment thereof, the deep TMS is delivered to each subject’s skull 4 cm anterior to the stimulation point that stimulates the muscle of the subject’s leg. In yet another embodiment thereof, the muscle is the tibialis muscle.
In a particular embodiment of the method, the stimulation intensity is 100% of the leg resting motor threshold (RMT) the deep TMS stimulates approximately 70 cm3 of target neuronal volume above neuronal activation threshold.
In a particular embodiment of the method, the subject afflicted with obsessive compulsive disorder is selected based on the subject’s baseline amplitude of theta frequency band during and/or following a Stroop task. In a still more particular embodiment thereof, the baseline amplitude of the theta frequency band ranges from 4-8 Hz.
In a particular embodiment of the method, the subject afflicted with obsessive compulsive disorder is selected based on the subject’s lack of responsiveness to at least one of serotonin reuptake inhibitors or cognitive behavioral therapy.
In a particular embodiment of the method, the stimulation is given in 29 sessions over a six week period of time.
In a particular embodiment of the method, the stimulation is given in a range of 20 to 30 sessions over a four week to six week period of time.
Also presented herein is a device for treating a subject afflicted with obsessive compulsive disorder, wherein the device is as set forth in Figure 33 and wherein the device is configured to deliver deep transcranial magnetic stimulation (dTMS) to the subject’s skull such that brain structures in at least one of the ACC or the mPFC of the subject’s brain are stimulated and wherein the dTMS is delivered repetitively and at a high frequency comprising at least 5Hz. In a particular embodiment, the device is implement on a subject afflicted with obsessive compulsive disorder wherein the subject has undergone induction of a personalized provocation related to at least one of obsessions or compulsions of the subject.
Other objects, features and advantages of the present invention will become clear from the following description and examples.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1: An illustration of the HAC-Coil Deep IMS System
FIG. 2: Kaplan Meier Curve of The Time To Drop-Out Up To 6 Weeks (ITT). Log-Rank p-value: 0.6109 FIG. 3: Total YBOCS Score Over Time To 6 Weeks And 10 Weeks Visit (mlTT)
FIG. 4: YBOCS Change From Baseline Over Time To 6 Weeks And 10 Weeks Visit (mlTT)
FIG. 5: Total CGI-I Score over Time to 6 Weeks and 10 Weeks Visit (mlTT)
FIG. 6: Total CGI-S Score over Time to 6 Weeks and 10 Weeks Visit (mlTT)
FIG. 7: CGI-S Change from Baseline over Time to 6 Weeks and 10 Weeks Visit (mlTT)
FIG. 8: Total SDS Score over Time to 6 Weeks and 10 Weeks Visit (mlTT)
FIG. 9: SDS Change from Baseline over Time to 6 Weeks and 10 Weeks Visit (mlTT)
FIG. 10: Total HDRS-21 Score over Time to 6 Weeks and 10 Weeks Visit (mlTT)
FIG. 11: HDRS-21 Change from Baseline over Time to 6 Weeks and 10 Weeks Visit (mlTT)
FIG. 12: Total YBOCS Score Over Time To 6 Weeks And 10 Weeks Visit (PP)
FIG. 13: YBOCS Change From Baseline Over Time To 6 Weeks And 10 Weeks Visit (PP)
FIG. 14: Total CGI-I Score Over Time To 6 Weeks And 10 Weeks Visit (PP) FIG. 15: Total CGI-S Score Over Time To 6 Weeks And 10 Weeks Visit (PP)
FIG. 16: CGI-S Change From Baseline Over Time To 6 Weeks And 10 Weeks Visit (PP)
FIG. 17: Total SDS Score Over Time To 6 Weeks And 10 Weeks Visit (PP)
FIG. 18: SDS Change From Baseline Over Time To 6 Weeks And 10 Weeks Visit (PP)
FIG. 19: Total HDRS-21 Score Over Time To 6 Weeks And 10 Weeks Visit (PP)
FIG. 20: HDRS-21 Change From Baseline Over Time To 6 Weeks And 10 Weeks Visit (PP)
FIG. 21A-D: Clinical effect of the treatment. Panel A presents mean J SEM changes in YBOCS scores from baseline along the study, for the HF and sham groups. Panel B presents the number and percentage of participants who responded to treatment (i.e. 30% reduction in symptoms at week 5) in each group. Panel C and Panel D present changes from baseline in CGI-I scores and the percentage of participants that benefit from the treatment, in each group. *p < 0.05, **p < 0.01, ***p < 0.001.
FIG. 22: Electrophysiological effect of the treatment. Grand averages of pre- and post-treatment EEG measurements during correct and mistake responses in the Stroop task, as recorded from the Cz electrode in theta band (4e8 Hz), are presented. Time point 0 is set at the motor response.
FIG. 23A-D: Treatment effect on theta power during the Stroop task. Panels A and C present wavelet expression of pre- and post-treatment activity, respectively. Time point 0 represents motor response. Panels B and D present mean J SEM theta power following correct and mistake responses, pre- and post-treatment, respectively, as detailed in the text. **p < 0.01.
FIG. 24: Correlation between the clinical and the electrophysiological changes. Correlation between changes in YBOCS scores and ERN amplitudes (Pre-minus post-treatment) are presented for the HF and sham groups. Analysis revealed a significant positive correlation between the two measurements only in the HF group (r % 0.63, p < 0.01).
FIG. 25: Consort Chart *see interim analysis for differences in sample size.
FIG. 26: Interim analysis for the clinical effect of the treatment. Mean + SEM changes in YBOCS scores from baseline along the study, for the LF, HF and sham groups. FIG. 27: Response to treatment by gender. The number of female and male responders within the HF stimulated group. *p<0.05
FIG. 28: Colored field maps for the H7 coil. The H7 coil consists of 16 windings arranged in two groups (8 in each group). The windings are flexible and designed conform to the human head. The maps indicate the electric field absolute magnitude in each pixel at 100% of the average leg motor threshold which was set to 100 V/m, for 14 coronal slices 1 cm apart. Red pixels indicate regions with field intensity above the threshold for neuronal activation.
FIG. 29: Consort diagram of the study design and allocations.
FIG. 30: Change in Y-BOCS scores (Mean +/- SE) from baseline throughout the study, for the high- frequency and Sham groups.
FIG. 31A-B: Percentage of full response (<30% decrease) (A) and individual distribution of responders and non responders (B) in Y-BOCS scores at the week 6 visit in both treatment groups.
FIG. 32: Percentage of patients reported as‘moderate’ to‘very much improved’ in CGI-I in both groups.
FIG. 33: Perspective illustration of a coil, which is an example of a central base coil in accordance with embodiments of the present invention.
Figure imgf000007_0001
In accordance with methods and systems described herein, the entire disclosures of each of U.S. Patent Numbers (USPN) 7,407,478; 8,608,634; 9,802,058; and 9,254,394 are incorporated herein by reference. In this regard, particular note is made with respect to disclosures pertaining to magnetic stimulators, which are used as transcranial magnetic stimulation (TMS) devices in, for example, USPN 7,407,478 and 9,802,058, and disclosures pertaining transcranial magnetic stimulation coils for location-specific stimulation of medial and lateral brain regions in USPN 9,802,058 and 9,254,394.
Figure 33 presents a perspective illustration of a coil 1010. Coil 1010 includes a base portion 12 having a base portion right side 16 and a base portion left side 18 on the two sides of central axis 14. Base portion right side 16 and base portion left side 18 are substantially horizontal and parallel to central axis 14. Base portion right side 16 includes multiple right side stimulating elements 20, which are spaced apart from one another by a distance D1 of approximately 0.3 cm. Base portion left side 18 includes multiple left side stimulating elements 22, which are spaced apart from one another by a distance D2 of approximately 0.3 cm. Right side stimulating elements 20 and left side stimulating elements 22 are configured such that when coil 1010 is placed on the head, the stimulating elements 20 and 22 lie along a top of a medial portion of the head. The distance D10 between base portion left side 18 and base portion right side 16 is between 4 and 8 cm. 10 is a central base coil
Coil 1010 further includes a return portion 32 including a return portion right side 36 and a return portion left side 38. Return portion right side 36 includes right side return elements 40 which are contacting return elements 50 since they are configured to contact a skull when coil 1010 is in place. Return portion left side 38 includes left side return elements 42 which are also contacting return elements 50. Connecting elements 44 connect right side stimulating elements 20 to right side return elements 40 and connect left side stimulating elements 22 to left side return elements 42. Connecting elements 44 and right and left side return elements 40 and 42 are curved such that right side stimu- lating elements 20, connecting elements 44 and right side return elements 40 form substantially a circular shape, and left side stimulating elements 22, connecting elements 44 and left side return elements 42 form substantially a circular shape. Each of the circular shapes are configured to lie on a top and side portion of a head. The distance D5 between base portion right side 16 and return portion right side 36 is approximately 6 cm. The distance D6 between base portion left side 18 and return portion left side 38 is approximately 6 cm. Coil 1010 is configured to be placed on medial frontal cortex regions such as medial prefrontal cortex or medial motor cortex, and is used to stimulate the medial cortex regions including motor cortex regions and, as described herein, is useful for treating OCD.
Accordingly, devices for use in treating OCD and methods for treating subjects afflicted with OCD are described herein. Evidence of the utility and efficacy of such devices and methods are presented in a study relating to a prospective, double blind, randomized, sham controlled, multi-center clinical trial in outpatients recruited in both academic and private research centers. The purpose of the study was to explore the safety and efficacy of Deep TMS for the treatment of Obsessive Compulsive Disorder. The study was conducted at 11 study sites around the globe.
The study consisted of three phases:
• Screening phase (approximately 2-3 weeks, with no treatment);
• 6 week treatment period (daily treatment with DTMS or sham); and
® 10 week follow-up visit.
Patients were screened based on the inclusion/exclusion criteria described in the study protocol after a written informed consent was obtained from the patient. At baseline visit subjects were randomly assigned to either active DTMS or Sham treatment (1 : 1 ratio) using an IWRS system. Subjects were stratified per center. During the treatment phase, TMS sessions were performed daily for 6 weeks (29 DTMS sessions). Treatment was administered according to a predefined treatment protocol (20 Hz, 100% stimulation intensity of the measured MT, 2 sec pulse trains, 20 sec inter-train intervals, 50 trains, 2000 pulses per session).
Hie primary psychiatric assessment conducted during the study to evaluate efficacy was the Yale-Brown Obsessive Compulsive Scale (YBOCS). Additionally, other psychiatric assessments were performed during tire study, including the Sheehan Disability Scale (SDS) and the Clinical Global impression (Severity and Improvement; CGI-S and CGI -I).
Safety was assessed at every treatment visit. Patients were asked to report any adverse event since their previous visit. Additional safety evaluations included the Scale for Suicide Ideations (SSI), mental status examination, physical and neurological examinations and vital signs. Safety assessments also included cognitive changes evaluations performed throughout the study, including the Mini-Mental Status.
Examination (MMSE), the Buschke Selective Reminding Test (BSRT) and the Autobiographical Memory' Interview' --- Short Form (AMI-SF).
A total number of 100 subjects were enrolled in the study. Eligible and consenting subjects were randomized to either the active treatment group (denoted as DTMS) or the sham control group (Sham). The Intent-to-treat (ITT) analysis set includes 99 randomized patients, as one subject withdrew consent (patient did not tolerate the stimulation used to measure the motor threshold). The subject withdrew' consent after randomization, but before receiving even one active/sham treatment. Thus, the subject is not included m the ITT analysis set. 48 subjects were randomized to receive active treatment (DTMS) and 51 to receive Sham treatment. Baseline demographic information and safety and tolerability' results are presented for the Intent-to-treat (ITT) analysis set. Efficacy results are presented for the modified ITT (mITT) analysis set, which included 94 subjects who met the study eligibility criteria. The subjects excluded from this analysis set were those subjects that did not meet the inclusion/exclusion criteria for the study and did not receive at least one treatment session.
There were no randomization errors and all subjects received the treatment to which they were originally allocated. The study groups were completely balanced at baseline.
The drop-out rate ( 10%) in this multicenter study w¾s extremely low with no differences m the treatment groups .
Hie baseline demographic data, general medical and psychiatric history, concomitant medications, baseline assessment scores and physical and neurological examination data were analyzed to assess if there were any basic differences between the treatment groups prior to commencement of the clinical study (Tables 9- 18). The baseline demographic information, including age, gender and the medical and psychiatric history' data did not show' any significant differences in the data between the treatment groups, except for age of onset of OCD. Although, the age at which professional help was first sought was not statistically different between the groups, therefore, this data does not seem to affect the study outcome. The baseline assessment scores were very similar between the treatment groups, with no significant differences. This was true of the physical and neurological examination data, as well . The above data demonstrated that there were no significant differences between the study treatment groups.
The primary' efficacy end-point was the change from baseline in YBOCS scores to the 6 week visit. The primary' efficacy analysis was conducted on all evaluable subject data, in the mITT analysis set. The change from baseline m the YBOCS score (Table 21) demonstrates that the YBOCS score decreased by 6.7 points in the DTMS group and by 3.6 points in the Sham group at the 6 week visit.
In both study group there was a statistically significant reduction in YBOCS scores (Tables 21-22 and Figures 3-4); the estimated slope in the DTMS group was -6.0 points across 6 weeks versus only -3.3 in the sham group and the difference between the slopes of 2.8 points across 6 weeks was found statistically significant, p=0.0127. Based on these results the Null Hypothesis of the study was rejected and the study is deemed successful.
Furthermore, the effect size of the study is 0.69 (Cohen's D). According to widely accepted guidelines, in which 0.2 is defined as a small effect, 0.5 as a medium effect, and 0.8 as a large effect, the DTMS multicenter study may be considered to have a greater than medium to large effect size.
Based on the primary efficacy analysis of the study, the DTMS has a positive treatment outcome and has demonstrated a beneficial effect in reducing OCD symptoms in moderate to severe OCD patients. The reduction in the YBOCS of 6.0 points is clinically meaningful and statistically significant compared to the sham and the effect size of 0.69 demonstrates a difference between the two groups, which is large enough and consistent enough to be clinically important. The positive treatment outcome was demonstrated immediately (as soon as 2 weeks) after treatment commence and was stable and even enhanced during treatment.
The primary efficacy endpoint of the study was substantiated by the success of the secondary endpoints including the change from baseline in the YBOCS score at 10 weeks. The change from baseline in the YBOCS score at the 10 week visit (Table 21) demonstrates that the YBOCS score decreased by 7.6 points in the DTMS group and by 4.7 points in the Sham group. At the 10-week visit, the adjusted YBOCS score decreased by 6.5 points (95% Cl) in the DTMS group versus 4.1 points (95% Cl) in the Sham group, these decreases were both statistically significant (Table 34). The difference between the treatment groups is also statistically significant (p-value: 0.0380) and clinically meaningful. Based on the 10 week YBOCS score results, the effect size of the study is 0.62 (Cohen's D). The DTMS multicenter study may he considered to have a greater than medium to large effect size. Thus, as aforementioned, the treatment effect is maintained for at least 4 weeks after completion of all treatment sessions, at 10 weeks.
Since there are no medical devices for the treatment of OCD, we have compared the DTMS treatment outcome to available FDA approved, SSRI medications for the treatment of OCD, including Luvox (Fluvoxamine), Prozac (Fluoxetine), Paxil (Paroxetine), and Zoloft (Sertraline) (see table below). The DTMS study results can be compared to the Luvox (F!uvoxamine) study (Study 3103) submitted in support of their FDA approved, NDA with a similar QCD patient population (mean baseline YBOCS score of 26), in which the 6 week adjusted YBOCS score decreased by 7.5 points (SE) in the drug group compared to 5.2 points (SE) in the Placebo group. This difference of 2.3 points (95% Cl, p value; 0.0024) was considered statistically and clinically significant. The 10 week Luvox study results reported a decrease in the adjusted YBOCS score of 8.2 points (SE in the drug group compared to 5.9 points (SE) in the Placebo group. This difference of 2.3 points (95% CL p value; 0.004) was also considered statistically significant. These results are consistent with the other FDA approved SSRI medications. The Prozac (Fluoxetine) studies (with baseline YBOCS score of 22-26) reported a decrease of 4 to 9 points in the YBOCS score in the drug group (depending on dosage 20-60mg), versus 1 point in the placebo group, a difference of 3 to 8 points, at 13 weeks. The Paxil (Paroxetine) study (Study 1) (with baseline YBOCS score of 23-26) reported a decrease of 4 to 7 points in die YBOCS score in the drug group (depending on dosage 20-60mg), versus 3 points in the placebo group, a difference of 1- 4 points, at 12 weeks. The Zoloft (Sertraline) study (with baseline YBOCS score of 23-25) reported a decrease of 4 points m the YBOCS score in the drug group, versus 2 points in the placebo group, a difference of 2 points at 8 weeks. In 2 additional Zoloft studies, a decrease of 6 and 7 points in the YBOCS score were reported in the drug group, versus 3 and 4 points in the placebo group, respectively, for a difference of 3 points at 12 weeks. It should be noted that the Prozac, Paxil and Zoloft studies included an QCD patient population with only moderate OCD, with a lower average baseline YBOCS score of 22-26.
Figure imgf000011_0001
In summary, the DTMS treatment outcome is similar to FDA approved, OCD medications both in the decrease in YBOCS score in the treatment group and with a similar difference in YBOCS score between the treatment and sham/placebo group. Furthermore, as will be discussed further in this summar , the DTMS positive treatment outcome in terms of supplemental assessment scores (CGI Improvement) also demonstrates similar positive results to those reported in the FDA approved SSRI NDAs. The DTMS treatment does not entail the complexity of the metabolism of these drugs or the complications of long-term usage, and the warnings and precautions regarding potential side effects are much less than those reported for drags. Furthermore, the DTMS treatment achieves the same reduction in OCD symptoms as expressed by the reduction in YBOCS and a significantly‘Improved” clinical state based on the CGI Improvement scale in half the time as medications, i.e., 6 weeks vs 12 weeks.
The prognostic factor analysis, including age, gender, treatment question, age of disease onset, duration of disease and CBT treatment (lifetime) at baseline were presented (Table 23). There were no statistically significant differences found between the study groups for any of the prognostic factors. It is important to note that the results of the treatment question did not affect the study results.
Poolability of US and outside the US sites was evaluated and concluded that the study sites may be pooled.
The positive effect of the treatment described herein based on the primary efficacy endpoint of change from baseline in YBOCS score was further corroborated by the success of additional secondary efficacy endpoints, including responder analysis, additional supporting OCD assessment scales (CGI Improvement and CGI Severity) and change from baseline in YBOCS scores at 10 weeks (4 weeks following completion of treatment - as described above), thus supporting the consistency and robustness of the clinical effect.
The Response rate (defined as a reduction from baseline of at least 30% in YBOCS score) at the 6 week visit m the DTMS group is 38.1% versus 11.1% in the Sham group (Table 33). The response rate was significantly higher in the DTMS group compared to the sham group (p=0.0033). The Partial Response rate (defined as a reduction from baseline of at least 20% in YBOCS score) at the 6 week visit in the DTMS group is 54.8% versus 26.7% in the Sham group (Table 33). This difference is also statistically significant p=0.0076.
The responder results are not only statistically significant but also clinically meaningful, as demonstrated by the effect size expressed in terms of Number Needed to Treat (NNT). Based on the study response rates, the effect size as obtained by the Number Needed to Treat (NNT = (1/difference in response rates) is 3.7, which means that for ever} 4 patients treated with the Deep TMS System, 1 subject will have a response due to the device. The number needed to treat (NNT) for OCD patients treated with SSRI monotherapy at standard (antidepressant) doses is approximately 5, meaning that if 5 patients are treated with an SSRI, one can be expected to respond who would not have responded to placebo. The NNT for a dose escalation from a medium dose to the higher doses is 13— 1528 Therefore, the results of this study demonstrate a much greater effect size than conventional SSRI treatments for OCD.
The Response rate at the 10 week visit was 45.2% in the DTMS group compared to 17.8% in the Sham group, with the difference in response rates between the DTMS group and the Sham group remaining statistically significant (p=0.0057) (Table 41). There was also a further increase in the response rate at the 10 week visit (45%) in the DTMS group compared to the 6 week visit (38%), demonstrating a further positive treatment effect maintained over time. The effect size as obtained by the Number Needed to Treat (NNT) was 3.64, which still means that for every 4 patients treated with the Deep TMS System, 1 subject will have a response due to the device. Consequently, the effect size remains larger than for SSRI treatment for OCD at 10 weeks. As aforementioned, the positive effect of the DTMS treatment described herein was supported by the secondary assessment scales measuring improvement and severity in subjects’ clinical status using the CGI Improvement (CGI-I) and CGI Severity (CGI-S) scales.
In the categorical analysis, 70% of the DTMS subjects reported some improvement (ranging from minimal improvement to very much improved) at 6 weeks as a result of the DTMS treatment, with 49% reporting an “Improved” (moderate to very much improved) clinical state (Table 24-25). This is compared to only 58% of the subjects in the Sham group reporting some improvement, with only 21% experiencing a moderate to very much“Improved” clinical state. There is a statistically significant difference (p=Q.Ql 12) between the percentage of DTMS subjects experiencing an“Improved” clinical state compared to the Sham group at 6 weeks. These results reported at 6 weeks are comparable to the CGI Improvement outcomes with FDA approved SSRI medications reported in their NDA summaries for the treatment of OCD at 12-13 weeks. The two Prozac (Fluoxetine) clinical studies reported 59%-71% of the subjects with some improvement in clinical status and 36%-47% of the subjects reported a moderate to very much“Improved” clinical state, depending on the dosage (20-60mg), at 13 weeks. The Paxil (Paroxetine) NDA reported 58%-78% of the subjects with some improvement in clinical status and 25%-44% of the subjects reported a moderate to very much“Improved” clinical state, depending on the dosage (20, 40 or 60mg), at 12 weeks. As aforementioned, the DTMS treatment achieves a significantly“Improved” clinical state based on the CGI Improvement scale, which is similar to the highest dosage of both SSRJs, in half the time as these medications, i.e., 6 weeks vs 12-13 weeks, with far less complications and side effects than drug usage.
The CGI Improvement results are maintained 4 weeks after treatment at the 10 week visit. That is, 72% of the DTMS subjects maintained some clinical improvement and 49% maintained a moderate to very much “Improved” clinical status. Although, those subjects reporting a moderate to very much“Improved” clinical state remained much higher in the DTMS group (49% of DTMS subjects versus only 27.5% in the Sham group), this was not statistically significant at 10 weeks (Table 24-2.5)
At week 6 more subjects had an“improved"’ CGI Severity (CGI-S) score in the DTMS group (61%) than in the Sham group (32.6%) and tins difference was statistically significant (p 0.032 ! ) (Table 28). The positive CGI- S results are maintained 4 weeks after completion of the DTMS treatment at the 10 week visit (CGI-S: 64% vs. 45%), although not statistically significant (Table 36). The CGI Improvement and CGI Severity results support and strengthen the significant clinical effect of the DTMS treatment.
The differences in the change from baseline in the Sheehan Disability Scale (SDS) scores in the DTMS group compared to the Sham group were not statistically significant at 6 or 10 weeks (Tables 31-32 and 37). The improvement in these parameters may be more latent and not yet apparent at 6 or 10 weeks. The remission rate (defined as YBOCS score < 10) at the week 6 visit was 4.8% in the DTMS group versus 4.4% in the sham group (Table 38) The remission rate was not significantly different between the DTMS and sham group (p=0.9437). It should be noted that the SDS assessment scale and remission rates are not commonly used as a study endpoint in evaluating SSRI medications in FDA approved NBAs and therefore, the clinical significance of these findings is limited.
The exploratory' efficacy end-points were the response and remission rates at 10 weeks and the change from baseline in HDRS-21 scores to 6 and 10 weeks.
The continued positive and significant effect of the response rate (defined as a reduction in YBOCS of at least 30% from baseline) at the week 10 visit (45.2% in the DTMS group versus 17.8% in the sham group, p:=0.QQ57) (Table 41) was discussed above. As was the continued medium to large effect size at 10 weeks (3.64). The partial response rate at the w'eek 10 visit in the DTMS group was 60% versus 42% in the sham group. The partial response rate was not significantly different in the DTMS group compared to the sham group (p=0.1059) (Table 41). The remission rate at the week 10 visit was 9.5% in the DTMS group versus 4.4% in the sham group (Table 41). The remission rate was not significantly different between the DTMS and sham group (p=0.3502). Although, this difference was still not statistically significant p=0.3502 (chi- squared test), there was an increase in the number of subjects in the DTMS group who reached remission at 10 weeks (9.5%) compared to the 6 w'eek visit (4.8%) and compared to the Sham group.
The differences within the treatment arms and between the treatment anus for HDRS-21 scores were not statistically significant (Tables 39-40). As the majority of tire study subjects did not suffer from co-morbid Major Depressive Disorder (MDD) (mean HDRS-21 score at baseline in both treatment groups was 10), we did not expect any significant changes or improvements in HDRS-21 score due to the treatment in non- MDD patients. Furthermore, we can infer that the improvement in OCD was not as a result of an improvement in depression.
Success of study blinding was assessed (Table 42). A logistic model was used to assess if the response to the treatment question is predictive to the treatment received. The p-value of the type III for the treatment question was 0.1043. The most frequent answer of subj ects in both groups was that they did not know which treatment they received. 43.75% of the subjects in the DTMS responded that they don’t know', versus 47.06% of the subjects in the Sham group. Overall, the majority of the study subjects, 56.25% of the DTMS subjects and 68.63% of the Sham subjects, were not aware of, or guessed wrongly the treatment they received during the study.
Safety and tolerability of the Deep TMS treatment were evaluated during the course of the study, including assessment of vital signs, physical and neurological examinations, SSI assessments, cognitive examinations (MMSE, BSRT and AM1-SF) and adverse event reporting.
No notable differences in vital signs, physical and neurological examination results were observed between the study groups at each of the time points (Tables 43-45). No statistically significant differences in SSI scores were found between the groups at 6 weeks and at 10 weeks (Table 46). These results demonstrate that the DTMS treatment does not affect the safety of the subjects treated with the system. No statistically significant differences in MMSE scores were found between the groups at 6 weeks and at 10 weeks (Table 47). No statistically significant differences were found between the groups at 6 weeks and at 10 weeks, in any of the components of the BSRT Score (Tables 48-51). No statistically significant differences were found between the groups at 6 weeks and at 10 weeks, in the AMI-SF Score (Table 52). The results of the cognitive tests demonstrate that the Deep TMS treatment does not have a negative cognitive effect on OCD subjects.
The adverse events are reported in the study according to system organ class and preferred term according to the medDRA adverse event classification, for each of the study group (Tables 54-56). 35 subjects (73%) reported adverse events in the DTMS group versus 35 (69%) subjects in the Sham group. The incidence of adverse event reporting w'as not statistically significant (chi-square p-vaiue: 0.6393).
The adverse events reported in the study are typical side effects reported previously with the Deep TMS system and with other marketed TMS devices. The most frequent AE was headache reported by 37.5% of the subjects who received the DTMS treatment and by 35.3% of the subjects who received the Sham treatment. Reporting of headaches was not statistically significantly different between the treatment groups.
Most other forms of pain and discomfort (administration/application site pain/discomfort, pain in jaw, facial pain, muscle pa /spasm/twitching, neck pain, etc.) were reported as either mild or moderate and mostly resolved after treatment with or without analgesic medications (e.g. Paracetamol, Ibuprofen). In most of the subjects the discomfort or pain disappeared once the subject became accustomed to the treatment.
Overall, there were no significant differences found between the treatment groups for any of the adverse events reported in the study. The adverse events reported in the study are commonly reported with commercially available TMS treatments. The incidence of these adverse events reported with the Deep TMS System for the treatment of OCD are similar to the incidence of these adverse events reported with the Deep TMS for MDD and other TMS systems, such as the NeuroStar TMS Therapy System.
These findings demonstrate the overall good safety of the Deep TMS System for treatment of Obsessive Compulsive Disorder (OCD).
There was one ( 1 ) SAE reported in the study (Table 53), which w'as assessed by the investigator and the sponsor as not related to the device treatment. After receiving 2 treatments, subject CH-08 reported having significant suicidal thoughts, which he indicated had preceded the beginning of the treatment sessions, but had neglected to mention prior to study commencement. The investigator and subject decidedthat hospital admission would be appropriate. Subject claimed his suicidal thoughts/urges were related to escalating problems with his family and not to the study treatments.
Die safety and efficacy results of the Multicenter DTMS clinical study presented above demonstrate the safety and effectiveness of the DTMS System for treatment of Obsessive Compulsive Disorder.
The robustness and integrity of the DTMS de vice treatment is demonstrated in the replication of the study primary and secondary efficacy endpoints (i.e., change from baseline in YBOCS score and Response rates and supplemental assessment scales (CGI-I), respectively), and in the safety profile of the DTMS treatment with the known and reported side effects of TMS treatments. Obsessive-compulsive disorder (OCD) is a highly debilitating condition, although SSRI medications can help control the obsessions and compulsions of OCD. The FDA approved SSRIs are Fluoxetine (Prozac), Fluvoxamine (Luvox), Sertraline (Zoloft) and Paroxetine (Paxil) These medications are considered to be equally effective, although some may work for some people and not for others. A notable percentage of patients (40-60%) have a partial or no response to medications. The onset of improvement in OCD symptoms may take weeks to months after starting a medication. Combining medications, such as antidepressants and antipsychotic medications may he effective in controlling OCD symptoms, although all psychiatric medications have side effects, such as stomach upset, sleep disturbance, sweating and reduced interest in sexual activity. Furthermore, adherence to anti-psychotic drugs is about 50% in the first year, and decreases to about 25% in the second year due to intolerable safety issues with low benefit over time. The above reported results of the multicenter DTMS study have demonstrated that the DTMS treatment can be as effective, or better than conventional SSRI medications in treating OCD. Furthermore, the adverse events reported in this study for DTMS treatment are known and well tolerated by OCD subjects. Additionally, the DTMS treatment enables patient compliance with the treatment during a 6 week treatment period. Thus, the safety profile of the DTMS treatment is better than that reported for SSRI medications.
In summary, the overwhelming clinical benefits enabled by the DTMS treatment, including high efficacy expressed in terms of a statistically significant reduction in YBOCS symptoms score, large effect size and low NNT, statistically significant response rates and improvement in CGI-I and CGI-S, outweigh the minimal risks involved with the administration of the treatment. Furthermore, the DTMS treatment provides clinically meaningful efficacy in a relatively short time of 6 weeks with a proven safety profile, high tolerability and extremely high treatment compliance by the OCD patient population compared to currently available medicinal treatments in the market.
Transcranial magnetic stimulation (TMS) is a noninvasive technique used to apply magnetic pulses to the brain. The device currently in use in research and clinical settings is a metallic coil shaped like a figure 8 (figure-8-coil). This device has been found to be capable of stimulating only superficial brain areas, primarily the cerebral cortex, at depths of 1-2 cm below the scalp. The pulses are administered by passing currents through the coil placed upon the patient’s scalp, inducing electrical activity in the underlying cortical tissue that can result in neuronal depolarization. When a train of pulses is delivered multiple times within one session, the stimulation method is referred to as“repetitive TMS” (rTMS). rTMS does not involve anesthesia administration and has tolerable side effects. Certain psychiatric medications can help control the obsessions and compulsions of OCD Serotonin plays a role in the pathophysiology of OCD and therefore, the main medications prescribed are serotonin reuptake inhibitors (SRIs). There are two types of FDA approved serotonin reuptake inhibitors (SRIs). The newer types are known as "selective" serotonin reuptake inhibitors (SSRIs) because their primary effect is on serotonin neurotransmitters. The FDA approved SSRIs are Fluoxetine (Prozac), Fluvoxamine (Luvox), Sertraline (Zoloft) and Paroxetine (Paxil). These medications are considered to be equally effective, although some may work for some people and not for others. The FDA approved SRI is Clomipramine (Anafranil). Clomipramine may be slightly more effective than the SSRIs, however, it is known to have a more complicated set of side-effects than the newer SSRIs. The onset of improvement in OCD symptoms may take weeks to months after starting a medication. Combining medications, such as antidepressants and antipsychotic medications may be effective in controlling OCD symptoms. Ail psychiatric medications have side effects, such as stomach upset, sleep disturbance, sweating and reduced interest in sexual activity. 40-60% of patients do not respond to medications for OCD.
Neurosurgery for OCD has described promising results (58-67% of patients in multiple studies have showed marked improvement). The main anatomical targets for ablation include the fiber tracts that connect the cortex to thalamic nuclei, the anterior limb of the internal capsule and the cingulate gyrus. However, there are also reports of both transient and persistent adverse effects of the neurosurgical procedures.
Invasive Implantable Deep brain stimulation (DBS) has several advantages over ablation. Surgeons using DBS can potentially achieve a clinical effect without producing an irreversible lesion. Both the increases and decreases of psychic complaints are observed with DBS in case of movement disorders. The striking improvement of OCD in case of Parkinson's disease among others led to applying the technique.
The exact operating mechanism of DBS is not known. There are two general hypotheses: (1 ) DBS causes a functional lesion by inhibiting the brain core which is stimulated. This inhibition can be caused by a depolarization blockage of the neurons, by synaptic depression (exhaustion) or by synaptic inhibition via “neuronal jamming,” inducing a meaningless activation pattern. (2) DBS activates the neuronal network connected to the brain core which is stimulated. Dien stimulation leads to a modulation of the pathological activity in the neuronal network. It is most likely that the therapeutic effects of DBS are caused by a combination of direct and indirect effects dependent on the specific cytoarchitecture of the stimulated brain area. Because the field intensity of the electrode decreases exponentially with distance, neurons are influenced in various ways. The neuronal cell body is probably inhibited in the center of the stimulation area, and the axonal terminals are stimulated on the edge of the stimulation area.
A systematic review of DBS identify several studies of OCD patients which were treated between 1999 and 2009. All patients were severely ill individuals, and availed themselves as their own controls by turning stimulation on and off (stimulation usually has a pulse width around 60 microseconds deli vered at 130 Hz). All studies were too small to support valid inferences about patient selection and choice of stimulation locations. In most studies electrodes were implanted into the anterior limb of the internal capsule (AL/IC); the site used in capsulotomy. The AL/IC contains the anterior thalamic peduncle, which connects the medial and anterior thalamic nuclei with the prefrontal cortex and the cingulate gyms. In those studies, high percentages of patients completing the study had improved or recovered. The inferior thalamic peduncle and the thalamic/capsular area were found favored for treatment of OCD. Imaging Studies in OCD
Positron emission tomography (PET) has demonstrated increased regional blood flow and metabolic activity within the OFC, anterior cingulate gyms, and caudate nucleus during symptom provocation in obsessive- compulsive disorder; and decreased activity in the DLPFC.
In one study, improvement in OCD patients treated with behavior modification or fluoxetine hydrochloride was accompanied by significant changes in glucose metabolic rates in the caudate nucleus, as measured with PET. Local cerebral metabolic rates for glucose m the head of the right caudate nucleus decreased significantly in comparison with pretreatment values in responders and in comparison with non-responders and normal controls, whose right caudate nucleus metabolism did not change from baseline.
In another study, behavior therapy responders had significant bilateral decreases in caudate glucose metabolic rates that were greater than those in poor responders. Furthermore, the pretreatment correlations of brain activity between the orbital gyri and both the head of the caudate nucleus and the right thalamus decreased significantly after effective treatment.
Executive functions such as planning are also impaired in OCD, and functional MR! during such tasks revealed decreased activity in the DLPFC and caudate nucleus. Voxel-based morphometry (VBM) studies on OCD have also provided some evidence for orbitofrontostriatal structural abnormalities. However, 2 of the 3 VBM studies report structural changes in parietal regions: the right supramarginal and angular gyri, and the left inferior parietal lobe. Fronto-striatal control of the limbic system, mediated through inputs to the amygdala, may also be reduced in OCD, and may be responsible for certain clinical manifestations, such as contamination fear. Imaging data (PET) showed that symptom provocation (dirty vs. clean pictures) in OCD patients (n=l l) was correlated with increased rCBF in left amygdala and bilateral extrastriatal cortex, while control subjects (n=10) showed increased activation of the basal forebrain extending into posterior orbitofrontal cortex, left dorsolateral prefrontal cortex, right caudate nucleus and bilateral extrastriatal cortex. Group by condition interactions were found in the left amygdala in the OCD group and in the left dorsolateral prefrontal cortex and right caudate in controls, whereas significant time by condition interactions were only observed in the right amygdala in the OCD group.
A recent fMRl study compared 21 OCD patient with 21 matched healthy controls during a Stroop Color Word Test. OCD patients revealed higher activation relative to controls in a predominantly fronto- cingulate network including the dorsal anterior cingulate cortex (ACC) and right dorsolateral prefrontal cortex (DLPFC). Specifically, results demonstrated enhanced dorsal ACC to left DLPFC input in patients with OCD during the higher demanding incongruent Stroop task condition (e.g., the word“green” shown in red). Within the patient group, the left DLPFC to dorsal ACC connectivity was lower as the severity' of obsessive and compulsive symptoms increased. The results are consistent with an overactive, but intact, error control system in OCD patients.
Deep Transcranial Magnetic Stimulation
Deep Transcranial Magnetic Stimulation (DTMS) is a relatively new form of TMS, winch allows direct stimulation of deeper neuronal pathways than standard TMS. This form of TMS makes use of novel H-coils w'hich are designed to allow deeper brain stimulation related to the control of motivation , reward and pleasure, specifically, fibers connecting the cingulate or prefrontal cortex with the nucleus accumbens and ventral tegmental area, without a significant increase of electric fields induced in superficial cortical regions, as tested on a phantom brain in order to optimize the cod design for maximizing the percentage of stimulation in depth relative to the cortical regions. The DTMS induces an effective field at a depth of approximately 3 cm below the skull, compared to less than 1.5 cm for the standard TMS figure-8 coil. The safety and efficacy of the DTMS device was evaluated in a multicenter, randomized, controlled study on subjects suffering from OCD.
The results of the multicenter, randomized, double blind trial demonstrating the safety and effectiveness of the DTMS treatment (compared to sham treatment) are presented in this clinical study report.
The following examples are presented in order to more fully illustrate some embodiments of the invention. They should, in no way be construed, however, as limiting the broad scope of the invention. One skilled in the art can readily devise many variations and modifications of the principles disclosed herein without departing from the scope of the invention.
EXAMPLE 1
General Device Description
The HAC-Coil Deep TMS treatment is provided with the HAC-Coil IMS System that is composed of the following four main components:
1. An Electromagnetic HAC-Coil
2. A TMS Neurostimulator
A Cooling System A Positioning Ann
5. A Personal Head Cap
The HAC-Coil Deep TMS System is illustrated in FIG. 1.
Figure imgf000020_0001
Tire HAC-Coil
The HAC-Coii is designed to stimulate neuronal pathways related to the control of motivation, reward and pleasure, specifically, the prefrontal cortex and fibers connecting the cingulate or prefrontal cortex with the nucleus accumhens and ventral tegmental area.
The HAC-Coil is made of insulated copper wires. The total length is about 500 cm, winded into 14 windings, connected in series. The windings are connected to a special power cable and a connector. This connector can be connected to the Magstim Rapid or Rapid2 stimulator. In addition, a temperature sensor is included with an appropriate cable.
The HAC Coil is designed to stimulate neuronal pathways m the medial prefrontal cortex or motor cortex, including the anterior cingulated cortex.
The effective part of the coil, in contact with the patient’s head has a shape of half a donut. The frame of the inner rim of the half donut is flexible in order to fit the variability in human skull shape. The electromagnetic coil is contained in a helmet, which is connected by an adaptor to a positioning device. The coil is connected to the neurostimulator cable and a connector. This connector can be connected to the neurostimulator. In addition, a temperature sensor is included with an appropriate cable.
Commercial TMS Neurostimulator
A commercial TMS neurostimulator, such as the Magstim Rapid, Rapid2 or Super Rapid2 is used to deliver electrical stimulation to the brain, enabling a controlled output, frequency, pulse duration and indication of coil temperature. The Magstim stimulators were cleared by FDA (K992911 and K051864) for peripheral nerve stimulation. The detailed technical specifications of the Magstim Stimulator are available on the Magstim Ltd. website.
The Positioning System
The positioning system includes a helmet that comprises the coils, an adjustable arm connected to the helmet and a device enabling rotation of the helmet around three orthogonal rotation axes. The positioning device enables accurate and comfortable displacement and positioning of the coil over the patient'shead.
Hie Cooling System The Cooling System is designed to maintain ambient temperature in the coils during repetitive operation. The Cooling System consists of an external unit and and an air hose streaming the cooled air into the helmet. The air flow cools tire coils during pulse trains and maintains them at ambient temperature.
The Cart
Hie TMS stimulator and the cooling system are placed in a mobile cart (ITD, Germany). The adjustable arm is connected to the cart.
Personal Head Cap
A personal cap is provided for each patient. The cap is made from a biocompatible material (Fabrifoam). A flexible ruler is attached along the cap midline, with the 0 mark positioned at the patient’s nasion. The cap is used for accurate positioning of the coil on the patient’s head, by moving the coil from the area above the motor cortex to the treatment location at the prefrontal cortex. In addition the cap guarantees hygienic treatment conditions.
Additional Components
The system used in the Multicenter OCD Study contained the active HAC-Coil and a sham coil both contained within the device helmet.
The system used in the clinical study also contained a card reader unit which enabled activation of the either the HAC-coil or the sham coil. The card reader activated tire real HAC-coil or the sham coil using a magnetic, pre programmed, randomization treatment card. The operator swiped the magnetic card by the card reader and according to the information programmed onto the randomization treatment card, the controller connected the correct coil to the stimulator, while the external indications were the same for both coils, thus maintaining study blindness.
Rationale for the HAC-Coil Deep TMS Treatment
Transcranial magnetic stimulation (TMS) is a non-invasive technique often used for treating Major Depressive Disorder by stimulating the brain. However, the standard FIG.-8 coils have been shown to have a major effect mostly confined to the superficial cortical regions under the windings of the coil. The intensity of the electric field decreases rapidly deeper in the brain. In order to stimulate deep brain regions, a very high intensity is needed. Such intensity cannot be reached by the magnetic stimulators available today, using standard circular or FIG.-8 coils. Moreover, the intensity needed to effectively stimulate deeper brain regions would over-stimulate cortical regions leading to undesirable side effects.
The Deep TMS System was developed and intended for deeper brain stimulation targeting the anterior cingulate for the treatment of Obsessive Compulsive Disorder (OCD).
Mathematical models in conjunction with tests performed in a phantom model and clinical studies demonstrated the ability of the system to stimulate, by means of the HAC-Coil, deeper brain regions. We hypothesized that the activation of deeper cortical regions and their interconnecting fibers may serve as a new approach in the treatment of neuropsychiatric disorders with a prominent advantage over the standard coil which is unable to affect regions as deeply as the HAC-Coil.
The Deep TMS device is intended to safely deliver high-frequency (20Hz) repetitive transcranial magnetic pulses (2 second trains) to induce electric field of sufficient magnitude, i.e., 100% of resting Motor Threshold (rMT) of the foot, for the treatment of Obsessive Compulsive Disorder (QCD), using a flexible coil conforming to the shape of the head.
Figure imgf000022_0001
Hie Deep TMS System is indicated for use in adult patients with Obsessive Compulsive Disorder (OCD). Patients already on OCD treatments (psychotropic medications and or psychotherapy) should be maintained at their current dosages during the Deep TMS treatment.
Figure imgf000022_0002
The DTMS device technology is based on applying deep brain TMS by means of repetitive pulse trains at a determined frequency A pre-selected treatment protocol is assumed to activate deep brain regions and their interconnecting fibers. This, in turn, may affect the mechanisms involved in the pathophysiology of OCD on one hand, as well as the rewarding circuits, motivation and pleasure on the other hand. The system employs and executes the rTMS method that is based on creating alternating magnetic fields of between 1 and 10 KHz in the brain. A Magstim Rapid or Rapid2 magnetic neurostimulator sends electrical pulses to the non-invasive stimulating coil placed adjacent to the patient's head. Hie stimulating coil, that is held and aligned by the Positioning System helmet, is placed near the intended site of stimulation, and the stimulator initiates brief magnetic pulses that induce electrical currents in the tissue thereby producing a localized axonal depolarization . Hie Cooling System maintains ambient temperature in the coils during repetitive operation.
The treatment protocol began with localization of the optimal spot on the scalp for stimulation of tire tibialis muscle and determination of the individual motor threshold. The coil was then be placed 4 cm anterior to the motor spot. Subjects in the treatment group received prefrontal rTMS (20 Hz at 100%, 2 s on 20 s off, 50 trains, over an 18 minute period, i.e., 2000 stimuli per session).
EXAMPLE 2 Investigation design
The Deep TMS study was designed as a prospective, double blind, randomized , sham -controlled multi-center study.
Clinical Investigation Plan Summary
The study was conducted at 11 study sites inside and outside the United States. Eligible subjects were outpatients, aged 22-68, with a DSM-IV diagnosis of OCD. Subject must have had at least moderate OCD, rating aYBQCS score of >20 to be enrolled in the study. Subjects were maintained on SSRI medications (with or without additional antidepressant or psychotropic augmentation for treatment of OCD), at a stable therapeutic dosage for at least 2 months prior to study entry and/or subjects were maintained on psychotherapeutic behavioral intervention therapy. Symptoms stability was required during the 2-3 weeks of screening. Instability was defined as a change of ±30% in the patient’s total YBOCS score between the screening assessment and baseline assessment.
Subjects were excluded from the study if they suffered from any other Axis I diagnosis as the primary diagnosis or if they were diagnosed with severe Personality Disorder (excluding Obsessive Compulsive Personality Disorder). Additional exclusion criteria included any significant neurological injury, disorder or insult; increased risk of seizure for any reason, including familial or personal history of epilepsy; prior treatment with rTMS (because they could not be blinded); history of significant hearing loss; history of substance abuse; pregnancy; presence of intracranial implants or any other metal object within or near the head excluding the mouth that cannot be safely removed. Additionally, subjects were excluded if they were assessed with a present risk of suicide or if they had a history of suicide attempt in tire last 3 years (because we did not want to assign them to sham).
The study consisted of three phases, including the Screening phase (approximately 2-3 weeks, with no treatment), followed by a 6 weeks of daily treatments with Deep TMS or sham treatments. Additionally, subjects wore followed up at 10 weeks (4 weeks after the last treatment).
At the Baseline visit subjects wore randomly assigned to either active Deep TMS or Sham treatment (1 : 1 ratio) using an Interactive Web-Based Randomization System (IWRS). Subjects were stratified by center. During the treatment phase, TMS sessions were performed daily in a 5-day sequence. Subjects were discontinued from the study at any point if they had elevated risk for suicide as assessed by the investigator; if they missed more than 3 treatments; or if the investigator concluded that for safety reasons (e.g. an adverse event) it was in the best interest of tire subject to stop treatment.
Prior to initiation of each treatment, OCD symptoms were provoked for each subject in an individual manner for up to 5 minutes. The symptom provocation had to induce a stress level between 4-7 on a visual analog scale (VAS) in order to proceed with DTMS treatment. Each DTMS treatment (for active and sham groups) was conducted as follow's. Before starting each treatment, the subject was instructed to insert earplugs to lessen any possible adverse effect on hearing. The patient’s motor threshold was measured at the beginning of each w'eek by delivering single stimulations over the leg area of the motor cortex. The anterior cingulate gyrus was chosen as the treatment location which was determined by locating the coil 4 cm anterior to the leg MT location using the ruler on the head cap. The treatment location was recorded in the operator case report forms. Subjects received treatment at a power output of 100% of the measured MT. The treatment group received DTMS at 20 Hz and 100% stimulation intensity of the measured MT. Each DTMS repetition included 2 second pulse trains and 20 second inter-train intervals. Subjects received 50 trains in each treatment session, for a total of 2000 pulses per session. Each session lasted about 30 minutes of which the DTMS session lasted approximately 20 minutes. The control group received sham (placebo) treatment with identical parameters. Subjects were told that facial and hand twitching may occur due to either sham or active treatment.
To evaluate the OCD symptoms efficacy, certified raters performed extensive psychiatric status examinations including the Yale-Brown Obsessive Compulsive Scale (YBOCS), the Clinical Global Impression (Severity and improvement) (CGI-S and CGI-I) and the Hamilton Depression Rating Scale (HDRS-21). Patients were also required to complete self-reporting outcome questionnaires, including the the Sheehan Disability Scale (SDS). Safety was assessed at every treatment visit. Patients were asked to report any adverse event since their previous visit. Additional safety evaluations included the Seale for Suicide Ideations (SSI), mini-mental status examination (MMSE), physical and neurological examinations and vital signs. Safety assessments also included cognitive changes evaluations performed throughout the study.
Figure imgf000024_0001
The aim of the study was to evaluate the safety and efficacy of the Deep TMS Treatment in subjects with Obsessive Compulsive Disorder (OCD).
Efficacy Endpoints
Primary Efficacy Objective
The primary objective of the study was to compare the change in Y BOCS scores from baseline to the 6 week (post-randomization) visit, between the two treatments groups.
Secondary Efficacy Objectives
i. Compare the change from baseline to the 6 week visit in the Sheehan Disability Scale (SDS) score and Clinical Global Impression - Severity (CGI-S) and Improvement (CGI-I) scores, between the treatment groups. ii. Response rate comparison at the 6 week visit, where response is defined as a reduction of at least 30% in YBOCS score from baseline, between the treatment groups;
hi. Partial Response rate comparison at the 6 week visit, where response is defined as a reduction of at least 20% in YBOCS score from baseline, between the treatment groups;
iv. Compare the change from baseline to the 10-week visit in the YBOCS score between the treatment groups. v. Compare the change from baseline to the 10 week visit in the Sheehan Disability Scale (SDS) score and Clinical Global Impression - Severity (CGf-S) and Improvement (CGI-I) scores, between the treatment groups.
vi. Remission rates comparison at tire 6-week visit, where remission is defined as YBOCS score < 10, between the treatment groups.
Exploratory Endpoints
• Compare the change from baseline to the 6 week and 10 week visit in the Hamilton Depression Rating Scale (HDRS-21) score, between the treatment groups.
® Remission rates comparison at the 6-week visit, where remission is defined as YBOCS score < 8, between the treatment groups.
® Comparison of Response rate, Partial Response rate and Remission rate at the 10 week visit, between the treatment groups.
Safety Endpoints
• To assess the safety of the DTMS treatment with the HAC-coil to treat OCD by maintained subject baseline, pre-treatment, physical and neurological status
® To evaluate possible cognitive changes using the Mini Mental State Exam (MMSE), Buschke Selective Reminding Test (BSRT) and Autobiographical Memory Interview - Short Form (AMI-S) cognitive tests.
• To evaluate the incidence, severity and frequency of all Adverse Events (AE), including seizures and suicidality (i.e., suicide attempts and completed suicides).
Figure imgf000025_0001
Inclusion / Exclusion criteria
Patients were screened for enrollment in the study according to the following eligibility criteria:
Inclusion criteria
Outpatients
* Men and women 22-68 years of age
Subjects was diagnosed as suffering from OCD according to the DSM-iV-TR.
Subjects with at least moderate OCD, rating a YBOCS score of >20.
* Subjects were maintained on SSRT medications (with or without additional antidepressant or psychotropic augmentation for treatment of OCD), at a stable therapeutic dosage for at least 2 months prior to study entry and for the duration of the trial and/or subjects were maintained on psychotherapeutic behavioral intervention therapy (subjects undergoing CBT treatment must be in the maintenance stage (i.e., not during the assessment or skills acquisition or training stages).
* Subjects with negative responses on the Transcraniai Magnetic Stimulation Safety Screening questionnaire (TASS).
* According to the treating physician the subject was compliant with taking medication, if applicable.
* Subject was capable and willing to provide informed consent. Subject was able to adhere to the treatment schedule.
Exclusion criteria
Subjects was diagnosed according to the SCID I as suffering from any other Axis I diagnosis as the primary diagnosis. Subjects was diagnosed according to the SCID II as suffering from severe Personality Disorder (excluding Obsessive Compulsive Personality Disorder) or hospitalized due to exacerbation related to borderline personality disorder. Present suicidal risk as assessed by the investigator using the Seale for Suicide Ideation (SSI), brief mental status exam and psychiatric interview or significant suicide risk based on HDRS-21 item 3 score of 3 or 4 or a history of attempted suicide in the past year.
* Subject had a history of epilepsy or seizure (EXCEPT those therapeutically induced by ECT) or history of such in first-degree relatives.
* Subject had an increased risk of seizure for any reason, including prior diagnosis of increased intracranial pressure, or history of significant head trauma with loss of consciousness forgreater than or equal to 5 minutes.
* Subject had a history of head injury necessitating cranial surgery or prolonged coma.
* Subject had a history of any metal in tire head including the eyes and ears (outside the mouth).
* Subject had known history of any metallic particles in the eye, implanted cardiac pacemaker or any intracardiac lines, implanted neurostimulators, intracranial implant (e.g., aneurysm clips, shunts, stimulators, cochlear implants, or electrodes) or implanted medical pumps.
Subject had a history of significant hearing loss. Subjects had a significant neurological disorder or insult including, but not limited to:
❖ Any condition likely to he associated with increased intracranial pressure
❖ Space occupying brain lesion
❖ History of cerebrovascular accident
❖ Transient ischemic attack within two years
❖ Cerebral aneurysm
❖ Dementia
❖ Parkinson s disease
❖ Huntington’s chorea
❖ Multiple sclerosis
❖ Mini Mental State Exam score of less than or equal to 24
® Subject had a history of substance abuse including alcoholism within the past 6 months (except nicotine and caffeine). Inadequate communication with the patient. Subject w'as participating in another clinical study or enrolled in another clinical study within 30 days prior to this study. Subjects who suffered from an unstable physical, systemic and metabolic disorder such as unstabilized blood pressure or acute, unstable cardiac disease. Subject was on high doses of antidepressant or psychotropic medications, which are known to lower the seizure threshold. Subject was currently on Clomipramine. Subject had previous treatment with TMS Women wlio were breast-feeding Women who were pregnant or with suspected pregnancy Women of childbearing potential and not using a medically accepted form of contraception when engaging in sexual intercourse
Study completion criteria
Subject was considered to have completed the study if he or she completed all required assessments at w¾ek 6 of the treatment trial period
Randomization and Blindin: Subjects were randomized into the study by center. After subjects met the eligibility criteria, they were equally allocated (with a 1 : i ratio) to one of the 2 treatment groups (Sham vs. Active TMS) stratified by center, based on a stratified randomization scheme using the SAS (version 9.1) random number generator. The study statistician prepared the randomization scheme. The block size was random and study personnel were blinded to the randomization block size.
A central Interactive Web-Based Randomization System (IWRS) was used during the study. The system was developed for the current study and was validated according to IEEE Standard for Software Development and Test Documentation. The subject randomization code was assigned upon entering the required data into the Interactive Web Response System (IWRS). Site users entered the IWRS by using their own user identification (ID) and password provided by tire CRO. Hie system recognized the user site automatically by the user unique identification. Users were then asked to enter the requested subject details (eligibility code, subject's initials, subject's ID, Date of Birth and Motor Threshold level). Based on this information, the IWRS assigned a unique subject randomization code, which determined the treatment assignment for the subject. The unique subject randomization code matched one of the pre-programmed treatment cards maintained at the clinical site. The operator was then asked to take the treatment card with the same randomization code from the box of pre programmed treatment cards and to complete the subject ID on the card label and place the treatment card inside the subject's Operator Binder
During the treatment session, the operator sw ped the patient’s treatment card by the card reader in the DTMS System. The card reader activated either active or sham treatment mode according to the treatment group to which the patient had been randomized. The study personnel did not have any knowledge of whether the active mode or sham mode was activated by the patient’s treatment card. Thus, all study personnel, including the operator, the independent rater and study subjects were blinded to the treatment administered. The study patients were asked whether they believe they had received active or sham stimulation after the first treatment session.
The validation of the pre-programmed treatment cards and the randomization number allocated to each card was performed by the CRO.
EXAMPLE 3
DTMS Treatment and Treatment Allocation
Administration of treatment
The system operator determined the motor threshold (MT) and administered the treatments. Each operator underwent extensive training including hands-on training regarding the procedures related to the administration of the treatment prior to treating study subjects.
After the coil was in the treatment position, but prior to initiation of each treatment, OCD symptoms were provoked for each subject in an individual manner to activate the relevant brain circuitry. The provocations consisted of text or props (e.g., photo, video, objects, etc.) tailored towards the subject’s specific obsessions and compulsions, which provoked or induced typical OCD symptoms in the subject. The subject was exposed to the provocation during a period of up to 5 minutes. Tire provocation had to induce a stress level between 4-7 on a visual analog scale (VAS) in order to proceed with DTMS treatment.
At the beginning of the first treatment session (and then weekly), the patient’s MT was measured by placing the H-coil above the leg area of the motor cortex. Tire MT was measured by gradually increasing the stimulation intensity by using the single pulse mode and applying one pulse ever}' 5 sec, i.e. 0.2 Hertz. The Threshold is defined as the lowest intensity of stimulation producing motor evoked potentials of at least 50pV in 5 of 10 trials. Both study groups received stimulations (real or sham) over tire anterior cingulate cortex. Tire coil was repositioned 4 cm anterior to the location of the MT for stimulation of the leg using the ruler on the patient’s cap, and a DTMS session was performed at 100% of the motorthreshold.
Each treatment session last 20 to 30 minutes (of which, the DTMS session takes approximately 20 minutes). During the treatment trial period the treatment group received the following dose of DTMS: 20 Hz, at 100% MT, 2 sec pulse train, 20 second inter-train interval, 50 trains, i.e. a total of 2000 pulses per session. Tire control group received inactive/ sham treatment with identical parameters. Patients were told that facial and hand twitching may occur due to either sham or active treatment.
During the treatment session, the operator observed the subject closely for any sign of imminent seizure activity or muscle twitching. Presence of a physician or nurse trained in seizure management, emergency equipment (oxygen, suction, blood pressure monitor, and CPR equipment) and antiepileptic medications were readily available in the immediate vicinity of the treatment room. Before starting each treatment, subjects were instructed to insert earplugs to mitigate any possible adverse effect on hearing. Subjects were informed of the risk of perm anent hearing loss if an earplug should become detached or fall out and were asked to immediately report any loosening or detachment of an earplug during treatment. In case of coil overheating, a warning was displayed and the operator removed the coil from the patient. The coil cooled down within several minutes and then treatment was resumed. Any events of coil overheating, removal and treatment resumption were recorded. Patients were asked not to meet or discuss the study treatment with other subjects before, during and after assessment or treatments in order to maintain study blinding.
Figure imgf000029_0001
Clinical efficacy measures
Yale-Brown Obsessive Compulsive Scale (YBOCS)
Subjects were interviewed at the screening visits (Visit S I & S2), baseline visit (Visit Bl), at the weekly assessment visits during the treatment period and at the 10 week follow-up visit. The scale is used extensively in research and clinical practice to both determine severity of OCD and to monitor improvement during treatment (Goodman, 1989). This scale, which measures obsessions separately from compulsions, specifically measures the severity of symptoms of obsessive --compulsive disorder without being biased towards the type of obsessions or compulsions present (Rosario-Campos, 2006).
Hamilton Depression Rating Scale (HDRS).
Subjects were interviewed at the baseline visit, at the weekly assessment visits during the treatment period and at the 10 week follow-up visit. Tire HDRS was published more than 40 years ago for the purpose of “quantifying the results of an interview’" (Hamilton, 1960). Although not designed for use in treatment studies, Hamilton anticipated that the scale would have value in evaluating the impact of treatment. During the past 40 years the HDRS has been the most widely used outcome measure in antidepressant efficacy trials (Prien et al., 1991).
Clinical Global Impression-Severity score (CGI-S)
Subjects were assessed for the severity of illnesses at the baseline visit, at the weekly assessment visits during the treatment period and at the 10 week follow-up visit . The CGI-S is a commonly used tool for assessing the overall severity of patient's illness. It uses 7 levels, ranging from normal to severely ill.
Clinical Global Impression Improvement scale (CGI-I)
Subjects were assessed for the improvement of illnesses at the baseline visit, at the weekly assessment visits during the treatment period and at the 10 week follow-up visit. Tire Global Improvement item requires the clinician to rate how much the patient's illness has improved or worsened relative to a baseline state.
Sheehan Disability Scale (SDS)
Subjects were assessed using tire Sheehan Disability Scale at the baseline visit, at the weekly assessment visits during the treatment period and at the 10 week follow-up visit. The Sheehan Disability Scale (SDS) was developed to assess functional impairment in three inter-related domains; work/school, social and family life. It is used by researchers and practicing clinicians (Rush, 2000). The SDS is a brief self-report tool. Hie subject rates the extent to which work/school, social life and home life or family responsibilities are impaired by his or her symptoms on a 10 point visual analog scale. This 10 point visual analog scale uses spatiovisua!, numeric and verbal descriptive anchors simultaneously to assess disability. This range of anchor options addresses the various ways that individuals approach rating a continuum. The change-over- time score is of interest to clinicians in monitoring response to treatment.
Safety Measures
Transcranial Magnetic Stimulation Adult Safety Screen (TASS)
Subjects were asked to complete the TMS safety questionnaire in order to assess any potential risk factors for using the Transcranial Magnetic Stimulation Adult Safety Screen (TASS) questionnaire, at the screening visit (Visit SI ) to ensure patient safety. The safety questionnaire is a safety tool meant to screen potential subjects for risks of adverse events during TMS. A positive screen is any 'yes' answer, indicates further investigation by the clinician (but not indicating exclusion from TMS).
Scale for Suicide Ideation (SSI)
Subjects were assessed using the Scale for Suicide Ideation (SSI) at the baseline visit, at the weekly assessment visits during the treatment period and at the 10 week follow-up visit. The Scale for Suicide Ideation (SSI; Beck et al., 1979 (33)) is a 21-item interviewer -administered rating scale that measures the current intensity of patients' specific atitude, behaviors, and plans to commit suicide on the day of the interview.
Mini-Mental State Exam (MMSE)
Subjects were assessed for cognitive changes using the MMSE, at the baseline visit, at the 6 week assessment visit and at the 10 week follow-up visit. The mini-mental state examination (MMSE) is a brief 30-point questionnaire test that is used to assess cognition. It is commonly used in medicine to screen for dementia. Any score over 24 (out of 30) is effectively normal.
Buschke Selective Reminding Test (BSRT)
The BSRT test was performed at the baseline visit, at 6 week assessment visit and at the 10 week follow- up visit or at the time of discontinuation. The test is used to provide a traditional measure of verbal learning and memory using l2-word lists, 6 trials, and 30 minutes delayed free recall, followed by reacquisition of the list (6 trials) (3 alternate forms). Since subjects are only reminded of words not recalled on the previous trial, this task provides more information on encoding and retention than other list learning tasks. This task is especially sensitive to anterograde amnestic effects of ECT and other interventions (41). The primary' dependent measure will be total words correctly reported at the second administration (reacquisition).
Autobiographical Memory Interview - Short Form (AMI-SF)
The AMI-S test was performed at the baseline visit, at the 6 week assessment visit and at the 10 week follow up visit or at the time of discontinuation. The test assesses memory for events in the past and the development of retrograde amnesia. This common side effect of ECT is not expected to be manifest with DTMS and a single task will be used for this purpose. The short form involves inquiries about the details of 6 events. Five questions are asked about each event, yielding 30 items. Following each phase patients are only asked about items for which they produced a response at baseline. Inconsistency in responses relative to baseline (including "don't know" responses) is the measure of retrograde amnesia.
Concomitant medications / Treatments SSRJ medications and any antidepressant or psychotropic augmentation medication, were allowed during the study. Insomnia/anxiety medications (up to 3 mg Lorivan, or equivalent) were allowed during the study. Acetaminophen or other medications for treatment of local pain, dental pain or headaches were allowed, as were medications for general medical conditions.
High doses of antidepressant or psychotropic medications, known to lower the seizure threshold, were not allowed throughout the study.
Duration of follow up
Patients were treated for a period of 6 weeks, with a 10 week follow-up visit (4 weeks after the last treatment).
Adverse Events
Adverse Events Reporting
All adverse events were reported during the course of the study on the appropriate Case Report Forms. Serious adverse events were reported to the Sponsor as well as the hospital Institutional Review Board (IRB). In the case of a serious, unusual or unexpected adverse event, the sponsor was contacted immediately by phone or e- mail. In the event that the sponsor was not reached, an emergency number was provided for contact within 24 hours.
Anticipated Adverse Events
The following adverse events were defined as anticipated during the course of the study.
• Headaches
Facial numbness and pain
Discomfort related to TMS treatment
• Reduce Hearing threshold.
• Accidental seizure
Brief dizziness
EXAMPLE 4
Study Design and Objectives
The study was planned as a randomized two-arm sham controlled, 10 week, double blind, multi-center trial in outpatients recruited in both academic and private research centers. The aim of the study was to evaluate the efficacy and safety of Deep TMS de vice (with the HAC-coil) in subjects with OCD.
Figure imgf000032_0001
Null Hypothesis:
The mean change in YBOCS score from baseline to 6 weeks in the DTMS group is equal to the mean change in YBOCS score from baseline to 6 weeks in the sham group.
Alternative Hypothesis
Hie mean change in YBOCS score from baseline to 6 weeks in the DTMS group is not equal to the mean change in YBOCS score from baseline to 6 weeks in the sham group.
Figure imgf000033_0001
A total of 78 subjects (39 per group), provided a power of approximately 90% at a 5% significance level, to detect a difference between the groups of 3 points in the mean YBOCS score assuming a standard deviation of 4.0 points and a larger placebo effect than the one observed in the pilot study.
The minimum sample size was increased to 49 subjects per arm to account for potential drop-outs, for a total of 98 subjects.
Randomization and Stratification
Subjects who met the eligibility criteria were equally allocated (with a 1 : 1 ratio) to one of the two treatment groups, DTMS or sham, based on a randomization scheme with blocks stratified by site. The randomization scheme was prepared by the study statistician using the SAS (version 9.3.) random number generator.
Study Analysis Sets
Each of tire following analysis sets were defined for the statistical analyses:
Intent-to-treat (ITT) Analysis Set Definition:
The intent-to-treat (ITT) analysis set includes all patients randomized to the study who have received at least one active/ sham treatment. According to the ITT principle, all subjects are analyzed in the treatment group as assigned by randomization.
Modified Intent-to-treat (mITT) Analysis Set Definition:
Hie modified intent-to-treat (mITT) analysis set includes all patients randomized to the study who have received at least one active/ sham treatment and met the study Eligibility Criteria. In the mITT set ail subjects are analyzed in the treatment group as treated. That is, the mITT set was analyzed in the pre-defined treatment assignment as provided in the original randomization list, as none of the study subjects received different treatment by mistake. Hie list of subjects who did not meet the study eligibility criteria w as documented in the“Clinical Study Guidelines for Data Review and Statistical Analysis” plan prepared prior to randomization code unblinding. Per-Protocol Analysis set (PP) Definition:
The per-protocol (PP) analysis set consists of all subjects included in the mITT analysis set who in addition have no major protocol deviation. Potential protocol deviations were defined and classified as minor or major before opening the randomization codes. The list of protocol deviation was documented in the “Clinical Study Guidelines for Data Review and Statistical Analysis” plan prepared prior to randomization code unblinding.
Statistical Analysi s of Analysis Sets
Safety assessments are performed on the ITT analysis set. The mITT data analysis set serves as the principal data analysis set for the primary and exploratory efficacy statistical inference. The primary efficacy assessment is also performed on per protocol (PP) analysis sets and on the ITT analysis set, by assigning treatment groups as randomized instead of as treated, as sensitivity analyses.
Significance Levels and Handling of Type I Error
Type I Error
The overall significance level for this study is 5% using two-tailed tests.
Approach for Controlling the Alpha Level
The hierarchy approach is adopted for the primary' and secondary' endpoints to control the ty'pe I error due to multiple endpoint testing. Thus, the primary' endpoint is first analyzed and only if p<0.05, will the secondary' endpoints be analyzed. The order of the secondary' endpoints appears herein above (ordered i, ii, and iii). This approach is maintaining the overall study type 1 error by continuing to analyze the next end-point in the hierarchy' only if the previous endpoint analysis is found significant.
The exploratory' end-points are not part of the hierarchy as descriptive statistics are mainly planned. Nevertheless, nominal p-values are presented for all statistical comparisons.
Statistical Analyses
General
Statistical analyses were performed using SAS V9.4 (SAS institute, Cary NC, USA).
The data collected at the last recorded visit prior to study treatment initiation are considered as baseline data. Generally, these are the data recorded at the baseline visit.
The standard summary statistics for continuous variables are: N, mean, standard deviation, median, minimum and maximum . Tire standard summary' statistics for categorical variables are: count and proportion .
All statistical tests are two-sided. Where confidence limits are appropriate, the confidence level is set to 95%. For comparison of means (continuous variables), the two-sample t-test or the Wilcoxon rank sum test are used as appropriate. For comparison of proportions (categorical variables), the Chi-square test or Fisher’s exact test are used as appropriate.
Baseline and Demographic Data
Demographic and baseline condition related characteristics are tabulated and compared between the study groups. Continuous variables will be summarized by a mean, standard deviation, minimum, median and maximum, and categorical variables by a count and percentage.
This data includes:
• Demographic data
• Medical history
• Psychiatric history
» Previous and Current Psychotropic Medication
» Physical and Neurological Examination
• Vital signs
Primary Efficacy Endpoint
The principal statistical analysis is performed using a Repeated Measures Analysis (RMA) of covariance model (SAS® MIXED procedure). The analysis, which aims to compare the YBOCS slopes of change from baseline between study aims, includes the following fixed effects: time from randomization, treatment group, time by treatment interaction, use of SSRIs and any other antidepressant or psychotropic medications, and/or psychotherapeutic behavioral interventions at enrollment, center and baseline YBOCS score. Baseline YBOCS scores are entered as continuous variables so that the potential for co-linearity problems will be minimized. The individual subject intercept and the time effects are also included m the model as random effects (random intercept and slope model).
The principal statistical analysis is a comparison between the treatments groups' slopes, derived from the time by treatment interaction term from the RMA model described above.
The covariance structures that were used initially are unstructured, compound symmetry, Toepelitz or autoregressive (whichever model has the lower AIC statistic), although other structures may be evaluated as well in the model selection process.
The adjusted mean changes from baseline in YBOCS scores to 6 weeks post randomization are estimated from the model (LS Means) for each group as well as the difference between the adjusted means and presented together with 95% confidence intervals.
Other efficacy measures of continuous variables are analyzed with similar models with baseline values as another covariate when relevant.
Binary efficacy and other categorical measures are compared between the study groups at the week 6 and week 10 with a chi-squared test or Fisher’s exact test.
Prognostic factors and sensitivity analysis for change in YBQCS from baseline to 6 weeks visit:
Adjustment for other covariates such as demographics or other baseline patient characteristics or the forced choice questionnaire regarding treatment received may be performed by adding these variables to the above described models.
Significant or important variables are entered as covariates in the primary efficacy endpoint model to evaluate their effect on the change from baseline YBOCS score.
Test of Linearity
To test if the relation between YBOCS and time-in-trial is linear, a repeated measures ANCOVA model (SAS® MIXED procedure) is fitted, similar to the one proposed forthe principal analysis, first with time as a continuous variable (representing a linear relation), and second, with time as a by-week categorical variable (representing a general relation).
The -2 log likelihood ratio test for nested models is used to test the contribution of the "general relation" beyond the "linear relation". The criterion to reject linearity is used if the p-value of the chi-square statistic with the appropriate degrees of freedom is less than 0.05.
If the hypothesis of linearity is rejected, the change in YBOCS from baseline to 6 week visit is assessed using models similar to those described herein with the time by-week as a categorical variable.
Missing data handling
The study outcome is not evaluated for patients who drop out prior to randomization.
Patients who drop out after one or more treatments and have data available for the analysis (i.e., at least one post baseline assessment) of continuous variables are analyzed with a repeated measures analysis of variance model using PROC mixed in S AS which can handle missing data at random.
At the 6 week, post-baseiine visit, we did not expect a high proportion of drop outs, thus, any missing data at 6 weeks post baseline can be considered missing at random. Therefore, for this evaluation no imputation of missing data is considered beyond the model estimates. Nevertheless, should the missing at random assumption prove to be incorrect at other time points, a sensitivity analysis using other methods, such as Last Observed value Carried Forward (LQCF), for data imputation is performed.
In the case of binary variables (such as response and remission rates at week 6 and week 10) the LOCF me thod is used, a“worst case scenario” analysis may also be considered.
Baseline characteristics of patients who drop out are evaluated by study group to evaluate the potential for differential drop out. Pooling
Subgroup analysis of the primary efficacy endpoint by center will be used to evaluate the poolability of the results. The significance of center-to-center variability in treatment effect will be evaluated by including an interaction temi of treatment by center in the regression model. In the case that poolability isquestionabie, the reasons for differential treatment effect, such as patient and clinical characteristics, will be investigated and reported.
Interim Analysis
No interim analysis was planned or performed for this study.
Safety Analysis
Adverse Events
Safety assessment, performed for the ITT analysis set, includes the following:
AE’s incidence tables, in general and by severity, by relationship to treatment and by baseline parameters are presented.
Adverse event rates compared between the study groups with a chi-squared test. Serious adverse events are listed and discussed individually.
Vital Signs
The incidence of potentially clinically significant vital signs measurements (BP, pulse and weight) are presented at each relevant visit by treatment group. Descriptive statistics as well as changes from baseline will also be presented by study group at each scheduled visit.
Other Safety Measurements
Descriptive statistics are presented per study group for the following measures at each relevant visit as well as the mean change from baseline, as additional supportive data:
* Scale for Suicide Ideation (SSI)
* Cognitive evaluation using the Mini -Mental State Exam (MMSE), Buschke Selective
* Reminding Test (BSRT) and Autobiographical Memory Interview --- Short Form (AMI-S) cognitive tests.
EXAMPLE 5
Introduction
A total number of 100 OCD subjects were enrolled in the study. Eligible and consenting subjects were randomized to either the active treatment group (denoted as DTMS) or the sham control group (Sham). The resul ts presented in this section demonstrate the safety and efficacy of the DTMS device for the treatment of Obsessive Compulsive Disorder (OCD).
Subject Accountability
Table 1 presents the overall subject accountability for each data analysis set. Table 2 presents subject accountability by study treatment group for each data analysis set. Of 131 subjects screened, a total number of 100 subjects were randomized to the study. Eligible and consenting subjects were randomized to either the active treatment group or the sham control group (Sham).
The Intent-to-treat (ITT) analysis set includes 99 randomized patients, as one subject withdrew consent while the motor threshold was being measured. The patient did not tolerate the stimulation used to measure the motor threshold. The subject withdrew consent after randomization, but before receiving even one active/sham treatment. Thus, the subject is not included in the ITT analysis set. 48 subjects were randomized to receive active treatment (DTMS) and 51 to receive Sham treatment.
The rrilTT analysis set includes 94 subjects who met the study eligibility criteria. The per-protocol (PP) analysis set includes 93 subjects who completed the study without any major protocol violations. The number of patients and reasons for their exclusion are shown in Table 3 and 4. Table 5 presents the distribution of patients among the 11 participating study centers, 7 centers enrolled fewer than 10 subjects and the remainder between 10 and 21. There were 9 US centers, 1 Israeli, and 1 Canadian site. Table 6 presents the distribution of patients in US centers and QUS centers.
Table 1: Patient Accountability
Figure imgf000039_0001
* Screen failures and reasons for failure are presented herein
**Percent calculated based on number of randomized subjects.
Table 2: Accountability Of Enrolled Subjects According to Treatment Group
Figure imgf000039_0002
Table 3: Accountability Reasons For Exclusion According to Treatment Group
Figure imgf000039_0003
*Average Stimulation Intensity <90% was calculated for DIMS Treatments no. 1 through treatment no 29.
A list of the excluded subjects from each analysis set with the reason for exclusion from the analysis set is provided in Table 4.
Table 4: Accountability Reasons For Exclusion for each Subject
Analysis set. Subject !D Reas n for Exclusion
Subjects Excluded f'rom ITT Analysis
Subjects Excluded from nUTT Analys
Figure imgf000040_0001
Figure imgf000040_0002
Figure imgf000040_0003
One subject was excluded from the ITT analysis set who withdrew consent while the motor threshold was being measured. The patient did not tolerate the stimulation used to measure the motor threshold. The subject withdrew consent after randomization, but before receiving even one active/ sham treatment. Thus, the subject is not included in the ITT analysis set.
Five (5) subjects were excluded from the mlTT Analysis Set who did not meet one of the study eligibility criteria, as noted in the table above. Although, these patients did receive treatments, they were excluded as they did not meet the study eligibility criteria and should not have been included in the study.
One (1) patient with a major protocol deviation was excluded from the Per Protocol Analysis Set. The major protocol deviation reported was a patient who did not receive treatment at the stimulation intensity (treatment dose) designated in the study protocol. The study protocol required that treatment be administered at a stimulation intensity that is 100% of the patient s measured Motor Threshold. This stimulation intensity is considered an adequate dose of DIMS treatment so that the treatment will be effective in treating QCD. Hence, treatment according to the study protocol was defined as an average stimulation intensity of at least > 90% of the patient’s measured Motor Threshold in treatment sessions 1 through 29. There was 1 subject who did not receive an adequate treatment dose and was considered a major protocol violation.
Table 5: Dist ibution Of Subjects Within Study Centers (In Order Of Size) (ITT)
Figure imgf000041_0001
Table 6: Distribution Of Subjects Within Study Centers (US and OUS) (ITT)
Figure imgf000042_0002
Drop-Out and Time to Withdrawal
Table 7 shows the number and percentage of subjects withdrawn or dropped out up to 6 weeks and 10 weeks. Table 8 summarizes the reasons for drop-out / withdrawal. FIG. 2. portrays the drop out pattern via Kaplan- Meier curves of time to drop-out in each group for the 6 week end-point. From Table 6 we see that only 10% of the subjects dropped out before the 6 week end-point in both of the study groups, thus demonstrating an extremely low drop-out rate in this study. Furthermore, FIG. 2 demonstrates that the“survival” pattern, i.e. the time to drop-out, in the two groups is very' similar. Additionally, the log-rank test, which compares the survival curves of the two groups is not significant, P value: 0.6109.
Table 7: Number Of Subjects Withdrawn or Dropped Out Up To 6 Week And 10 Week (ITT)
Figure imgf000042_0001
Subject completed up to visit number - 10 Week Visit 40 83.33% 44 86.27% i Table 8: Reasons For Drop-Out Or Withdrawal (ITT)
Figure imgf000043_0001
Demographics and Baseline Characteristics
The demographic and baseline characteristics are provided in this section for the ITT analysis set. The OCD patient population recruited in this study are typical of the US OCD patient population enrolled in OCD clinical trials, as demonstrated in the demographic and baseline characteristics tables reported in this section.
Demographics
Demographic data are presented in Table 9. The age range of the subjects in both groups was 23/22 to 68/66, approximately 41% were female and 58% were male. The large majority of both groups were of ethnic origin “Not Hispanic or Latino” and“Write” race. No statistically significant differences were found between the study groups with respect to age, gender, race, ethnicity, marital status or education.
TaSn!e 9: Patients Demographic Data (ITT)
Figure imgf000044_0001
(*) t-test
(&) Chi-square test (#) Fisher's exact test
(**) Subject lias selected more than one category
Baseline Assessment Scale Values
Table 10 shows the distribution of baseline values of all assessment scale data represented in the efficacy analyses, including the Yale-Brown OCD Scale (YBOCS), the Sheehan Disability Scale (SDS), the Clinical Global Impression - Severity scale (CG1-S), the Clinical Global Impression - Improvement scale (CGI-I) and the Hamilton Depression Rating Scale (HDRS-21) scores. We find that at baseline YBOCS mean values in both groups were similar, with 27.6 points in the DTMS treatment group and 26.9 in the Sham group The baseline SDS scores were 19 in both treatment groups. The baseline CGI-S and CGI-I scores were both 5 in both of the treatment groups. The baseline HDRS-21 means were approximately 10 in both treatment groups. No statistically significant differences were found between the study groups with respect to the baseline efficacy assessment scale data and more importantly for the primary', secondary' and exploratory' efficacy end point variables. Table 10: Baseline Assessment Scale Data (ITT)
Figure imgf000045_0001
(*) t-test
Medical history
Table 11 presents the patient’s medical history by body system. No statistically significant differences were found between the study groups with respect to percent of abnormalities. The full listing of abnormalities by body system per group is detailed herein.
Table 11: Medical History by Body System (ITT)
Figure imgf000046_0001
(#) Fisher's exact test
Psychiatric History
Table 12 shows the patients’ psychiatric history according to treatment group. The mean age of OCD onset was 14.4 years in the DIMS group and 11.7 years in the Sham group. The age at which professional help was first sought was not different between the groups. 93.8% of the subjects in the DTMS group and 98% of the subjects in the Sham group indicated that their OCD symptoms affected their function at school or work. Almost all study subjects in both treatment groups (100% and 96%) had used medication m past treatments and over 50% of subjects in both treatment groups has past treatment of Cognitive Behavioral Therapy (CBT). A similar percentage of subjects had a family history of OCD (50% in the DTMS group and 58.8% in the Sham group) and no prior hospitalizations (77.1 % in the DTMS group vs. 88.2% in the Sham group). The vast majority of the subjects did not have a history of suicide attempts (97.9% in the DTMS group and 90.2% in the Sham group). There were no statistically significant differences found between the study groups for any of the psychiatric history parameters, except for age of onset of OCD. Although, the age at which professional help was first sought was not statistically different between the groups. Therefore, this data does not seem to affect the study outcome.
Table 12: Psychiatric History (ITT)
Figure imgf000047_0001
P t-test
(&) Chi-squared test (#} Fisher's exact test
Previous medications
Tables 13 presents the number (and percentage) of subjects treated with SSRJ, antidepressant and other psychiatric medications at baseline by study group and Table 14 presents the number (and percentage) of subjects treated with other concomitant medications at baseline by study group.
Table 13: SSRI, Antidepressant and Other Psychiatric Medications Taken at Baseline (ITT)
Figure imgf000047_0002
Figure imgf000048_0001
Table 14: Concomitant Medications Taken at Baseline (ITT)
!DT S {N=· 8) Shaw (N=5 )
Figure imgf000049_0001
Figure imgf000049_0002
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000051_0002
Physical Examination
Table 15 presents the results of the physical examination performed at screening by body system for each study group. There were no statistically significant differences found between the study groups with respect to percent of abnormalities.
Table 15: Physical Examination by Body System (ITT)
Figure imgf000052_0001
(#) Fisher's exact test N.E.: Not Estimable
Neurological Examination
Table 16 presents the results of the neurological examination performed at screening by test for each study group. There were no statistically significant differences found between the study groups with respect to percent of neurological examination abnormalities.
Table 16: Neurological examination at screening visit (ITT)
Figure imgf000053_0001
(#) Fisher's exact test N.E.: Not Estimable
Vital signs
Table 17 presents the subjects’ baseline height and weight in each study group. There were no statistically significant differences found between the study groups with respect to height as screening and weight at baseline. The average height in both groups was approximately 172-173 meters and the BMI was approximately 26. Table 18 shows the temperature, pulse rate, and blood pressure at screening visits and at baseline in both study groups, we see that the groups have similar values for all vital signs.
Table 17: Screening Height, Baseline Weight and jBMI ITT)
Figure imgf000053_0002
(*) t-test Table 18: Vita! Signs Up To Baseline Visit (ITT)
Figure imgf000054_0001
(*) t-test
The QCD patient population recruited in this study are typical of the US QCD patient population enrolled in OCD clinical trials, as demonstrated in the demographic and baseline characteristics tables reported in this section
Disposition of Subjects
Table 19 presents the number of subjects who attended each visit per study group.
Table 19: Subject Disposition (ITT)
Figure imgf000054_0002
Treatments Received
Table 20 shows the number of treatments received at each treatment visit (from treatment 1 to treatment 29} for all subjects in each study group. Note that the protocol allowed subjects to miss up to 3 treatments out of the 29 treatment sessions.
Table 20: Number of Subjects at each Treatment Visit (ITT)
Figure imgf000055_0001
As can be seen from the above table, there is high compliance with the treatment schedule by the study subjects with more than 80% of the subjects receiving almost all treatments. The protocol allowed subjects to miss up to 3 treatments out of the 29 daily treatment sessions. There was a slightly lower number of subjects in the DTMS treatment group who received all the study treatments compared to the Sham treatment group. Nonetheless, the results presented in the following study analyses demonstrate a strong treatment effect and positive results outcome with the DTMS treatment. DTMS treatment compliance in the OCD patient population is higher than treatment compliance to medicinal products in the same OCD patient population.
Randomization Distribution
As explained previously in this report, central randomization was performed using an Interactive Web Based System (IWRS). The site personnel entered the center and the system automatically allocated the next randomization number for that site. There were no randomization errors and all subjects received the treatment to which they were originally allocated. The study groups were completely balanced at baseline.
EXAMPLE 6
Primary Efficacy Analysis
Main Study Hypothesis (Change in YBOCS from Baseline at 6 Weeks)
The primary efficacy end-point as dictated in the study protocol was the change from baseline in YBOCS scores to the 6 week visit. The primary efficacy analysis is conducted on all evaluable subject data, in the mITT analysis set. Table 21 show's the unadjusted total YBOCS score and change in score from baseline. FIGs. 3 and 4 are graphical representations of the table and present the mean (±SE) of the YBOCS scores and changes from baseline, respectively. We see from these representations that in both study groups there was a reduction over time in YBOCS scores.
Table 21: Distribution of YBOCS Score and Change from Baseline to 6 and 10 Week Visits (mITT)
Figure imgf000057_0001
The change front baseline in the Y BOCS score extracted from Table 19 demonstrates that the YBOCS score decreased by 6 7 points in the DTMS group and by 3.6 points in the Sham group at the 6 week visit.
The change from baseline in YBOCS as shown in FIG. 2 and FIG. 3 is not linear over time. This is confirmed by the -2 log likelihood ratio test for nested models (p-value: 0.0198). As defined in the protocol, the unstructured covariance structure had the lower AIC statistic, and is chosen for the primary endpoint analysis. Tire change m YBOC demonstrates an initial phase of improvement, followed by a brief plateau and then another period of improvement. This is similar to the typical profile of improvement following OCD medication treatment.
Table 22 presents the adjusted means extracted from the model at the 6-week visit. The YBOCS score decreased by 6.0 points (95% Cl) in the DTMS group and by 3.3 points (95% Cl) in the Sham control group, these decreases were both statistically significant. The difference between the slopes of 2.8 points across 6 weeks between the treatment arms is also statistically significant (p-value: 0.0127). Table 22: Adjusted Means of the Change from Baseline to 6 Weeks in YBOCS (mITT)
Figure imgf000058_0001
The YBOCS primary efficacy analysis at the 6 visit was also conducted on all evaluable subject data, in the PP cohort and the ITT cohort and are presented herein.
The Null Hypothesis of the study that the mean change in YBOCS score from baseline to 6 weeks in the DTMS group is equal to the mean change in YBOCS score from baseline to 6 weeks in the sham group has been rejected and therefore, the study is deemed successful.
Furthermore, based on the YBOCS score results at 6 weeks, an effect size can be calculated using methods described in ‘Effect sizes for growth-modeling analysis for controlled clinical trial in the same metric as for classical analysis”, Psychol Methods. 2009 March; 14(1): 43-53), where ES = difference between slopes / Pooled SD of baseline YBOCS score. The effect size of the study is 0.69. According to the widely accepted guidelines of Cohen·5, in which 0.2 is defined as a small effect, 0.5 as a medium effect, and 0.8 as a large effect, the DTMS multicenter study may be considered to have a greater than medium to large effect size.
Based on the primary efficacy analysis of the study, the DTMS has a positive treatment outcome and has demonstrated a beneficial effect in reducing OCD symptoms in moderate to severe OCD patients. The reduction the YBOCS of 6.0 points is clinically meaningful and statistically significant compared to the sham and the effect size of 0.69 demonstrates a difference between the two groups, which is large enough and consistent enough to be clinically important. The positive treatment outcome was demonstrated immediately (as soon as 2 weeks) after treatment commence and was stable and even enhanced during treatment. Hie DTMS treatment effect was also confirmed at week 10 (4 weeks after treatment completion) .
Tire primary efficacy endpoint of the study was substantiated by the success of the secondary endpoints including the change from baseline in the YBOCS score at 10 weeks. The change from baseline in the unadjusted YBOCS score at the 10 week visit extracted from Table 21 demonstrates that the YBOCS score decreased by 7.6 points in the DTMS group and by 4.7 points in the Sham group. Table 34 presents the adjusted means extracted from the model at the 10-week visit. The YBOCS score decreased by 6.5 points (95% Cl) in the DTMS group versus 4.1 points (95% Cl) in the Sham group, these decreases were both statistically significant. The difference between the treatment groups is also statistically significant (p-value: 0.0380). Based on the 10 week YBOCS score results, the effect size of the study is 0.62. The DTMS multicenter study may be considered to have a greater than medium to large effect size. Thus, as aforementioned, the treatment effect is maintained for at least 4 weeks after completion of all treatment sessions, at 10 weeks.
The positive effect was corroborated by responder analysis, thus supporting the robustness of the clinical effect. The Response rate (defined as a reduction from baseline of at least 30% in the YBOCS score) at the 6 week visit m the DTMS group is 38.1% versus 11.1% in the Sham group (Table 33). Tins difference is statistically significant p=0.0033 (chi-squared test). The Partial Response rate (defined as a reduction from baseline of at least 20% in the YBOCS score) at the 6 week visit in the DTMS group is 54.8% versus 26.7% in the Shain group (Table 33). Tins difference is also statistically significant p=0.0076 (chi-squared test).
Based on the study response rates, the effect size as obtained by the Number Needed to Treat (NNT = (1/difference in response rates) is 3.7, which means that for every 4 patients treated with the Deep TMS System, I subject will have a response due to the device. The number needed to treat (NNT) for OCD patients treated with SSRI monotherapy at standard (antidepressant) doses is approximately 5, meaning that if 5 patients are treated with an SSRI, one can be expected to respond who would not have responded to placebo. The NNT for a dose escalation from a medium dose to the higher doses is 13—15.
Therefore, the results of this study demonstrate a much greater effect size than conventional SSRI treatments for OCD.
The positive effect of the DTMS treatment was further supported by the secondary assessment scales measuring clinical improvement and severity in subjects’ clinical status using the CGI Improvement (CGI-I) and CGI Severity (CGI-S) scales. The CGI Improvement (CGI-I) categorical analyses results demonstrate that 49% of the subjects in the DTMS group reported a moderate to very much“Improved” clinical state at 6 weeks compared to only 21% of the subjects in the Sham group (Tables 24-25). This difference was statistically significant (p=0.0112). These results obtained at 6 weeks are comparable to the CGI Improvement outcomes reported in NDA summaries for FDA approved SSRI medications, reported at 12-13 weeks. At week 6 more subjects had an“improved” CGI Severity (CGI-S) score in the DTMS group (61%) than in the Sham group (32.6%) and this difference was statistically significant (p 0.022 1 ). The positive CGI-1 and CGI-S results are maintained 4 weeks after completion of the DTMS treatment at the 10 week visit (CGI-I: 49% vs. 27.5% and CGI-S: 64% vs. 45%), although not statistically significant (Table 24-25). The CGI Improvement and CGI Severity results support and strengthen the significant clinical effect of the DTMS treatment.
The DTMS benefit is also reported by the excellent safety profile for the DTMS device, with similar known side effects of conventional TMS treatments and no reported differences in adverse events between the DTMS and Sham treatments.
In summary, the DTMS treatment described herein has been demonstrated as effective for the treatment of OCD as reported by the primary efficacy analysis and as supported by the secondary efficacy analyses and is a safe treatment as demonstrated by the known side effects and lack of adverse events. Prognostic Factors
Table 23 presents the results of the prognostic factor analysis including age, gender, treatment questi on, age of onset, duration of disease and CBT treatment (lifetime) Tire Type III p-value is the statistical significance of the factor in the model. The adjusted slope per group and the difference between the slopes are presented in the table together with level of significance and 95% CL According to Table 23, none of the variables were found to be related to the change from baseline in YBOCS score.
Table 23: Prognostic Factors Adjusted Slopes of YBOCS Change from Baseline to 6 Week Visit (mlTT)
Figure imgf000060_0001
Pooling
Ήie poolability between the centers was assessed by adding the site by visit by treatment interaction to the main model . The type III p-value of this factor for all sites (US and OUS) is 0.3961 , therefore no differential treatment effect is observed. In addition, this analysis was repeated for the US sites only to confirm the poolability of only the US centers. The type III p-value of this factor for the US sites only is 0.6878, therefore no differential treatment effect is observed. Consequently, we can conclude that all the study sites may be pooled.
Secondary Efficacy Endpoints
CGI Improvement (CGI-I), CGI Severity (CGI-S) & Sheehan Disability Scale (SDS) Scores at 6 weeks CGI Improvement (CGI-I) at 6 Weeks
Table 24 presents the CGI-I score distribution with the percent of subjects m each treatment group according to the outcome classification on the CGI Improvement Scale.
Figure imgf000061_0001
Improvement Scale
Figure imgf000061_0002
Outcome Classification DTMS sham
( ~4?) ίN=·Ί7>
Figure imgf000061_0003
The CGI-I scores were categorized into the following two categories:
® Improved: Moderately improved to Very much improved
® Minimally improved, No change or Worsened: Very much worse to Minimally improved (The score of“Does not apply” was filtered from this analysis).
Table 25 presents the distribution of the CGI-I scores per visit and treatment arm along with the p-value of the Fisher’s exact test per visit. Table 25: Comparison of CGI-I Outcome Categories (mITT)
Figure imgf000062_0001
The categorical analysis of the CGI Improvement results at 6 weeks demonstrate that only 17% of the DTMS subjects experienced“No Change” compared to 32 5% in the Sham group. More importantly, 70% of the DTMS subjects reported some improvement (ranging from minimal improvement to very much improved) at 6 weeks as a result of the DTMS treatment, with 49% reporting an“Improved” (moderate to very much improved) clinical state. This is compared to only 58% of the subjects in the Sham group reporting some improvement, with only 21% experiencing a moderate to very much“Improved” clinical state. There is a statistically significant difference (p-0.0112) between the percentage of DTMS subjects experiencing an“Improved” clinical state compared to the Sham group at 6 weeks.
The CGI Improvement results are maintained 4 weeks after treatment at the 10 week visit. That is, 72% of the DTMS subjects maintained some clinical improvement. Although, those subjects reporting a moderate to very much‘Improved” clinical state remained much higher in the DTMS group (49% of DTMS subjects versus only 27 5% in the Sham group), this was not statistically significant at 10 weeks.
These results obtained at 6 weeks are comparable to the CGI Improvement outcomes with FDA approved SSRI medications reported in their NDA summaries for the treatment of QCD at 12-13 weeks. The two Prozac (Fluoxetine) clinical studies reported 59%-71% of the subjects with some improvement in clinical status and 36%-47% of the subjects reported a moderate to very much“Improved” clinical state, depending on the dosage (20-60rng), at 13 weeks. The Paxil (Paroxetine) NDA reported 58%-78% of the subjects with some improvement in clinical status and 25%-44% of the subjects reported a moderate to very much“Improved” clinical state, depending on the dosage (20, 40 or 60mg), at 12 weeks. . Consequently, the DTMS treatment achieves a significantly“Improved” clinical state based on the CGI Improvement scale, which is similar to the highest dosage of both SSRIs, in half the time as these medications, i.e., 6 weeks vs 12-13 weeks, with far less complications and side effects than drug usage . In addition, the CGI Improvement score is also presented as a continuous variable. Table 26 presents descriptive statistics of the unadjusted CGI-I score at each visit and the change from baseline to week 6 and
10. FIG. 5 presents the mean (±SE) of the CGI-I scores and changes from baseline, respectively.
In general, we see a reduction in CGI-I score over time in both groups.
Table 26: Distribution of CGI-I Score and Change from Baseline to 6 and 10 Weeks Visit (mlTT)
Figure imgf000063_0001
Table 27 presents the adjusted means extracted from the model at the 6-week visit. The CGI-I score at the 6 weeks visit was 3.8 points (95% Cl) in the DTMS group and by 4.2 points (95% Cl) in the Sham group. The difference between the treatment arms is not statistically significant (p-value: 0.0985)
Table 27: Adjusted Means at the 6 Weeks Visit in CGI-I (mlTT)
Figure imgf000063_0002
Table 35 provided below presents the adjusted means extracted from the model at the 10-week visit. The CGI- I score at the 10 weeks visit was 3.6 points (95% Cl) in the DTMS arm and 3.9 points (95% Cl) in the control arm. The difference between the treatment arms is not statistically significant (p-value: 0.3339). CGI Severity (CGI-S) Score at 6 Weeks
Table 28 presents the CGI-S score distribution with the percent of subjects in each treatment group according to the outcome classification on the CGI Seventy Scale.
The change from baseline in CGI-S scores were categorized into the following categories:
• Improved
® No change
® Worsened
Table 35 presents the distribution of the changes in CGI-S scores per visit and treatment ann along with the p~ value of the Fisher’s exact test per visit.
Table 28: Comparison of Change from Baseline in CGI-S, Outcome Categories (mlTT)
Figure imgf000064_0001
The categorical analysis of the CGI Severity results demonstrate that approximately double the percentage of subjects in the DTMS group experienced an“Improved” clinical status based on their CGI-S scores compared to the Sham group at 6 weeks, i.e., 61% versus 32.6%, respectively. Only 36.6% of the subjects in the DTMS group reported No Change at 6 weeks compared to 62.8% in the Sham group. Only one subject (2.4%) had a “Worsened” effect of the DTMS treatment, compared to 2 subjects (4.7%) in the Sham group. The differences between the DTMS group and the Sham group at 6 weeks, including significantly more subjects with an “Improved” CGI-S score in the DTMS arm than in the Sham arm, were statistically significant (p-value: 0.0221).
The CGI Severity results are maintained 4 weeks after completion of the DTMS treatment at the 10 week visit. That is, 64% of the DTMS subjects maintained an“Improvement” in their CGI-S scores compared to 61% at 6 weeks. Although, those subjects reporting an“Improved” clinical status remained much higher in the DTMS group (64% of DTMS subjects versus only 45% in the Sham group), this was not statistically significant at 10 weeks.
In addition, the CGI-S is also presented as a continuous variable. Table 29 presents descriptive statistics of the CGI-S score at each visit and the change from baseline to week 6 and 10. FIGs 6 and 7 present the mean (±SE) of the CGI-S scores and changes from baseline, respectively. In general, we see a reduction in CGI-S score over time in both groups.
Table 29: Distribution of CGI-S Score and Change from Baseline to 6 & 10 Week Visits (mlTT)
Figure imgf000065_0001
Table 30 presents the adjusted means of the change from baseline extracted from the model at the 6-week visit. The CGI-S decreased by 0.71 points (95% Cl) in the DTMS group and by 0.40 points (95% Cl) in the Sham group. Although, there is a trend towards better improvement in CGI-S scores in the DTMS group compared to the Sham group, the difference between the treatment groups is not statistically significant (p-va!ue: 0.1183).
Table 30: Adjusted Means of the Change from Baseline to 6 Weeks in CGI-S (mlTT)
Figure imgf000065_0002
Table 36 provided below presents the adjusted means of the change from baseline extracted from the model at the 10-week visit. The CGI-S decreased by 0.94 points (95% Cl) in the DTMS group and by 0.66 points (95% Cl) in the Sham group, these decreases were both statistically significant. The difference between the treatment groups is not statistically significant (p-value: 0.2343).
Sheehan Disability Scale (SDS) at 6 Weeks
The Sheehan disability scale score at each visit, along with the change from baseline is summarized in Table 31 FIG. 8 and 9 present the mean (±SE) of the SDS scores and change from baseline respectively.
Table 31: Distribution of SDS Score and Change from Baseline to 6 and 10 Week Visits (mITT)
Figure imgf000066_0001
Table 32 presents the adjusted means of the change from baseline extracted from the model at the 6-week visit. SDS decreased by 3.8 points (95% Cl) in the DTMS group and by 3.0 points (95% Cl) in the Sham group, at 6 week visit these decreases were both statistically significant. Although, there is a trend towards better improvement in SDS scores in the DTMS group compared to the Sham group, the difference between the treatment groups is not statistically significant (p-value: 0.4786).
Table 32: Adjusted Means of the Change from Baseline to 6 Weeks in SDS (mITT)
Figure imgf000066_0002
Table 37 provided below presents the adjusted means of the change from basehne extracted from the model at the 10-week visit. The SDS decreased by 2.6 points (95% Cl) in the DIMS group and by 3.3 points (95% Cl) in the Sham group. The difference between the treatment groups w¾s not found statistically significant (p-value: 0.5519). The improvement in these parameters may be more latent and not yet apparent at 6 or 10 weeks. It should be noted that the Sheehan Disability Scale is not commonly used as a study endpoint in evaluating SSRI medications in FDA approved NDAs and therefore, the clinical significance of this finding is limited.
The CGI-I, CGI-S and SDS secondary efficacy analyses at the 6 week visit were also conducted on all evaluable subject data, in the PP cohort and the ITT cohort.
The primary endpoint of the DTMS Study (change in YBOCS score) was further supported by the first secondary endpoint in which we found a statistically significant difference between the DTMS treatment and the Sham treatment with regards to CGI Improvement and CGI Severity. The hierarchy approach was followed in performing the statistical analyses of the secondary efficacy endpoints. As the first secondary endpoint (CGI-I and CGI-S scores at 6 weeks) reached statistical significance (albeit without the SDS score at 6 weeks), the subsequent secondary' endpoint, i.e., Response Rate was analyzed. The next secondary endpoint based on Response Rates of subjects to the DIMS treatment demonstrated a further positive treatment outcome and further supported the primary' efficacy endpoint of the study with statistically significant results as presented in the next section.
Response Rates at 6 weeks
The Response rate and Partial Response rate at the 6 week visit, are presented in Table 33. Response is defined as a reduction from baseline of at least 30% in the YBOCS score. Partial Response is defined as a reduction from baseline of at least 20% in the YBOC score. Remission rate is defined as a YBOCS score less than (<) 10.
In case of missing YBOCS score at the 6 weeks visit, the Last Observed Value (LOV) method was used.
Table 33: Response Rate and Partial Response i the 6 Week Visit (mITT)
Figure imgf000067_0001
The Response rate at the 6 week visit in the DTMS group is 38.1% versus 11.1% in the Sham group. This difference is statistically significant p=0.0033 (chi-squared test). The Partial Response rate at the 6 week visit in the DTMS group is 54.8% versus 26.7% in the Sham group. This difference is also statistically significant p 0.0076 (chi-squared test).
Based on the study response rates, the effect size as obtained by the Number Needed to Treat (NNT = (1/difference in response rates) is 3 7, which means that for every 4 patients treated with the Deep TMS System, 1 subject will have a response due to the device. The number needed to treat (NNT) for OCD patients treated with SSR1 monotherapy at standard (antidepressant) doses is approximately 5, meaning that if 5 patients are treated with an SSR1, one can be expected to respond who would not have responded to placebo. The NNT for a dose escalation from a medium dose to the higher doses is 13-1528. Therefore, the results of tins study demonstrate a much greater effect size than conventional SSRJ treatments for OCD.
The Response rate (as presented in Table 41 and below) at the 10 week visit was 45.2% in the DTMS group compared to 17 8% in the Sham group. The difference in response rates between the DTMS group and the Sham group remained statistically significant p=0.0057 (chi-squared test) at the 10 week visit. There was also a further increase in the response rate at the 10 week visit (45%) in the DTMS group compared to the 6 week visit (38%), demonstrating a further positive treatment effect over time.
The secondary efficacy analyses for Response rates were also conducted on all evaluable subject data, in the PP cohort and the ITT cohort and are presented herein.
Continuing with the hierarchal approach to analyzing the study secondary endpoints, as the second and third secondary endpoints (Response Rate and Partial Response Rate at 6 weeks) reached statistical significance, the subsequent secondary endpoint, i.e., Change from Baseline in YBOCS score at 10 weeks, was analyzed. The next secondary endpoint based on YBOCS score at 10 weeks demonstrated a further positive treatment outcome and further supported the primary efficacy endpoint of the study with statistically significant results as presented in the next section.
Change from Baseline in YBOCS at 10 Weeks
The change from baseline in the unadjusted YBOCS score at the 10 week visit (secondary efficacy endpoint) extracted from Table 21 demonstrates that the YBOCS score decreased by 7.6 points in the DTMS group and by 4.7 points in the Sham group.
Table 34 presents tire adjusted means extracted from the model at the 10-week visit. The YBOCS score decreased by 6.5 points (95% Cl) in the DTMS group versus 4.1 points (95% Cl) in the Sham group, these decreases were both statistically significant. The difference between the treatment groups is also statistically significant (p-value: 0.0380). Thus, the treatment effect is maintained for at least 4 weeks after completion of all treatment sessions, at 10 weeks.
Table 34: Adjusted Means of the Change from Baseline to 10 Weeks in YBOCS (mITT)
Figure imgf000069_0001
Based on the 10 week YBOCS score results, the effect size of the study is 0.62. The DTMS multicenter study- may be considered to have a greater than medium to large effect size.
The reduction in the YBOCS of 6.5 points is clinically meaningful and statistical significant compared to the sham and the effect size of 0.62 demonstrates a difference between the two groups, which is large enough and consistent enough to be clinically important. As aforementioned, the positive treatment outcome was demonstrated immediately (as soon as 2 weeks) after treatment commencement and was stable and even enhanced during treatment at 6 weeks and subsequently, confirmed 4 weeks after treatment completion at the 10 week visit.
Here too, according to the hierarchal approach to analyzing the study secondary endpoints, as the fourth secondary endpoints (Change from Baseline in YBOCS score at 10 weeks) reached statistical significance, the subsequent secondary' endpoint, i.e., Change from Baseline in CGI-I, CGI-S and SDS score at 10 weeks, was analyzed. The next two secondary' endpoints are presented in the next sections, although statistical significant was not found for the following endpoints.
CGI-1, CG1-S and SDS Change from Baseline at 10 Weeks
CGI-I Change from Baseline at 10 Weeks
The CGI Improvement results are maintained 4 weeks after treatment at the 10 week visit (Tables 24). That is, 72% of the DTMS subjects maintained some clinical improvement. Although, those subjects reporting a moderate to very much“Improved"’ clinical state remained much higher in the DTMS group (49% of DTMS subjects versus only 27.5% in the Sham group), this was not statistically significant at 10 weeks (Table 25).
Table 35 below presents the adjusted means extracted from the model at the 10-week visit. The CGI-I score at the 10 week visit was 3.6 points (95% Cl) in the DTMS arm and 3.9 points (95% Cl) in the control arm. Tire difference between the treatment arms is not statistically significant (p-value: 0.3339).
Table 35: Adjusted Means at the 10 Weeks Visit in CGI-I (mITT)
Figure imgf000070_0001
CGI-S Change from Baseline at 10 Weeks
The CGI Seventy results are maintained 4 weeks after completion of the DTMS treatment at the 10 week visit (Table 28). That is, 64% of the DTMS subjects maintained an“Improvement” in their CGI-S scores compared to 61 % at 6 weeks. And although, those subjects reporting an“Improved” clinical status remained much higher in the DTMS group (64% of DTMS subjects versus only 45% in the Sham group), this was not statistically significant at 10 w'eeks.
Table 36 presents the adjusted means extracted from the model at the 10-week visit. The CGI-S decreased by 0.94 points (95% Cl) in the DTMS group and by 0.66 points (95% Cl) in the Sham group, these decreases were both statistically significant. The difference between the treatment groups is not statistically significant (p-value: 0.2343) Table 36: Adjusted Means of the Change from Baseline to 10 Weeks in CGI-S (mITT)
Figure imgf000071_0002
SDS Change from Baseline at 10 Weeks
Table 37 presents the adjusted means extracted from the model at the 10-week visit. The SDS decreased by 2.6 points (95% Cl) in the DTMS group and by 3.3 points (95% Cl) in the Sham group. The difference between the treatment groups was not found statistically significant (p~value: 0.5530).
Table 37: Adjusted Means of the Change from Baseline to 10 Weeks in SDS (mITT)
Figure imgf000071_0003
The secondary efficacy analyses for the 10 week CG1-I, CGI-S and SDS scores were also conducted on all evaluable subject data, in the PP cohort and the ITT cohort.
Remission Rate at 6 Weeks
The Remission Rate at the 6 week visit, are presented in Table 38. Remission rate was defined as a YBOCS score of less than (<) 10.
In case of missing YBOCS score at the 6 weeks visit, the Last Observed Value (LOV) method was used.
Table 38: Remission Rates at the 6 Week Visit (mTTT)
Figure imgf000071_0001
The Remission rate at the 6 week visit in both groups was minimal, with 4.8% in the DTMS group and 4.4% in the Sham group. This difference was not statistically significant p=0.9437 (chi-squared test). It should be noted that remission rates are not commonly used as a study endpoint in evaluating SSRI medications FDA approved NDAs and therefore, the clinical significance of this finding is limited.
The secondary efficacy analyses for Remission rates were also conducted on all evaluable subject data, in the PP cohort and the ITT cohort.
Exploratory Efficacy Endpoints
The exploratory end-points are not part of the hierarchy approach as descriptive statistics are mainly planned
HDRS-21 Score
The exploratory efficacy end-point as dictated in tire study protocol was the change from baseline in HDRS- 21 scores to 6 and 10 weeks. Table 39 shows the unadjusted HDRS-21 scores at each visit along with the change from baseline in HDRS-21 scores. FIGs. 10 and 1 1 present the mean (±SE) of the HDRS-21 scores and changes from baseline, respectively.
Table 39: HDRS-21 Score and Change from Baseline (mITT)
Figure imgf000073_0001
Table 40 presents the adjusted means extracted from the model at the 6 and 10 week visits for the mITT analysis sets. The differences within the treatment arms and between the treatment arms were not statistically significant. As the majority of the study subjects did not suffer from co-morbid Major Depressive Disorder (MDD) (mean HDRS-21 score at baseline in both treatment groups was 10), we do not expect any significant changes or improvements in HDRS-21 score due to the treatment in non-MDD patients. Furthermore, we can infer that the improvement in OCD was not as a result of an improvement in depression.
Table 40: Adjusted Means at the 6 Week Visit in HDRS-21 (mITT)
Figure imgf000074_0001
The HDRS-21 exploratory efficacy analysis at 10 week visit was also conducted on ail evaluable subject data, in the PP cohort and the ITT cohort and is presented herein.
Remission Rate (YBOCS score < 8)
Remission rate at the 6 week visit, where remission is defined as YBOCS score < 8 was defined in the study protocol as an exploratory endpoint . The results of the Remission Rates defined as YBOCS < 10 did not show results that justified performing this statistical analysis.
Response Rate and Remission Rate at 10 Weeks
The Response rate, Partial Response rate and Remission rate at the 10 week visit, are presented in Table 41. Response, Partial Response and Remission rate are as defined herein.
Table 41: Response, Partial Response and Remission Rates at 10 Week Visit (mITT)
Figure imgf000074_0002
Hie Response rate at the 10 week visit in the DTMS group is 45.2% versus 17.8% in the Sham group. This difference is statistically significant p=0.0057 (chi-squared test). There was also a further increase in the response rate at the 10 week visit (45%) in the DTMS group compared to the 6 week visit (38%), demonstrating a further positive treatment effect over time.
The Partial Response rate at the 10 week visit in the DIMS group is 59.5% versus 42.2% in the Sham group. This difference is not statistically significant p:=0.1059 (chi-squared test).
The Remission rate at the 10 week visit grew in the DTMS group with a rate of 9.5% (compared to 4.8% at 6 weeks) versus 4.4% in the Sham group (no change from 6 weeks). Although, this difference was still not statistically significant p==0.3502 (chi-squared test), there was an increase in the number of subjects in the D'TMS group who reached remission at 10 weeks compared to the 6 week visit and compared to the Sham group.
The exploratory efficacy analyses for Response, Partial Response and Remission rates were also conducted on all evaluable subject data, in the PP and the ITT analysis sets.
Blinding Assessment
After the first treatment, subjects were asked which treatment (DTSM or Sham) did they think they received. Table 42 presents the responses to the treatment question presented to tire study subjects, according to treatment group.
Only 31.37% of the subjects who received Sham treatment had a moderate to strong belief that they received Sham. A slightly larger percentage of subjects (43.75%) in the DTMS group had a moderate to strong belief that they received the DTMS treatment 12.50% of the subjects in the DTMS incorrectly guessed the treatment they received (i.e., they responded that they received Sham treatment) and 21.57% of the subjects in the Sham group incorrectly guessed the treatment they received (i.e., they responded that they received DTMS treatment). The most frequent answer of subjects in both groups was that they did not know which treatment they received . That is, 43.75% of the subjects in the DTMS responded that they don’t know , versus 47.06% of the subjects in the Sham group. Tlius, the majority of the study subjects, 56.25% of the DTMS subjects and 68.63% of the Sham subjects, were not aware of the treatment they received during the study.
A logistic model was used to assess if the response to the treatment question is predictive to the treatment received. The p-value of the type Ill for the treatment question was 0.1043. Table 42: Blinding Assessment according to Treatment Question (ITT)
Safety and Tolerability
Safety data is presented for all subjects in the ITT analysis set, for every available time point. Time points range from baseline to week 6 and week 10 Furthermore, the“early termination” time point which refers to the assessment visit at or after the last treatment in the study in case of early termination from the study is provided, as relevant.
Vital Signs
Table 43 presents the vital signs in both study groups as measured at baseline, and during the course of the study up to 6 weeks and 10 weeks. Vital signs include weight, body temperature, pulse and blood pressure (systolic and diastolic BP). No notable differences were observed between the study groups overtime in all vital signs.
Table 43: Vital Sigsas over Time (ITT) ge
Figure imgf000077_0002
Figure imgf000077_0001
eline
Figure imgf000077_0003
Figure imgf000078_0001
Figure imgf000079_0001
Physical Examination
Table 44 shows the results of the physical examinations performed throughout the study with respect to the percent abnormal in each of the study groups by body area. No notable differences in the percentage of normal tests are observed between the study groups at each of the time points.
Table 44: Physical Examination (ITT)
Figure imgf000080_0001
Neurological Examination
Tables 45 shows the results of the neurological examinations performed throughout the study with respect to the percent abnormal in each of the study groups by test type. No notable differences in the percentage of normal tests are observed between the study groups at each of the time points.
Table 45: Neurological Test (ITT)
Figure imgf000081_0001
Safety Assessments
Scale of Suicide Ideation (SSI)
Table 46 presents descriptive statistics of the SSI at each visit along with the change from baseline.
No statistically significant differences were found between the groups in the change from baseline in SSI, at the 6 week visit or at the 10 week visit.
Table 46: SSI Score and Change From Baseline in Score (ITT)
Figure imgf000082_0001
Cognitive Assessments
MMSE
Table 47 presents descriptive statistics of the MMSE at each visit along with the change from baseline. No statistically significant differences were found between the groups at the 6 week or at the 10 weeks visit.
Table 47: MMSE Score and Change from Baseline (ITT)
Figure imgf000083_0001
BSRT
Tables 48 to 51 present descriptive statistics of the unadjusted components of BSRT Score components, LTS, CLTR, Total Number of Intrusions, and Total Number of Recalls at Delayed Recall, along with the change from baseline to week 10, respectively. Long Term Storage (LTS) is defined as any word that is spontaneously, recalled, i.e. without reminding, and is identified by 2 consecutive recalls of the word. A vOrd is considered to be in LTS on all subsequent trials regardless of whether the word is recalled. If a word in LTS is consistently recalled on all subsequent trials (but not just the last trial), then it is scored as in Consistent Long Term Retrieval (CLTR).
No statistically significant differences were found between the groups in the change from baseline in LTS, CTLR, total number of intrusions and total number of delay recalls at the 6 week or at the 10 week visits. Table 48: BSKT LTS Score and Change from Baseline (ITT)
Figure imgf000084_0001
Table 49: BSRT CLTR Score a d Change from Baseline (ITT)
Figure imgf000084_0002
Table 50: BSRT Total Number of Intrusions Score and Change from Baseline (ITT)
Figure imgf000084_0003
Table 51: BSRT Total Number of Recalls at Delayed Recall Score and Change from Baseline (ITT)
Figure imgf000085_0001
AMI-SF
Table 52 presents descripti ve statistics of the unadjusted AMI-SF Score and the change from baseline to week 10
No statistically significant differences were found between the groups in the change from baseline in AMI- S and amnesia score at the 6 Week or at the 10 Week Visits.
Table 52: AMI-SF Score and Change from Baseline (ITT)
Figure imgf000085_0002
Adverse Events
In this section, we present details of all adverse events, which occurred during the study. Very few new or unanticipated device related adverse events occurred. As for the serious adverse event a full description is given. In total, 1 SAE’s was reported in the study, which was assessed by the investigator and the sponsor as not related to the device treatment. The SAE is described in detail below.
SAE’s
One serious adverse event w¾s reported in the study. After receiving 2 treatments, subject CH-08 reported having significant suicidal thoughts, which he indicated had preceded the beginning of the treatment sessions, but had neglected to mention prior to study commencement. The investigator and subject decided that hospital admission would be appropriate. Subject claimed his suicidal thoughts/urges were related to escalating problems with his family and not to the study treatments.
Table 53: Serious Adverse Events Listings (ITT)
Figure imgf000086_0001
Adverse Events
All reports of AE’s with the same description, start and end date were combined into one report and reported according to the highest severity and causality.
The following tables present the number of AE reports, the number of subjects and the incidence of the AE’s by System Organ Class (SOC), causality and severity. Table 54 presents details of the adverse event by system organ class and preferred term according to the medDRA adverse event classification, in each of the study groups. As can be seen from Table 54, there are no statistically significant differences in any of the Adverse Events between the DTMS and Sham treatment groups. Table 55 presents details of the adverse event by system organ class and preferred term by Causality, in each of the study groups. Table 56 presents details of the adverse event by system organ class and preferred term by Severity , in each of the study groups. T)
Figure imgf000087_0001
Figure imgf000088_0001
Neck Pain 417%, 588% 10000
Figure imgf000089_0001
Table 55: Adverse Events by System Organ Class and Preferred Term and by Causality per Group (ITT)
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Table 56: Adverse Events by System Organ Class and Preferred Term and by Severity per Group (ITT)
Figure imgf000094_0002
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Summary of Adverse Even ts
The adverse events reported in the study are presented above in Tables 54 to 56 according to system organ class and preferred term according to the medDRA adverse event classification, for each ofthe study group. 35 subjects (73%) reported adverse events in the DTMS group versus 35 (69%) subjects in the Sham group. The incidence of adverse event reporting was not statistically significant (chi-square p-value: 0.6393).
The adverse events reported in the study are typical side effects reported previously with the Deep TMS system and with other marketed TMS devices. The most frequent AE was headache reported by 37.5% of the subjects who received the DTMS treatment and by 35.3% ofthe subjects who received the Sham treatment. Reporting of headaches was not statistically significantly different between the treatment groups. Most other forms of pain and discomfort (administration/application site pain/discomfort, pain in jaw, facial pain, muscle pain/spasm/twitching, neck pain, etc.) were reported as either mild or moderate and mostly resolved after treatment with or without analgesic medications (e.g. Paracetamol, Ibuprofen). In most of the subjects, the discomfort or pain disappeared once the subject became accustomed to the treatment.
There were no significant differences found between the treatment groups for any of the adverse events reported in the study.
These findings demonstrate the overall safety ofthe Deep TMS System for treatment of Obsessive Compulsive Disorder (OCD).
Below is a summary' of the adverse events commonly observed with TMS treatments, presented according to system organ class and adverse events.
Congenital, familial, genetic disorder:
Three (3) subjects (6%) in the Deep TMS treatment group and 1 subject (2%) in the Sham group were reported with diarrhea. All events were spontaneously resolved.
Ear Disorders:
One (1) subject (2%) was reported with tinnitus in the Deep TMS treatment group. Tins event was reported as mild and was considered as probably not related to the DTMS treatment. There were no events of hypoacusis reported in the study.
Eye Disorders:
One case (2%) of forgetfulness was reported in the Deep TMS treatment group. This event was reported as mild and was considered as probably not related to the DTMS treatment.
Gastrointestinal Signs and Symptoms:
The most important GI related ad verse events were pain in the jaw, gastrointestinal symptoms NOS, abdominal pain and abdominal discomfort. Only four subjects (8%) reported jaw pain in the Deep TMS treatment group and 1 subject (2%) in the Sham group. This event was reported as moderate in 1 subject and mild in 3 subjects. All events were spontaneously resolved. General gastrointestinal symptoms NOS were reported in 4 subjects (8%) in the Deep TMS treatment group, although all events were reported as not related to the DTMS treatment. Abdominal pain was reported in 2 subjects (4%) in the DTMS treatment group and 1 subject (2%) in the Sham group. Abdominal discomfort was reported in 2 subjects (4%) in the Deep TMS treatment group and 1 subject (2%) in the Sham group. None of these events were reported as related to the treatment. No other gastrointestinal adverse e vents were reported as related to the DTMS treatment.
General:
Facial pain is a common adverse event reported with TMS treatment. There were 2 subjects (4%) reported in the Deep TMS treatment group with facial pain. The e vents were mild and were spontaneously resolved. Fatigue was more common in the Sham group, with 5 subjects (10%) compared to 1 subject (2%) in the Deep TMS treatment group. All events were mild and were spontaneously resolved or resolved following treatment with medications. Fatigue was reported as not related to the DTMS treatment. One (i) subject (2%) reported a sensation of pressure in the Deep TMS treatment group. The event was mild and reported as not related to the treatment. One (1) subject (2%) reported discomfort during the treatment in the DTMS treatment group, compare to none in the Sham group. Although reported as moderate, the subject withdrew his/her participation in the study due to this adverse event after two treatment sessions.
Injury, poisoning and procedural complications:
Fdght (8) subjects (17%) reported application site/administration site discomfort or pain in the DTMS group compared to 2 subjects (4%)in the Sham group. All events are associated with the device contact and are expected based on other TMS treatment.
Muscoloskeletal Disorders:
Adverse events related to musculoskeletal disorders include pain in different body areas, such as back, knee, muscle, neck, etc and muscle pain/spasm/strain/twitching and myalgia. There were 2 subjects (4%) with reported back pain in the DTMS treatment group and 1 subject (2%) in the Sham group. Ail of the back pain events were reported as not related to the DTMS treatment. These events were reported as mild or moderate, and all cases were resolved following treatment with medications. There was one subject (2%) reported with knee pain in the DTMS group. The knee pain was reported as moderate and not related to DTMS treatment. Two subjects (4%) reported Neck pain in the DTMS treatment group and 3 subjects (6%) in the Sham group. Only one event of neck pain was reported as possibly related to the DTMS treatment. Neck pain was reported as mild or moderate in the Deep TMS treatment group and was resolved following treatment with medications. There were few cases of muscle pain/spasm/strain/twitching and myalgia, 3 subjects (6%) in the DTMS group and 6 subjects (12.5%) in the Sham group. Only 2 events were reported as possibly related to the DTMS treatment and all cases were reported as mild, except for one case in the Sham group which was reported as moderate.
Nervous System Disorders:
Headache (and pain in head), eye pain, dizziness, tremor and night terrors were reported under nervous system disorder. Hie most frequently reported Adverse Event was Headache, which was reported by 18 subjects (37.5%) who received the DTMS treatment and also by 18 subjects (35.3%) who received the Sham treatment. Most events were mild or moderate and only 3 events in the DTMS group were reported as severe and 1 event in the Sham group. Most headache events resolved following treatment with medications. In any case, there was no statistically significant difference between the treatment groups with regard to reporting of headaches. There was one subject (2%) who reported eye pain in the Sham group. This event was reported as mild and possibly related. Dizziness was reported in 1 subject (2%) in the DTMS group and 2 subjects (4%) in the Sham group. The event was reported as mild or moderate and possibly related to treatment in both groups. Both the tremor and the night terrors w'ere each reported in one subject (2%) in the DTMS group as mild and not related to the treatment.
Psychiatric Disorders:
As would be expected in a study with a patient population suffering from Compulsive Obsessive Disorder, there is bound to be psychiatric disorders reported during the course of the study. Interestingly though, the incidence of the psychiatric disorders were not significantly different between the treatment groups. Anxiety was reported in 6 subjects (12 5%) in the DTMS treatment group and in 2 subjects (4%) in the Sham group. Most cases in the DTMS group were reported as possibly or probably related to treatment and most cases were reported as mild, except one, which w¾s moderate. There were 3 subjects with insomnia, 1 (2%) in the Deep TMS treatment group and 2 (4%) in the Sham group. There was 1 subject reported with intentional self-injury in the DTMS group, the event was moderate and resulted in discontinuation of the subject’s participation in the study. In addition, there was 1 subject (2%) with Bruxism and 1 subject with Rash Mouth in the Deep TMS treatment group. One subject (2%) reported Postnasal drip in the Sham group. There were three subjects with nervous/restlessness/tension, one subject (2%) in the DTMS group and 2 subjects (4%) in the Sham group.
Respiratory, Thoracic and Mediastinal Disorders:
There were no differences between the treatment groups in the adverse events m this organ system including allergic sinusitis, sinusitis, cold, coughing and nasopharyngitis/pharyngitis. The only noteworthy event in this organ system is short-term memory loss reported in one subject (2%) in the DTMS group. The event was reported as moderate and probably related to the treatment, although it was reported as resolving without any treatment. Vascular Disorders:
There was 1 subject (2%) with hypertension and 1 subject (2%) with hypotension in the DTMS group. Both of these events were reported as moderate and not related to the DTMS treatment. Migraine occurred in 2 subjects (4%) in the Sham group, both events were moderate and 1 was reported as possibly related to the treatment.
In summary, there were no adverse events for which a significant difference between the study groups was found. Ail adverse events reported with the DTMS are commonly reported with commercially available TMS treatments. The incidence ofthese adverse events reported with the Deep TMS System for the treatment of OCD are similar to the incidence of these adverse events reported with the Deep TMS for MDD (cleared in 5 l0(k) K122288) and other TMS systems, such as the NeuroStar TMS Therapy System.
These findings demonstrate the overall safety of the Deep TMS System for treatment of Obsessive Compulsive Disorder (OCD)
Device Malfunctions
Table 57 presents the number of treatments interrupted per group and overall by treatment number and reason. Table 57: Number of Treatments Interrupted and Reason for Interruption (ITT)
Figure imgf000102_0001
Figure imgf000103_0001
There were a total of 49 treatment interruptions including the following:
® 14 e vents in which the coil o verheated (coil cooled off and treatment resumed in all cases);
® 14 events in which the coil was repositioned for optimal patient comfort; * 3 cases in which the sy stem shutdown and needed to be restarted;
• 3 events in which the subjects’ earplugs fell out and needed to be re-inserted before treatment could continue; and
® 16 interruptions due to other reasons (reasons not reported by the sites)
The 49 treatment interruptions occurred in a total of 2544 treatment sessions in 99 subjects receiving treatment in the study.
SUMMARY AND CONCLUSIONS
A total number of 100 subjects were enrolled in the study. Eligible and consenting subjects were randomized to either the active treatment group (denoted as DTMS) or the sham control group (Sham). The Intent-to- treat (ITT) analysis set includes 99 randomized patients, as one subject withdrew consent (patient did not tolerate the stimulation used to measure the motor threshold). The subject withdrew consent after randomization, but before receiving even one active/sham treatment. Tims, the subject is not included in the ITT analysis set. 48 subjects were randomized to receive active treatment (DTMS) and 51 to receive Sham treatment. Baseline demographic information and safety and tolerability results are presented for the Intent- to-treat (ITT) analysis set. Efficacy results are presented for the modified ITT (mITT) analysis set, which included 94 subjects who met the study eligibility criteria, as pre- defined in the Study Protocol, Statistical Considerations - Analysis Sets.
There were no randomization errors and all subjects received the treatment to which they were originally allocated. The study groups w'ere completely balanced at baseline.
The drop-out rate (10%) in this multicenter study was extremely lo ' with no differences in the treatment groups.
The baseline demographic data, general medical and psy chiatric history, concomitant medications, baseline assessment scores and physical and neurological examination data were analyzed to assess if there were any basic differences between the treatment groups prior to commencement of the clinical study (Tables 9-18). The baseline demographic information, including age, gender and the medical and psychiatric history' data did not show' any significant differences in the data between the treatment groups, except for age of onset of QCD. Although, the age at which professional help was first sought was not statistically different bet een the groups, therefore, this data does not seem to affect the study outcome. The baseline assessment scores w'ere very similar between the treatment groups, with no significant differences. This was true of the physical and neurological examination data, as well. The above data demonstrated that there were no significant differences between the study treatment groups.
The primary efficacy end-point was the change from baseline in YBOCS scores to the 6 week visit. The primary' efficacy analysis was conducted on all evaluable subject data, in the inlTT analysis set. The change from baseline in the YBOCS score (Table 21) demonstrates that the YBOCS score decreased by 6 7 points in the DTMS group and by 3 6 points in the Sham group at the 6 week visit.
In both study group there w¾s a statistically significant reduction in YBOCS scores (T abies 21 -22 and FIGs. 3-4); the estimated slope in the DTMS group was -6 0 points across 6 weeks versus only -3.3 in the sham group and the difference between the slopes of 2.8 points across 6 weeks was found statistically significant. p==0.0127. Based on these results the Null Hypothesis of the study was rejected and the study is deemed successful.
Furthermore, the effect size of the study is 0.69 (Cohen's D). According to widely accepted guidelines, in which 0.2 is defined as a small effect, 0.5 as a medium effect, and 0.8 as a large effect, the DTMS multicenter study may be considered to have a greater than medium to large effect size.
Based on the primary' efficacy analysis of the study, the DTMS has a positive treatment outcome and has demonstrated a beneficial effect in reducing OCD symptoms in moderate to severe QCD patients. The reduction in the YBOCS of 6 0 points is clinically meaningful and statistically significant compared to the sham and the effect size of 0.69 demonstrates a difference between the two groups, which is large enough and consistent enough to be clinically important. The positive treatment outcome was demonstrated immediately (as soon as 2 weeks) after treatment commence and was stable and even enhanced during treatment.
The primary efficacy endpoint of the study was substantiated by the success of the secondary endpoints including the change from baseline in the YBOCS score at 10 weeks. The change from baseline in the YBOCS score at the 10 week visit (Table 21) demonstrates that the YBOCS score decreased by 7 6 points in the DTMS group and by 4.7 points in the Sham group. At the 10-week visit, the adjusted YBOCS score decreased by 6.5 points (95% Cl) in the DTMS group versus 4.1 points (95% Cl) in the Sham group, these decreases were both statistically significant (Table 34). The difference between the treatment groups is also statistically significant (p- value: 0.0380) and clinically meaningful. Based on the 10 week YBOCS score results, the effect size of the study is 0.62 (Cohen's D). The DTMS multicenter study may be considered to have a greater than medium to large effect size. Thus, as aforementioned, the treatment effect is maintained for at least 4 weeks after completion of all treatment sessions, at 10 weeks.
Since there are no medical devices for the treatment of OCD, we have compared the DTMS treatment outcome to available FDA approved, SSR1 medications for the treatment of OCD, including Luvox (Fluvoxamine), Prozac (Fluoxetine), Paxil (Paroxetine), and Zoloft (Sertraline) (see Table 58 below). The DTMS study results can be compared to the Luvox (Fluvoxamine) study (Study 3103) submitted in support of their FDA approved, NDA with a similar OCD patient population (mean baseline YBOCS score of 26), in which the 6 week adjusted YBOCS score decreased by 7.5 points (SE) in the drug group compared to 5.2 points (SE) in the Placebo group. This difference of 2.3 points (95% Cl, p value; 0.0024) w¾s considered statistically significant. The 10 week Luvox study results reported a decrease in the adjusted YBOCS score of 8.2 points (SE in the drug group compared to 5.9 points (SE) in the Placebo group. This difference of 2.3 points (95% Cl, p value; 0.004) was also considered statistically significant. These results are consistent with the other FDA approved SSRI medications. The Prozac (Fluoxetine) studies (with baseline YBOCS score of 22-
26) reported a decrease of 4 to 9 points in the YBOCS score in the drug group (depending on dosage 20- 60mg), versus 1 point in the placebo group, a difference of 3 to 8 points, at 13 weeks. The Paxil (Paroxetine) study (Study 1) (with baseline YBOCS score of 23-26) reported a decrease of 4 to 7 points in the YBOCS score in the drug group (depending on dosage 20-60mg), versus 3 points in the placebo group, a difference of 1-4 points, at 12 weeks. The Zoloft (Sertraline) study (with baseline YBOCS score of 23-25) reported a decrease of 4 points in the YBOCS score in the drag group, versus 2 points in the placebo group, a difference of 2 points at 8 weeks. In 2 additional Zoloft studies, a decrease of 6 and 7 points in the YBOCS score were reported in the drag group, versus 3 and 4 points in the placebo group, respectively, for a difference of 3 points at 12 weeks. It should be noted that the Prozac, Paxil and Zoloft studies included an OCD patient population with only moderate OCD, wnth a lower average baseline YBOCS score of 22-26
Table 58: Comparison of YBOCS Scores
Figure imgf000106_0001
In summary, the DTMS treatment outcome is similar to FDA approved, OCD medications both in the decrease in YBOCS score in the treatment group and with a similar difference in YBOCS score between the treatment and sham/placebo group. Furthermore, as discussed further in this summary the DTMS positive treatment outcome in terms of supplemental assessment scores (CGI Improvement) also demonstrates similar positive results to those reported in the FDA approved SSRI NDAs. The DTMS treatment does not entail the complexity of the metabolism of these drugs or the complications of long-term usage, and the warnings and precautions regarding potential side effects are much less than those reported for drugs. Furthermore, the DTMS treatment achieves the same reduction in OCD symptoms as expressed by the reduction in YBOCS and a significantly“Improved” clinical state based on the CGI Improvement scale (see further discussion below)) in half the time as medications, i.e., 6 weeks vs 12 weeks.
The prognostic factor analysis, including age, gender, treatment question, age of disease onset, duration of disease and CBT treatment (lifetime) at baseline were presented (Table 23). There were no statistically significant differences found between the study groups for any of the prognostic factors. It is important to note that the results of the treatment question did not affect the study results.
Poolability of US and OUS sites was evaluated and concluded that the study sites may be pooled.
The positive effect of the treatment based on the primary efficacy endpoint of change from baseline in YBOCS score was further corroborated by the success of additional secondary efficacy endpoints, including responder analysis, additional supporting OCD assessment scales (CGI Improvement and CGI Severity) and change from baseline in YBOCS scores at 10 weeks (4 weeks following completion of treatment - as described above), thus supporting the consistency and robustness of the clinical effect.
The Response rate (defined as a reduction from baseline of at least 30% in YBOCS score) at the 6 week visit in the DTMS group is 38 1% versus 11.1% in the Sham group (Table 33) The response rate was significantly higher in the DTMS group compared to the sham group (p=0.0033). The Partial Response rate (defined as a reduction from baseline of at least 20% in YBOCS score) at the 6 week visit in the DTMS group is 54 8% versus 26.7% in the Sham group (Table 33). This difference is also statistically significant p 0 0070.
The responder results are not only statistically significant but also clinically meaningful, as demonstrated by the effect size expressed in terms of Number Needed to Treat (NNT). Based on the study response rates, the effect size as obtained by the Number Needed to Treat (NNT = (i/difference in response rates) is 3 7, which means that for every 4 patients treated with the Deep TMS System, 1 subject wall have a response due to the device. The number needed to treat (NNT) for QCD patients treated with SSRI monotherapy at standard (antidepressant) doses is approximately 5, meaning that if 5 patients are treated with an SSRI, one can be expected to respond who would not have responded to placebo. The NNT for a dose escalation from a medium dose to the higher doses is 13- 15. Therefore, the results of this study demonstrate a much greater effect size than conventional SSRI treatments for GCD.
The Response rate at the 10 week visit was 45.2% in the DTMS group compared to 17.8% in the Sham group, with the difference in response rates between the DTMS group and the Sham group remaining statistically significant (p=0.0057) (Table 41). There was also a further increase in the response rate at the 10 week visit (45%) in the DTMS group compared to the 6 week visit (38%), demonstrating a further positive treatment effect maintained over time. The effect size as obtained by the Number Needed to Treat (NNT) was 3.64, which still means that for every 4 patients treated with the Deep TMS System, 1 subject will have a response due to the device. Consequently, the effect size remains larger than for SSRI treatment for OCD at 10 weeks.
As aforementioned, the positive effect of the DTMS treatment was supported by the secondary assessment scales measuring improvement and severity in subjects’ clinical status using the CGI Improvement (CGI-I) and CGI Severity (CGI-S) scales.
In the categorical analysis, 70% of the DTMS subjects reported some improvement (ranging from minimal improvement to very' much improved) at 6 weeks as a result of the DTMS treatment, with 49% reporting an “Improved” (moderate to very' much improved) clinical state (Table 24-25). This is compared to only 58% of the subjects in the Sham group reporting some improvement, with only 21 % experiencing a moderate to very much“Improved” clinical state. There is a statistically significant difference (p=0.0112) between the percentage of DTMS subjects experiencing an“Improved” clinical state compared to the Sham group at 6 weeks. These results reported at 6 weeks are comparable to the CGI Improvement outcomes with FDA approved SSRI medications reported iu their NDA summaries for the treatment of OCD at 12-13 weeks. The two Prozac (Fluoxetine) clinical studies reported 59%-71 % of the subjects with some improvement in clinical status and 36%-47% of the subjects reported a moderate to very much“Improved” clinical state, depending on the dosage (20- 60mg), at 13 weeks. The Paxil (Paroxetine) NDA reported 58%~78% of the subjects with some improvement in clinical status and 25%-44% of the subjects reported a moderate to very much“Improved” clinical state, depending on the dosage (20, 40 or 60mg), at 12 weeks. As aforementioned, the DTMS treatment achieves a significantly“Improved” clinical state based on the CGI Improvement scale, which is similar to the highest dosage of both SSRIs, in half the time as these medications, i.e., 6 weeks vs 12-13 weeks, with far less complications and side effects than drug usage.
The CGI Improvement results are maintained 4 weeks after treatment at the 10 week visit. That is, 72% of the DTMS subjects maintained some clinical improvement and 49% maintained a moderate to very much “Improved” clinical status. Although, those subjects reporting a moderate to very much“Improved” clinical state remained much higher in the DTMS group (49% of DTMS subjects versus only 27.5% in the Sham group), this was not statistically significant at 10 w¾eks (Table 24-25).
At week 6 more subjects had an“improved” CGI Severity (CGI-S) score in the DTMS group (61%) than in the Sham group (32.6%) and this difference was statistically significant (p=0.0221) (Table 28). The positive CGI-S results are maintained 4 weeks after completion of the DTMS treatment at the 10 week visit (CGI-S: 64% vs. 45%), although not statistically significant (Table 36). The CGI Improvement and CGI Severity results support and strengthen the significant clinical effect of the DTMS treatment. The differences in the change from baseline in the Sheehan Disability Scale (SDS) scores in the DTMS group compared to the Sham group were not statistically significant at 6 or 10 weeks (Tables 31-32 and 37). The improvement in these parameters may be more latent and not yet apparent at 6 or 10 weeks. The remission rate (defined as YBOCS score < 10) at the week 6 visit was 4.8% in the DTMS group versus 4.4% in the sham group (Table 38) The remission rate was not significantly between the DTMS and sham group (p=0.9437). It should be noted that the SDS assessment scale and remission rates are not commonly used as a study endpoint in evaluating SSRI medications in FDA approved NDAs and therefore, the clinical significance of these findings is limited.
The exploratory' efficacy end-points were the response and remission rates at 10 weeks and the change from baseline in HDRS-2I scores to 6 and 10 weeks.
The continued positive and significant effect of the response rate (defined as a reduction in YBOCS of at least 30% from baseline) at the week 10 visit (45.2% in the DIMS group versus 17.8% in the sham group, p=0.0057) (Table 41) was discussed above. As was the continued medium to large effect size at 10 weeks (3 64). The partial response rate at the week 10 visit in the DTMS group was 60% versus 42% in the sham group. The partial response rate was not significantly different in the DTMS group compared to the sham group (p=0.1059) (Table 41). The remission rate at the week 10 visit was 9 5% in the DTMS group versus 4.4% in the sham group (Table 41). The remission rate was not significantly between the DTMS and sham group (p=0.3502). Although, this difference was still not statistically significant p=0.3502 (chi-squared test), there was an increase in the number of subjects in the DTMS group who reached remission at 10 weeks (9.5%) compared to the 6 week visit (4.8%) and compared to the Sham group.
The differences within the treatment arms and between the treatment arms for HDRS-21 scores were not statistically significant (Tables 39-40). As the majority of the study subjects did not suffer from co- morbid Major Depressive Disorder (MOD) (mean HDRS-21 score at baseline in both treatment groups was 10), we did not expect any significant changes or improvements in HDRS-21 score due to the treatment in non- MDD patients. Furthermore, we can infer that the improvement in OCD was not as a result of an improvement in depression.
Success of study blinding was assessed (Table 42). A logistic model was used to assess if the response to the treatment question is predictive to the treatment received. The p-value of the type III for the treatment question was 0.1043. The most frequent answer of subjects in both groups was that they did not kno which treatment they received. 43.75% of the subjects m the DTMS responded that they don’t know, versus 47.06% of the subjects in the Sham group. Overall, the majority of the study subjects, 56.25% of the DTMS subjects and 68.63% of tire Sham subjects, were not aware of, or guessed wrongly the treatment they received during the study.
Safety' and tolerability of the Deep TMS treatment were evaluated during the course of the study, including assessment of vital signs, physical and neurological examinations, SSI assessments, cognitive examinations (MMSE, BSRT and AMI-SF) and adverse e vent reporting.
No notable differences in vital signs, ph sical and neurological examination results were observed between the study groups at each of the time points (Tables 43-45). No statistically significant differences in SSI scores were found between the groups at 6 weeks and at 10 weeks (Table 46). These results demonstrate that the DTMS treatment does not affect the safety of the subjects treated with the system.
No statistically significant differences in MMSE scores were found between the groups at 6 weeks and at 10 weeks (Table 47). No statistically significant differences were found between the groups at 6 weeks and at 10 weeks, in any of the components of the BSRT Score (Tables 48-51). No statistically significant differences were found between the groups at 6 weeks and at 10 weeks, in the AMI-SF Score (Table 52). The results of the cognitive tests demonstrate that the Deep TMS treatment does not have a negative cognitive effect on OCD subjects.
The adverse events are reported in the study according to system organ class and preferred term according to the medDRA adverse event classification, for each of the study group (Tables 54-56). 35 subjects (73%) reported adverse events in the DTMS group versus 35 (69%) subjects in the Sham group. The incidence of adverse event reporting was not statistically significant (chi-square p-value: 0.6393).
The adverse events reported in the study are typical side effects reported previously with the Deep TMS system and with other marketed TMS devices. The most frequent AE was headache reported by 37.5% of the subjects who received the DTMS treatment and by 35.3% of the subjects who received the Sham treatment. Reporting of Headaches was not statistically significantly different between the treatment groups. Most other forms of pain and discomfort (administration/application site pain/diseomfort, pain in jaw, facial pain, muscle pain/spasm/twitching, neck pain, etc.) were reported as either mild or moderate and mostly resolved after treatment with or without analgesic medications (e.g. Paracetamol, Ibuprofen). In most of the subjects the discomfort or pain disappeared once the subject became accustomed to the treatment.
Overall, there were no significant differences found between the treatment groups for any of the adverse events reported in the study. The adverse events reported in the study are commonly reported with commercially available TMS treatments. The incidence of these adverse events reported with the Deep TMS System for the treatment of OCD are similar to the incidence of these adverse events reported with the Deep TMS for MDD and other TMS systems, such as the NeuroStar TMS Therapy System.
These findings demonstrate the overall good safety of the Deep TMS System for treatment of Obsessive Compulsive Disorder (OCD).
There was one (1) SAE reported in the study (Table 53), which was assessed by the investigator and the sponsor as not related to the device treatment. After receiving 2 treatments, subject CH-08 reported having significant suicidal thoughts, which he indicated had preceded the beginning of the treatment sessions, but had neglected to mention prior to study commencement. The investigator and subject decided that hospital admission would be appropriate. Subject claimed his suicidal thoughts/urges were related to escalating problems with his family and not to the study treatments.
The safety and efficacy results of the Multicenter DTMS clinical study presented above demonstrate the safety and effectiveness of the DTMS System for treatment of Obsessive Compulsive Disorder.
Obsessive-compulsive disorder (OCD) is a highly debilitating condition, although SSR1 medications can help control the obsessions and compulsions of OCD. The FDA approved SSRIs are Fluoxetine (Prozac), Fluvoxamine (Luvox), Sertraline (Zoloft) and Paroxetine (Paxil). These medications are considered to be equally effective, although some may work for some people and not for others. A notable percentage of patients (40-60%) have a partial or no response to medications. The onset of improvement in OCD symptoms may take weeks to months after starting a medication. Combining medications, such as antidepressants and antipsychotic medications may be effective in controlling OCD symptoms, although all psychiatric medications have side effects, such as stomach upset, sleep disturbance, sweating and reduced interest in sexual activity'. Furthermore, adherence to anti-psychotic drugs is about 50% in the first year, and decreases to about 25% in the second year due to intolerable safety issues with low benefit over time. The above reported results of the multicenter DTMS study have demonstrated that the DTMS treatment can be as effective, or better than conventional SSRI medications in treating OCD. Furthermore, the adverse events reported in this study for DTMS treatment are known and well tolerated by OCD subjects. Additionally, the DTMS treatment enables patient compliance with the treatment during a 6 week treatment period. Thus, the safety profile of the DTMS treatment is better than that reported for SSRI medications. The performance data provided in the regulatory' submission further supports the safety of the DTMS device.
In summary, the overwhelming clinical benefits enabled by the DTMS treatment, including high efficacy expressed in terms of a statistically significant reduction in YBOCS symptoms score, large effect size and low NNT, statistically significant response rates and improvement in CGI-1 and CGI-S, outweigh the minimal risks involved with the administration of the treatment. Furthermore, the DTMS treatment provides clinically meaningful efficacy in a relatively short time of 6 weeks with a proven safety profile, high tolerability and extremely high treatment compliance by the OCD patient population compared to currently available medicinal treatments in the market.
Figure imgf000111_0001
Main Study Hypothesis (Change in YBOCS from Baseline at 6 Weeks)
The primary efficacy end-point as dictated in the study protocol was the change from baseline in YBOCS scores to the 6 week visit. The primary' efficacy analysis is conducted on all evaluable subject data, in the PP analysis set. Table 59 show's the unadjusted total YBOCS score and change in score from baseline. FIGs. 12 and 13 are graphical representations of the table and present the mean (±SE) of the YBOCS scores and changes from baseline, respectively. We see from these representations that in both study groups there was a reduction over time in YBOCS scores.
Table 59: Distribution Of YBOCS Score And Change From Baseline To 6 and 10 Week Visits (PP)
Figure imgf000111_0002
The change from baseline in the YBOCS score extracted from Table 59 demonstrates that the YBOCS score decreased by 6.7 points in the DTMS group and by 3.6 points in the Sham group at the 6 week visit.
Table 60 presents the adjusted means extracted from the model at the 6-week visit. The YBOCS score decreased by 6.0 points (95% Cl) in the DTMS group and by 3.3 points (95% Cl) in tire Sham control group, these decreases were both statistically significant. The difference between the treatment arms is also statistically significant (p-value: 0.0127). The effect size observed is 0.69.
Table 60: Adjusted Means Of The Change From Baseline To 6 Weeks In YBOCS (PP)
Figure imgf000112_0001
The effect size of the study is 0.69. According to widely accepted guidelines, in which 0.2 is defined as a small effect, 0.5 as a medium effect, and 0.8 as a large effect, the DTMS multicenter study may be considered to have a greater than medium to large effect size based on the PP subject cohort.
Based on the primary efficacy anal sis of the study, the DTMS has a positive treatment outcome and has demonstrated a beneficial effect in reducing OCD symptoms in moderate to severe OCD patients. The reduction in the YBOCS of 6.0 points is clinically meaningful and statistically significant compared to the sham and the effect size of 0.69 demonstrates a difference between the two groups, which is large enough and consistent enough to be clinically important.
The primary efficacy endpoint of the study was substantiated by the success of the secondary endpoints including the change from baseline in the YBOCS score at 10 weeks. The change from baseline in the unadjusted YBOCS score at the 10 week visit extracted from Table 79 demonstrates that the YBOCS score decreased by 7.6 points in the DTMS group and by 4.7 points in the Sham group "fable 71 presents the adjusted means extracted from the model at the 10-week visit. The YBOCS score decreased by 6.5 points (95% Cl) in the DTMS group versus 4.1 points (95% Cl) in the Sham group, these decreases were both statistically significant. The difference between the treatment groups is also statistically significant (p-value: 0.0380). Based on the 10 week YBOCS score results, the effect size of the study is 0.62. The DTMS multicenter study may be considered to have a greater than medium to large effect size. Thus, as aforementioned, the treatment effect is maintained for at least 4 weeks after completion of all treatment sessions, at 10 weeks.
The positive effect was corroborated by responder analysis, thus supporting the robustness of the clinical effect. The Response rate (defined as a reduction from baseline of at least 30% in the YBOCS score) at the 6 week visit in the DTMS group is 36.6% versus 11.1% in the Sham group (Table 70). This difference is statistically significant p=0.0052 (chi-squared test). The Partial Response rate (defined as a reduction from baseline of at least 20% in the YBOCS score) at the 6 w¾ek visit in the DTMS group is 53.7% versus 26.7% in the Sham group (Table 70). This difference is also statistically significant p=0.0106 (chi- squared test).
Based on the study response rates, the effect size as obtained by the Number Needed to Treat (NNT = (1/difference in response rates) is 3.9, which means that for every 4 patients treated with the Deep TMS System, 1 subject will have a response due to the device. The number needed to treat (NNT) for OCD patients treated with SSRI monotherapy at standard (antidepressant) doses is approximately 5, meaning that if 5 patients are treated with an SSRI, one can be expected to respond who would not have responded to placebo. The NNT for a dose escalation from a medium dose to the higher doses is 13-1527. Therefore, the results of this study demonstrate a much greater effect size than conventional SSRI treatments forGCD.
The positive effect of the D'TMS treatment was further supported by the secondary assessment scales measuring clinical improvement and severity in subjects’ clinical status using the CGI Improvement (CGI-I) and CGI Severity (CGI-S) scales. The CGI Improvement (CGI-I) categorical analyses results demonstrate that 49% of the subjects reported a moderate to very much“Improved” clinical state at 6 weeks compared to only 21% of the subjects in the Sham group (Tables 61 and 62). This difference was statistically significant (p=0.0112). These results obtained at 6 weeks are comparable to the CGI Improvement outcomes reported in NDA summaries for FDA approved SSRI medications, reported at 12-13 weeks. At week 6 more subjects had an“improved” CGI Severity (CGI-S) score in the DTMS group (61%) than in the Sham group (32.6%) and this difference was statistically significant (p=0.0221) (Tables 65). The positive CGI-I and CGI-S results are maintained 4 weeks after completion of the DTMS treatment at the 10 week visit (CGI-1: 49% vs. 27.5% and CGI-S: 64% vs. 45%), although not statistically significant. The CGI Improvement and CGI Severity results support and strengthen the significant clinical effect of the DTMS treatment.
The DTMS benefit is also reported by the excellent safety profile reported in the clinical study report for the DTMS de vice, with similar known side effects of conventi onal TMS treatments and no reported differences in adverse events between the DTMS and Sham treatments.
In summary, the DTMS treatment has been demonstrated as effective for the treatment of OCD as reported by the primary efficacy analysis and as supported by the secondary efficacy analyses and is a safe treatment as demonstrated by the known side effects and lack of adverse events.
Secondary Efficacy Endpoints
CGI Improvement (CGI -I), CGI Severity (CGI-S) & Sheehan Disability Scale (SDS) Scores at 6 weeks CGI Improvement (CGI-I) at 6 Weeks
Table 61 presents the CGI-I score distribution with the percent of subjects in each treatment group according to the outcome classification on the CGI Improvement Scale. Table 61: Outcome Classification (%) in CGI Improvement Scale (PP)
Figure imgf000114_0001
The CGI-I scores were categorized into die following two categories:
® Improved: Moderately improved to Very much improved
• Minimally improved, No change or Worsened: Very much worse to Minimally improved
(The score of“Does not apply” was filtered from this analysis).
Table 62 presents the distribution of the CGI-I scores per visit and treatment arm along with the p-value of the Fisher’s exact test per visit. At week 6 more subjects had a CGi-i score improved in the DTMS arm than in the Sham arm (p-value: 0.0112). Table 62: Comparison of CGI-I Outcome Categories (PP)
Figure imgf000115_0001
The categorical analy sis of the CGI Improvement results at 6 weeks demonstrate that only 17% of the DTMS subjects experienced“No Change” compared to 32.5% in the Sham group. More importantly, 71% of the DTMS subjects reported some improvement (ranging from minimal improvement to very much improved) at 6 weeks as a result of the DTMS treatment, with 49% reporting an“Improved” (moderate to very much improved) clinical state. This is compared to only 58% of the subjects in the Sham group reporting some improvement, with only 21% experiencing a moderate to very much“Improved” clinical state. There is a statistically significant difference (p=0.0112) between the percentage of DTMS subjects experiencing an “Improved” clinical state compared to the Sham group at 6 weeks.
These results obtained at 6 weeks are comparable to the CGI Improvement outcomes with FDA approved SSRT medications reported in their NDA summaries for the treatment of OCD at 12- 13 weeks. The two Prozac (Fluoxetine) clinical studies reported 59%-71% of the subjects with some improvement in clinical status and 36%-47% of the subjects reported a moderate to very much“Improved” clinical state, depending on the dosage (2G-60mg), at 13 weeks. The Paxil (Paroxetine) NDA reported 58%-78% of the subjects with some improvement in clinical status and 25%-44% of the subjects reported a moderate to very much “Improved” clinical state, depending on the dosage (20, 40 or 60mg), at 12 weeks. Consequently, the DTMS treatment achie ves a significantly“Improved” clinical state based on the CGI Improvement scale, which is similar to the highest dosage of both SSRls, in half die time as these medications, i.e., 6 weeks vs 12-13 weeks, with far less complications and side effects than drug usage.
In addition, the CGI Improvement score is also presented as a continuous variable. Table 63 presents descriptive statistics of the unadjusted CGI-1 score at each visit and the change from baseline to week 6 and 10. FIG. 14 presents the mean (±SE) of the CGI-I scores and changes from baseline, respectively. In general, we see a reduction in CGI-I score over time in both groups. Table 63: Distribution Of CGI-I Score And Change From Baseline To 6 and 10 Weeks Visit (PP)
Figure imgf000116_0002
Table 64 presents the adjusted means extracted from the model at the 6-week visit. The CGI-I score at the 6 weeks visit was 3 75 points (95% Cl) in the DTMS group and by 4.2 points (95% Cl) in the Sham group. The difference between the treatment arms is not statistically significant (p-value: 0.0985).
Table 64 : Adjusted means at the 6 weeks visit in C G
Figure imgf000116_0001
Figure imgf000116_0003
CGI Severity' (CGI-S) Score at 6 Weeks
Table 65 presents the CGI-S score distribution with the percent of subjects in each treatment group according to the outcome classification on the CGI Severity' Scale.
The change from baseline in CGI-S scores were categorized into the following categories:
• Improved
• No change
• Worsened
Table 65 presents the distribution of the changes in CGI-S scores per visit and treatm ent arm along with the p-value of the Fisher’s exact test per visit. At week 6 more subjects had a CGI- S score improved in the DTMS ami than in the Sham arm (p-value: 0.0221).
Table 65: Comparison of Change from Baseline in CGI-S, Outcome Categories (PP)
Figure imgf000117_0001
The categorical analysis of the CGI Severity results demonstrate that approximately double the percentage of subjects in the DTMS group experienced an“improved" clinical status based on their CGI-S scores compared to the Sham group at 6 weeks, i.e., 61% versus 32.6%, respectively. Only 36.6% of the subjects in the DTMS group reported No Change at 6 weeks compared to 62.8% in the Sham group. Only one subject (2,4%) had a“Worsened" effect of the DTMS treatment, compared to 2 subjects (4.7%) in the Sham group. The differences between the DTMS group and the Sham group at 6 weeks, including significantly more subjects with an“improved” CGI-S score in the DTMS arm than in the Sham arm, were statistically significant (p-value: 0.0221).
In addition, the CGI-S is also presented as a continuous variable. Table 66 presents descriptive statistics of the CGI-S score at each visit and the change from baseline to week 6 and 10. FIGs. 15 and 16 present the mean (±SE) of the CGI-S scores and changes from baseline, respectively . In general, we see a reduction in CGI-S score over time in both groups. Table 66: Distribution Of CGI-S Score And Change From Baseline To 6 & 10 Week Visits (PP)
Figure imgf000118_0001
Table 67 presents the adjusted means extracted from the model at the 6-week visit. The CGI- S decreased by 0.71 points (95% Cl) in the DTMS group and by 0.40 points (95% Cl) in the Sham group. Although, there is a trend towards better improvement in CGI-S scores in the DTMS group compared to the Sham group, the difference between the treatment groups is not statistically significant (p-value: 0.1183).
Table 67: Adjusted means of the change from baseline to 6 weeks in CGI-S (PP)
Figure imgf000118_0002
Sheehan Disability Scale (SDS) at 6 Weeks
The Sheehan disability scale score at each visit, along with the change from baseline is summarized in Table 68. FIG. 17 and 18 present the mean (±SE) of the SDS scores and change from baseline respectively .
Table 68: Distribution Of SDS Score And Change From Baseline To 6 and 10 Week Visits (PP)
Figure imgf000119_0001
Table 69 presents the adjusted means extracted from the model at the 6-week visit. SDS decreased by 3.8 points (95% Cl) in the DTMS group and by 3.0 points (95% Cl) in the Sham group, at 6 week visit these decreases were both statistically significant. Although, there is a trend towards better improvement in SDS scores in the DTMS group compared to the Sham group, the difference between the treatment groups is not statistically significant (p-value: 0.4786).
Table 69: Adjusted means of the change from baseline to 6 weeks in SDS (PP)
Figure imgf000119_0002
Response Rates at 6 weeks
The Response rate and Partial Response rate at the 6 week visit, are presented in Table 70. Response is defined as a reduction from baseline of at least 30% in the YBOCS score. Partial Response is defined as a reduction from baseline of at least 20% in the YBOC score. Remission rate is defined as a YBOCS score less than (<) 10.
In case of missing YBOCS score at the 6 weeks visit, the Last Observed Value (LOV) method was used.
Table 70: Response Rate and Partial Response at the 6 Week Visit (PP)
Figure imgf000120_0001
The Response rate at the 6 week visit in the DTMS group is 36.6% versus 11.1% in the Sham group. This difference is statistically significant p=0.0052 (chi-squared test). The Partial Response rate at the 6 week visit in the DTMS group is 53.66% versus 26.67% in the Sham group. This difference is also statistically significant p=0.0106 (chi-squared test).
Based on the study response rates, the effect size as obtained by the Number Needed to Treat (NNT - (1/difference in response rates) is 3.9, which means that for every 4 patients treated witlr the Deep 'IMS System, 1 subject will have a response due to the device. The number needed to treat (NNT) for OCD patients treated with SSRI monotherapy at standard (antidepressant) doses is approximately 5, meaning that if 5 patients are treated with an SSRI, one can be expected to respond who would not have responded to placebo. The NNT for a dose escalation from a medium dose to the higher doses is 13-15% Therefore, the results of this study demonstrate a much greater effect size than con ventional SSRI treatments for OCD.
The Response rate (as presented in Table 94 below) at the 10 week visit was 44.2% in the DTMS group compared to 22.5% in the Sham group. The difference in response rates between the DTMS group and the Sham group remained statistically significant p=0. 0265 (chi-squared test) at the 10 week visit. There was also a further increase in the response rate at the 10 week visit (44.2%) in the DTMS group compared to the 6 week visit (36.6%), demonstrating a further positive treatment effect over time. Change from Baseline in YBOCS at 10 Weeks
The change from baseline in the unadjusted YBOCS score at the 10 week visit (secondary efficacy endpoint) extracted from Table 59 demonstrates that the YBOCS score decreased by
7.6 points in die DTMS group and by 4.7 points in the Sham group.
Table 71 presents the adjusted means extracted from the model at the 10-week visit. The YBOCS score decreased by 6.5 points (95% Cl) in the DTMS group versus 4.1 points (95% Cl) in the Sham group, these decreases were both statistically significant. The difference between the treatment groups is also statistically signifi cant (p- value: 0.0380). Thus, the treatment effect is maintained for at least 4 weeks after completion of all treatment sessions, at 10 weeks. The effect size observed is 0.62.
Table 71 : Adjusted means of the change from baseline to 10 weeks in YBOCS (PP)
Estimate Standa
Figure imgf000121_0002
Erroi-
Adjusted means of the changes DTMS
Figure imgf000121_0001
Figure imgf000121_0003
-6.533 1.105 <.0001 |-8.725;-4.341 |
Figure imgf000121_0004
Based on the 10 week YBOCS score results, the effect size of the study is 0.62. The DTMS multicenter study may be considered to have a greater than medium to large effect size, based on the PP patient cohort.
The reduction in the YBOCS of 7.6 points is clinically meaningful and statistical significant compared to the sham and the effect size of 0.62 demonstrates a difference between the two groups, which is large enough and consistent enough to be clinically important. As aforementioned, the positive treatment outcome was demonstrated immediately (as soon as 2 weeks) after treatment commence and was stable and even enhanced during treatment at 6 weeks and subsequently, confirmed 4 weeks after treatment completion at the 10 week visit.
CGI-I, CGI-S and SDS Change From Baseline at 10 Weeks
CGI-1 Change From Baseline at 10 "Weeks
The CGI Improvement results are maintained 4 weeks after treatment at the 10 week visit. That is, 72% of the DTMS subjects maintained some clinical improvement. Although, those subjects reporting a moderate to very much“Improved” clinical state remained much higher in the DTMS group (49% of DTMS subjects versus only 27.5% in the Sham group), this was not statistically significant at 10 weeks.
Table 72 presents the adjusted means extracted from the model at the 10-week visit. The CGI- 1 score at the 10 weeks visit was 3.6 points (95% Cl) in the DTMS arm and 3.9 points (95% Cl) in the control arm. The difference between the treatment arms is not statistically significant (p-value: 0.3339). Table 72; Adjusted means at the 10 weeks visit in CGI-I (PP)
iEstimatc Standard
Figure imgf000122_0001
Figure imgf000122_0002
Error
Figure imgf000122_0003
Figure imgf000122_0004
CGI-S Change From Baseline at 10 Weeks
The CGI Severity results are maintained 4 weeks after completion of the DTMS treatment at the 10 week visit (Table 65). That is, 64% of the DTMS subjects maintained an“Improvement" in their CGI-S scores compared to 61% at 6 weeks. And although, those subjects reporting an“Impro ved” clinical status remained much higher in the DTMS group (64% of DTMS subjects versus only 45% in the Sham group), this was not statistically significant at 10 weeks.
Table 73 provided below presents the adjusted means extracted from the model at the 10-week visit. The CGI-S decreased by 0.935 points (95% Cl) in the DTMS group and by 0.66 points (95% Cl) in the Sham group, these decreases were both statistically significant. The difference between the treatment groups is not statistically significant (p-value: 0.2343).
Table 73 : Adjuste means of the change fro baseline to 10 weeks in CGI-S (PP)
Figure imgf000122_0005
SDS Change From Baseline at 10 Weeks
Table 74 presents the adjusted means extracted from the model at the 10-week visit. The SDS decreased by 2.6 points (95% Cl) in the DTMS group and by 3.3 points (95% Cl) in the Sham group. The difference between the treatment groups was not found statistically significant (p-value: 0.5519).
Table 74; Adjusted means of the change from baseline to 10 weeks in SDS (PP)
Figure imgf000122_0006
Remission Rate at 6 Weeks
The Remission Rate at the 6 week visit, are presented in Table 75. Remission rate was defined as a YBOCS score of less than {<) 10.
In case of missing YBOCS score at the 6 weeks visit, the Last Observed Value (LOV) method was used.
Table 75: Remission Rates at the 6 Week Visit (PP)
Figure imgf000123_0002
The Remission rate at the 6 week visit in both groups was minimal, with 2.44% in the DTMS group and 4.4% in the Sham group. This difference was not statistically significant p=0.6127(chi-squared test).
Figure imgf000123_0001
HDRS-21 Score
The exploratory efficacy end-point as dictated in the study protocol was the change from baseline in HDRS- 21 scores to 6 and 10 weeks. Table 76 shows the unadjusted HDRS-21 scores at each visit along with the change from baseline in HDRS-21 scores. FIGs. 19 and 20 present the mean (±SE) of the HDRS-21 scores and changes from baseline, respectively.
Table 76: HDRS-21 Score And Change From Baseline (PP)
Figure imgf000124_0001
Table 77 presents the adjusted means extracted from the model at the 6 and 10 week visits for the PP analysis sets. The differences within the treatment arms and between the treatment arms were not statistically significant. As the majority of the study subjects did not suffer from co- morbid Major Depressive Disorder (MDD) (mean HDRS-21 score at baseline in both treatment groups was 10), we do not expect any significant changes or improvements in HDRS-21 score due to the treatment in non -MDD patients. Furthermore, we can infer that the improvement in GCD was not as a result of an improvement in depression.
Table 77: Adjusted means at the 6 weeks visit in HDRS-21 (PP)
Figure imgf000124_0002
Remission Rate (YBOCS score < 8)
Remission rate at the 6 week visit, where remission is defined as YBOCS score < 8 was defined in the study protocol as an exploratory endpoint. The results of the Remission Rates defined as YBQCS < 10 did not show results that justified performing this statistical analysis.
Response Rate and Remission Rate at 10 Weeks
The Response rate, Partial Response rate and Remission rate at the 10 week visit, are presented in Table 78. Response, Partial Response and Remission rate are as defined elsewhere herein.
Table 78; Response, Partial Response and Remission Rates at 10 Week Visit (PP)
Figure imgf000125_0002
The Response rate at the 10 week visit in the DTMS group is 43.9% versus 17.8% in the Sham group. This difference is statistically significant p=:0.0084(chi-squared test). There was also a further increase in the response rate at tire 10 week visit (43.9%) in the DTMS group compared to tire 6 week visit (36 6%), demonstrating a further positive treatment effect overtime.
The Partial Response rate at the 10 week visit in the DTMS group is 58.3% versus 42.2% in the Sham group. This difference is not statistically significant p=0.1307(chi-squared test).
The Remission Rate at the 10 week visit in the DTMS group is 7.3% versus 4.4% in the Sham group. This difference is not statistically significant p=0.5696 (chi-squared test).
Figure imgf000125_0001
ysis
Mam Study Hypothesis (Change in YBOCS from Baseline at 6 Weeks)
The primary efficacy end-point as dictated in the study protocol was the change from baseline in YBOCS scores to the 6 week visit. The primary efficacy analysis is conducted on all evaluable subject data, in the ITT analysis set. Table 79 show's the unadjusted total YBOCS score and change in score from baseline. We see from these representations that in both study groups there was a reduction over time in YBOCS scores. Table 79: Distribution Of YBOCS Score And Change From Baseline To 6 am! 10 Week Visits (ITT)
Figure imgf000126_0001
The change from baseline in the YBOCS score extracted from Table 79 demonstrates that the YBOCS score decreased by 6.6 points in the DTMS group and by 4.6 points in the Sham group at the 6 week visit.
Table 80 presents the adjusted means extracted from the model at the 6-week visit. The YBOCS score decreased by 6.0 points (95% Cl) in the DTMS group and by 4.1 points (95% Cl) in the Sham control group, these decreases were both statistically significant. The difference between the treatment groups is not statistically significant (p-value: 0 0988) The effect size observed is 0 48.
Table 80: Adjusted Means Of The Change From Baseline To 6 Weeks In YBOCS (ITT)
Figure imgf000126_0002
Although, the change from baseline in YBOCS score did not result in a statistically significant difference, the results are presented by the Effect Size were clinically significant and showed a medium effect size. The effect size of the study is 0.48. According to the widely accepted guidelines of Cohen3, in which 0.2 is defined as a small effect, 0.5 as a medium effect, and 0.8 as a large effect, the DTMS multicenter study may be considered to have a medium effect size based on the ITT subject cohort.
Based on the primary efficacy anal sis of the study, the DTMS has a positive treatment outcome and has demonstrated a beneficial effect in reducing OCD symptoms in moderate to severe OCD patients. The reduction in the YBOCS of 6.0 points is clinically meaningful and statistically significant and the effect size of 0.48 demonstrates a large enough and consistent enough treatment outcome to be clinically important. The placebo effect in the ITT patient cohort showed a higher reduction in YBOCS score than in the mITT patient cohort and therefore, statistical significant between the treatment groups was not found.
The positive effect was corroborated by responder analysis, thus supporting the robustness of the clinical effect. The Response rate (defined as a reduction from baseline of at least 30% in the YBOCS score) at the 6 week visit in the DTMS group is 37.2% versus 27.1% in the Sham group (Table 90). This difference is statistically significant p=0.0427 (chi-squared test). The Partial Response rate (defined as a reduction from baseline of at least 20% in the YBOCS score) at the 6 week visit in the DTMS group is 53.5% versus 42.4% in the Sham group (Table 93). This difference is also statistically significant p=: 0.0436 (chi- squared test).
Based on the study response rates, the effect size as obtained by the Number Needed to Treat (NNT = (1/difference in response rates) is 5.3, which means that for every 5 patients treated with the Deep TMS System, 1 subject will have a response due to the device. The number needed to treat (NNT) for OCD patients treated with SSR1 monotherapy at standard (antidepressant) doses is approximately 5, meaning that if 5 patients are treated with an SSRI, one can be expected to respond who would not have responded to placebo. The NNT for a dose escalation from a medium dose to the higher doses is 13-15. Therefore, the results of this study demonstrate an effect size equal to or better than conventional SSRI treatments for OCD.
The DTMS benefit is also reported by the excellent safety profile reported in the Clinical Study Report for the DTMS device, with similar known side effects of conventional TMS treatments and no reported differences in adverse events between tire DTMS and Sham treatments.
In summary, the DTMS treatment has been demonstrated as effective for the treatment of OCD as reported by the primary efficacy analysis and as supported by some of the secondary efficacy analyses and is a safe treatment as demonstrated by the known side effects and lack of adverse events.
Secondary Efficacy Endpoints
CGI improvement (CGI-1), CGI Severity (CGI-S) & Sheehan Disability Scale (SDS) Scores at 6 weeks CGI Improvement (CGI-I) at 6 Weeks
Table 81 presents the CGI-I score distribution with the percent of subjects in each treatment group according to the outcome classification on the CGI Improvement Scale Table 81: Outcome Classification (%) in CGI Improvement Scale (ITT)
Figure imgf000128_0001
The CGI-I scores were categorized into the following two categories:
• Improved: Moderately improved to Very much improved
• Minimally improved, No change or Worsened: Very' much worse to Minimally improved
(The score of“Does not apply” was filtered from this analysis).
Table 82 presents the distribution of the CGI-I scores per visit and treatment arm along with the p-vaiue of the Fisher’s exact test per visit. At week 6 more subjects had a CGI-I score improved in the DTMS arm than in the Sham arm (p-value: 0.0459). Table 82: Comparison of CGI-I Outcome Categories (ITT)
Figure imgf000129_0001
The categorical analysis of the CGI Improvement results at 6 weeks demonstrate that only 17% of the DTMS subjects experienced“No Change” compared to 30% in the Sham group. 71 % of the DTMS subjects reported some improvement (ranging from minimal improvement to very much improved) at 6 weeks as a result of the DTMS treatment, with 48% reporting an“Improved” (moderate to very much improved) clinical state. This is compared to 62% of the subjects in the Sham group reporting some improvement, with only 25.5% experiencing a moderate to very much“Improved” clinical state. There is a statistically significant difference (p=0.0459) between the percentage of DTMS subjects experiencing an“Improved” clinical state compared to the Sham group at 6 weeks.
These results obtained at 6 weeks are comparable to the CGI Improvement outcomes with FDA approved SSRI medications reported in their NDA summaries for the treatment of OCD at 12- 13 weeks. The two Prozac (Fluoxetine) clinical studies reported 59%-7I% of the subjects with some improvement in clinical status and 36%-47% of the subjects reported a moderate to very' much“Improved” clinical state, depending on the dosage (20-60mg), at 13 weeks. The Paxil (Paroxetine) NDA reported 58%-78% of the subjects with some improvement in clinical status and 25%-44% of the subjects reported a moderate to very much “Improved” clinical state, depending on the dosage (20, 40 or 60mg), at 12 weeks. Consequently , the DTMS treatment achieves a significantly“Improved” clinical state based on the CGI Improvement scale, which is similar to the highest dosage of both SSRIs, inhalfthe time as these medications, i.e., 6 weeks vs 12-13 weeks, with far less complications and side effects than drug usage.
In addition, the CGI Improvement score is also presented as a continuous variable. Table 83 presents descriptive statistics of the unadjusted CGI -I score at each visit and the change from baseline to week 6 and 10. In general, we see a reduction in CGI-I score over time in both groups. Table 83: Distribution Of CGI-I Score And Change From Baseline To 6 and 10 Weeks Visit (ITT)
Figure imgf000130_0001
Table 84 presents the adjusted means extracted from the model at the 6-week visit. The CGI-I score at the 6 weeks visit was 3.7 points (95% Cl) in the DTMS group and by 4.1 points (95% Cl) in the Sham group. The difference between the treatment arms is not statistically significant (p-value: 0.2247).
Table 84: Adjusted means at the 6 weeks visit in CGI-I (ITT)
Figure imgf000130_0002
CGI Severity (CGI-S) Score at 6 Weeks
Table 85 presents the CGI-S score distribution with the percent of subjects in each treatment group according to the outcome classification on the CGI Severity Scale
The change from baseline in CGI-S scores were categorized into the following categories:
® Improved
® No change
® Worsened
Table 85 presents the distribution of the changes in CGI-S scores per visit and treatment arm along with the p-value of the Fisher’s exact test per visit. At week 6 more subjects had a CGI- S score improved in the DTMS arm than in the Sham ami (p-value: 0.0562). Table 85: Comparison of Change from Baseline in CGI-S, Outcome Categories (ITT)
Figure imgf000131_0001
The categorical analysis of the CGI Severity results demonstrate that approximately double the percentage of subjects in the D'TMS group experienced an“Improved” clinical status based on their CGI-S scores compared to the Sham group at 6 weeks, i.e , 59.5% versus 32.6%, respectively. Only 38.1% of the subjects in the DTMS group reported No Change at 6 weeks compared to 59.6% in the Sham group. Only one subject (2.4%) had a“Worsened” effect of the DTMS treatment, compared to 2 subjects (4.3%) in the Sham group. The differences between the DTMS group attd the Sham group at 6 weeks, including significantly more subjects with an“Improved” CGI-S score in the DTMS arm than in the Sham arm, were not statistically significant (p-value: 0.0562), although a clear trend towards statistical significance was observed.
In addition, the CGI-S is also presented as a continuous variable. Table 86 presents descriptive statistics of the CGI-S score at each visit and the change from baseline to week 6 and 10.
Table 86: Distribution Of CGI-S Score And Change From Baseline To 6 & 10 Week Visits (ITT)
Figure imgf000131_0002
Table 87 presents the adjusted means extracted from the model at the 6-week visit. The CGT-S decreased by 0.73 points (95% Cl) in the DTMS group and by 0.53 points (95% Cl) in the Sham group. Although, there is a trend towards better improvement in CGI-S scores in the DTMS group compared to the Sham group, the difference between the treatment groups is not statistically significant (p-value: 0.3182).
Table 87: Adjusted means of the change from baseline to 6 weeks in CGI-S (ITT)
Figure imgf000132_0001
Sheehan Disability Scale (SDS) at 6 Weeks
The Sheehan disability scale score at each visit, along with the change from baseline is summarized in Table
Table 88: Distribution Of SDS Score And Change From Baseline To 6 and 10 Week Visits (ITT)
Figure imgf000132_0002
Table 89 presents the adjusted means extracted from the model at the 6-week visit. SDS decreased by 3.9 points (95% Cl) in the DTMS group and by 3.3 points (95% Cl) in the Sham group, at 6 week visit these decreases were both statistically significant. The difference between the treatment groups is not statistically significant (p-value: 0.5628)
Table 89: Adjusted means of the change from baseline to 6 weeks in SDS (ITT)
Figure imgf000133_0001
Response Rates at 6 weeks
The Response rate and Partial Response rate at the 6 week visit, are presented in Table 90. Response is defined as a reduction from baseline of at least 30% in the YBOCS score. Partial Response is defined as a reduction from baseline of at least 20% in the YBOC score. Remission rate is defined as a YBOCS score less than (<) 10.
In case of missing YBOCS score at the 6 weeks visit, the Last Observed Value (LGV) method was used.
Table 90: Response Rate and Partial Response at the 6 Week Visit (ITT)
Figure imgf000133_0002
The Response rate at the 6 week visit in the DTMS group is 37.2% versus 18.37% in the Sham group. This difference is statistically significant p=0.0427 (chi-squared test). The Partial Response rate at the 6 week visit in the DTMS group is 53 5% versus 32.65% in the Sham group. This difference is also statistically significant p=0.0436 (chi-squared test).
Based on the study response rates, the effect size as obtained by the Number Needed to Treat (NNT = (l/difference in response rates) is 5.3, which means that for every 5 patients treated with the Deep TMS System, i subject will have a response due to the device. The number needed to treat (NNT) for QCD patients treated with SSRI monotherapy at standard (antidepressant) doses is approximately 5, meaning that if 5 patients are treated with an SSRI, one can be expected to respond who would not have responded to placebo. The NNT for a dose escalation from a medium dose to the higher doses is 13-15. Therefore, the results of this study demonstrate an effect size equal to or better than conventional SSRI treatments for QCD. The Response rate (as presented in Table 94) at the 10 week visit was 44.2% in the DTMS group compared to 22.45% in the Sham group. The difference in response rates between the DTMS group and the Sham group remained statistically significant p=0.0265 (chi-squared test) at the 10 week visit. There w'as also a further increase in the response rate at the 10 week visit (44.2%) in the DTMS group compared to the 6 week visit (37.2%), demonstrating a further positive treatment effect over time.
Change from Baseline in YBOCS at 10 Weeks
The change from baseline in the unadjusted YBOCS score at the 10 week visit (secondary efficacy endpoint) extracted from Table 79 demonstrates that the YBOCS score decreased by
7.4 points in die DTMS group and by 5.4 points in the Sham group.
Table 91 presents the adjusted means extracted from the model at the 10-week visit. The YBOCS score decreased by 6 5 points (95% Cl) in the DTMS group versus 4.7 points (95% Cl) in the Sham group, these decreases were both statistically significant. The difference between the treatment groups was not found statistically significant (p-value: 0.1406). The effect size observed is 0.45.
Table 91: Adjusted means of (the change from baseline to 10 weeks in YBOCS (ITT)
Figure imgf000134_0001
Based on the 10 week YBOCS score results, the effect size of the study is 0.45. The DTMS multicenter study may be considered to have a medium effect size, based on the ITT patient cohort. The reduction in the YBOCS of 7.4 points is clinically meaningful and statistical significant compared to the sham and the effect size of 0.45 demonstrates a large enough and consistent enough treatment outcome to be clinically important.
CGI-i, CGI-S and SDS Change From Baseline at 10 Weeks
CGI-I Change From Baseline at 10 Weeks
The CGI Improvement results are maintained 4 weeks after treatment at the 10 week visit. Thai is, 72.5% of the DTMS subjects maintained some clinical improvement. Although, those subjects reporting a moderate to very much "Improved” clinical state remained much higher in the DTMS group (47.5% of DTMS subjects versus only 31.8% in the Sham group), this was not statistically significant at 10 weeks.
Table 92 below presents the adjusted means extracted from the model at the 10-week visit. The CGI-I score at the 10 weeks visit was 3.6 points (95% Cl) in the DTMS arm and 3.8 points (95% Cl) in the control arm. The difference between the treatment arms is not statistically significant (p-value: 0.4351). Table 92: Adjusted moans at the 10 weeks visii in CG i i (ITT)
Figure imgf000135_0001
CGI-S Change From Baseline at 10 Weeks
The CGI Se verity results are maintained 4 weeks after completion of the DTMS treatment at the 10 week visit (Table 85). That is, 62.5% of the DTMS subjects maintained an“Improvement” in their CGI-S scores compared to 61% at 6 weeks. And although, those subjects reporting an“Improved” clinical status remained much higher in the DTMS group (62.5% of DTMS subjects versus only 50% in the Sham group), this was not statistically significant at 10 weeks.
Table 93 presents the adjusted means extracted from the model at the 10-week visit. The CGI- S decreased by 0.95 points (95% Cl) in the DTMS group and by 0.76 points (95% Cl) in the Sham group, these decreases were both statistically significant. The difference between the treatment groups is not statistically significant (p-value: 0.4251).
Table 93: Adjusted means of the change from baseline to 10 weeks in CGI-S (ITT)
Figure imgf000135_0002
SDS Change From Baseline at 10 Weeks
Table 94 presents the adjusted means extracted from the model at the 10-week visit. The SDS decreased by 2.6 points (95% Cl) in the DTMS group and by 3.5 points (95% Cl) in the Sham group. The difference between the treatment groups was not found statistically significant (p-value: 0.4469).
Table 94: Adjusted means of the change from baseline to 10 weeks in SDS (ITT)
Figure imgf000135_0003
Remission Rate at 6 Weeks
The Remission Rate at the 6 week visit, are presented in Table 95. Remission rate was defined as a YBOCS score of less than (<) 10.
In ease of missing YBOCS score at the 6 weeks visit, the Last Observed Value (LOV) method was used. Table 95: Remission Rates at the 6 Week Visit (ITT)
Figure imgf000136_0001
The Remission rate at the 6 week w¾s 4.65% in the DTMS group and 8.16% in the Sham group. This difference was not statistically significant p=0. 4960(chi-squared test).
Exploratory Efficacy Endpoints HDRS-21 Score
The exploratory efficacy end-point as dictated in the study protocol w¾s the change from baseline in HDRS- 21 scores to 6 and 10 weeks. Table 96 sho 's the unadjusted HDRS-21 scores at each visit along w'ith the change from baseline in HDRS-21 scores.
Table 96: HDRS-21 Score And Change From Baseline (ITT)
Figure imgf000137_0001
Table 97 presents the adjusted means extracted from the model at the 6 and 10 week visits for the ITT analysis sets. The differences within the treatment arms and between the treatment arms were not statistically significant. As the majority of the study subjects did not suffer from co- morbid Major Depressive Disorder (MDD) (mean HDRS-21 score at baseline in both treatment groups was 10), we do not expect any significant changes or improvements in HDRS-21 score due to the treatment in non-MDD patients. Furthermore, we can infer that the improvement in OCD was not as a result of an improvement in depression.
Table 97: Adjusted means at the 6 weeks visit in HDRS-21 (ITT)
Figure imgf000137_0002
Remission Rate (YBOCS score < 8)
Remission rate at the 6 week visit, where remission is defined as YBOCS score < 8 was defined in the study protocol as an exploratory endpoint. The results of the Remission Rates defined as YBOCS < 10 did not show results that justified performing this statistical analysis.
Response Rate and Remission Rate at 10 Weeks
The Response rate, Partial Response rate and Remission rate at the 10 week visit, are presented in Table 98 Table 98: Response, Partial Response and Remission Rates at 10 Week Visit (ITT)
Figure imgf000138_0001
Figure imgf000138_0002
The Response rate at the 10 week visit in the DTMS group is 44.19% versus 22.45% in the Sham group. This difference is statistically significant p=0.0265 (chi-squared test). There was also a further increase in the response rate at the 10 week visit (44.19%) in the DTMS group compared to the 6 week visit (37.2%), demonstrating a further positive treatment effect overtime. The Partial Response rate at the 10 week visit in the DTMS group is 58.1 % versus 46.9% in the Sham group. This difference is not statistically significant p=G.2832 (chi-squared test).
The Remission Rate at the 10 week visit in the DTMS group is 9.3% versus 6.1% in the Sham group.
This difference is not statistically significant p==G.5660 (chi-squared test).
EXAMPLE 7
BACKGROUND
Obsessive Compulsive Disorder (OCD) is a chronic and disabling disorder with poor response to pharmacological treatments. Converging evidence suggests that OCD patients suffer from dysfunction of the cortico-striato-thalamo-cortical (CSTC) circuit, including in the medial prefrontal cortex (mPFC) and the anterior cingulate cortex (ACC). Objective: To examine whether modulation of mPFC-ACC activity by deep transcranial magnetic stimulation (DTMS) affects OCD symptoms. Methods: Treatment resistant OCD participants were treated with either high-frequency (HF; 20 Hz), low- frequency (LF; 1 Hz), or sham DTMS of the mPFC and ACC for five weeks, in a double-blinded manner. All treatments were administered following symptoms provocation, and EEG measurements during a Stroop task were acquired to examine changes in error-related activity. Clinical response to treatment was determined using the Yale-Brown-Obsessive-Compulsive Scale (YBOCS).
Results: Interim analysis revealed that YBOCS scores were significantly improved following HF (n = 7), but not LF stimulation (n = 8), compared to sham (n = 8), and thus recruitment for the LF group was terminated. Following completion of the study, the response rate in the HF group (n = 18) was significantly higher than that of the sham group (n = 15) for at least one month following the end of the treatment. Notably, the clinical response in the HF group correlated with increased Error Related Negativity (ERN) in the Stroop task, an electrophysiological component that is attributed to ACC activity. Conclusion: HF DTMS over the mPFC-ACC alleviates OCD symptoms and may be used as a novel thera-peutic intervention. Notwithstanding alternative explanations, this may stem from DTMS ability to directly modify ACC activity.
METHODS AND MATERIALS
Procedure
The experiment included baseline clinical and electrophysiological measurements in 41 OCD patients, a 5- weeks treatment phase, corresponding measurements, and a one month follow-up phase. The study was performed at Chaim Sheba Medical Center, Israel (20l2e20l4), and the protocol was approved by the local Institutional Review Board and the Israeli Ministry of Health.
Participants
Forty one OCD participants who met stage III criteria (failure of two SRI trials plus CBT, Table 100) were recruited via newspapers and internet advertisements, and from the outpatient program at Chaim Sheba Medical Center. The inclusion criteria were: 18-65 years old; current DSM-IV diagnosis of OCD; a score of >20 in the Y-BOCS (20 items); CBT at maintenance phase (if conducted); and stable SSRI medications maintenance for 8 weeks prior to enrollment, and unchanged during treatment. Exclusion criteria included any other Axis-I psychopathology or a current depressive episode. All participants signed a written informed consent form.
Clinical procedure
All participants underwent clinical assessment that included the Mini-International Neuropsychiatric Interview (MINI), the Yale-Brown-Obsessive-Compulsive Scale (YBOCS), anIQ assessment using the Raven's Progressive Matrices test (RSPM), the Hamilton's depression rating scale (HAM-D; 24-item), and the Clinical Global Impressions of severity (CGI-S). Participants were randomly assigned to receive 1 Hz stimulation (LF), 20 Hz stimulation (HF), or sham stimulation, using a computer program (Interactive Web Randomization System; Medpace's ClinTrak, USA). All groups were treated five times per week for five weeks (for a total of 25 sessions), and each treatment session began with an exposure to personalized obsessive-compulsive cues.
The primary and secondary efficacy measures, YBOCS and CGI-I, were performed at baseline (pre-treatment), prior to the second treatment session in weeks 2-4, prior to the last treatment session (post-treatment), and at 1- week and 1 -month follow-ups (1 W and 1M FU) visits. Evaluations were performed by clinically trained raters in a blinded manner, and the efficacy outcome in these measures was the change from Pre-to Post-treatment. For YBOCS, the clinical response was defined as a reduction of 30%. This threshold was set in accordance with the literature, taking into account the study population (stage III criteria). Nevertheless, results using the more common threshold of 35% reduction in YBOCS scores are also reported. For CGI-I, response was defined as a score<2 (very much improved or much improved).
Provocation of OCD symptoms
The effects of DTMS seem to be most pronounced when the targeted circuit is active. For example, a brief exposure to the traumatic memory in post-traumatic stress disorder (PTSD) participants, or to smoking cues in heavy smokers, increased treatment response compared to the unexposed group. This phenomenon can be explained, at least in part, by accumulating evidences suggesting that items that are stored in long-term memory become prone to change (e.g., by stimulation) upon their retrieval (e.g., following provocation).
Specifically for OCD, hyperactivity of different components of the CSTC circuit was observed following symptom provocation. Therefore, prior to each session a provocation was administrated by the operator. For each patient, a list of personalized provocations was designed by a clinician during the first assessment meeting. These provocations were designed to achieve a self-report score between 4 and 7 on a 1 to 10 visual analog scale (VAS), and were recorded on the case report forms (CRFs). Following each treatment, participants were allowed to perform any relevant ritual they desired.
Deep rTMS
DTMS offers a non-invasive tool to stimulate deep-located re-gions such as the ACC. DTMS was administered using a Magstim Rapid2 TMS stimulator (The Magstim Co. Ltd., Whitland, Carmarthenshire, United Kingdom) equipped with an H7-coil (specifically designed to stimulate the ACC).
During each DTMS session, the optimal spot on the scalp for leg motor cortex stimulation was localized, and the leg resting motor threshold (RMT) was defined. The coil was then moved forward 4 cm anterior to the motor spot and aligned symmetrically over the mPFC. HF and LF stimulation trains of pulses were delivered at 100% and 110% of the leg RMT, respectively (different intensities were employed for safety reasons, taking into account patients with augmentation medications such as D2 antagonists and the higher risk for HF stimulation). HF (20 Hz) sessions consisted of 50 trains lasting 2 s each, with an inter-train interval of 20 s (2000 pulses in total), while LF (1 Hz) sessions consisted of 900 consecutive pulses. Sham stimulation (randomized to mimic either HF and LF stimulation), and the determination of the type of stimulation for each individual (HF, LF or sham) were performed as previously described. Participants were told that physical sensations may be induced by both real and sham coils, operators and raters were blind to the type of treatment, and raters were not allowed to be present during treatments. Following the first treatment, participants were asked to guess which treatment they were assigned to (active\sham) by choosing one of the following answers: 1. 1 do not know, 2. Uncertain that I received active\sham treatment, 3. Strong feeling that I received active\sham treatment. 4. Active\sham group.
Electrophysiological recording during a stroop task
EEG recordings during a Stroop task were performed at Pre- and Post-treatment time-points. The Stroop task was administered using E-Prime software (Psychology Software Tools, Inc.) on a 17 inch computer screen, as previously described. Participants were instructed to press the key associated with the color of the word while ignoring the word's meaning. EEG was recorded using the ASA lab (A.N.T. Enschede, Netherlands), with a 32 channels cap (Waveguard) and two Electrooculography (EOG) channels. Electrode impedances were kept below 10 KU, and all channels were average referenced. Data were collected at 250 samples per second and digitized with a 24-bit AD converter.
EEG analysis
In brief, continuous EEG data were filtered using 1-100 Hz band-pass and 50 Hz notch, and were segmented into trials that were time-locked to the participants' response. The segmented data were baseline corrected, and noisy segments or channels were removed. Data were then gathered according to conditions (congruent/incongruent), divided by response type (correct/mistake) and filtered to the theta band (4-8 Hz). Since most of the mistakes (93%) were made within the incongruent trials, analysis was carried out solely for this condition. The amplitudes following responses (0-120 ms) were computed using an adaptive mean measure. In addition, we used a wavelet transform analysis to convert the data from a time to a frequency domain. Thus, the mean theta power from the Cz electrode, ranging between 0 and 120 ms post response, was converted to decibels (dB), and the power spectral perturbation was expressed as a change from baseline (in dB). All EEG analysis was performed using MATLAB's EEGLAB toolbox.
Statistical analysis
Data analysis was performed using STATISTICA software, version 12 (StatSoft, Tulsa, OK).
Interim analysis - In an attempt to maximize the clinical benefit to the participants, an interim analysis was carried out midway through the experiment (n = 7, 8, and 8 for the HF, LF, and sham groups, respectively). We used a mixed model ANOVA with Group (HF, LF and sham) and Time (baseline and weeks 2-5) as independent variables and YBOCS scores as the dependent variable. Thereafter, we performed a 3X2 ANOVA analysis with Group (HF, LF and sham) and Time (Pre- and Post-treatment) to compare the effect of stimulation. Following this analysis, the LF group was excluded from the study due to the lack of consistent response in this group (as detailed below) and given the limited rate of recruitment of the study population.
Final analysis - For the behavioral data, we used a mixed-model ANOVA with Group (HF and sham) and Time (baseline and weeks 2-5) as independent variables, and the scores of YBOCS and CGI-I as dependent variables. Significant results were further analyzed with Tukie post-hoc. Analyses of 1 W and 1M FU results were compared using T-tests and the required p value for significance was corrected (pc) for the relevant number of comparisons. Chi-square test was used to compare blinding and response rates.
EEG amplitude and power were analyzed using a mixed-model measure ANOVA with Group (HF and sham), Time (Pre- and Post-treatment), and Response type (correct and mistake) as independent variables, and with theta band dB mean power (0-120 ms post response) as the dependent variable. Significant results were further analyzed using Tukey post-hoc. All data are presented as mean±SEM.
RESULTS
The three groups did not differ in their baseline characteristics of gender, age, IQ, concomitant medication, depression, or OCD severity (Table 99). No severe adverse events were recorded, and the treatment was well- tolerated by most participants. Side-effects that included headaches and fatigue were reported by four participants (three from the HF group and 1 from the sham group). Three participants dropped out during treatment - one due to conflicting schedule (sham group) and two due to inconvenience with the treatment (HF group). Thus, the final analysis consisted of 38 participants (out of 41 randomized) that completed the treatment (see Consort chart in Figure 25). Most of the participants did not guess which group (active \ sham) they were assigned to (75%, 88% and 86% chose option #1 (“I don't Know”) from the LF, HF, and sham groups, respectively; C2 1/4= 0.66, p1/4 = 0.71). One participant out of each group correctly chose option #2 (uncertain that I received active\sham), and one out of each group falsely chose option #3 (Strong feeling that I received active\sham treatment). These percentages imply that the blinding process was well established.
Interim analysis
Repeated measures analysis for the five weeks of treatment revealed a near significant Group X Time interaction (F8, so 1/4 = 1.81, p < 0.08), and analysis comparing the change from Pre to Post treatment revealed a near significant effect for the HF (F^ 20 = 5.38, p = 0.055), but not for the LF (T 20 = 1.23, p = 0.28) treatment over sham (see Figure 26). Taking into account the lack of trend in the LF group, the fact that 2 out of 8 patients in the LF group demonstrated an increased YBOCS score following treatment, and given the limitation of resources and slow recruitment rate, the LF arm of the study was omitted. Further recruitment was carried out only for the HF and sham groups, using the same double-blind arrangements, and all forthcoming analysis will compare the results of these two groups. Table 99
Baseline demographic and clinical characteristics.
Sham LF"‘ HF p
Sample size 14 8 16
Female\Male 7/7 4/4 7/9 n.s.
Age 35 ± 3.5 28 ± 3.1 36 ± 2.1 n.s.
Raven IQ 38 ± 5.8 34 ± 6.3 47 ± 6.6 n.s.
YBOCS 26 ± 1 25 ± 1.2 28 ± 0.7 n.s.
HAMD-21 9 ± 0.88 10 ± 1.2 9 ± 0.97 n.s.
CGI - S 5 ± 0.6 5 ± 0.5 5 ± 0.5 n.s.
D2 antagonist augmentation 6/14 3/8 5/16 n.s
YBOCS, YaleeBrown Obsessive Compulsive Scale; HAMD-24, Hamilton Depression
Rating Scale e 24-item; CGI-S, Clinical Global Impression e Severity. All means are accompanied with SEM scores.
a See interim analysis for differences in sample size.
Final analysis
Sixteen participants in the HF group and 14 participants from the sham group completed all stages of the study and were included in the final analysis.
Clinical results
The primary analysis for the efficacy of the treatment was the percent change in YBOCS scores. This analysis revealed a significant Group X Time interaction (F4, 112 = 7.81, p < 0.001), and a post-hoc analysis revealed significant differences between the groups at weeks 4 (p < 0.01) and 5 (p < 0.01; Figure 2 la). In accordance with these results, a significantly higher proportion of participants from the HF group (seven participants; 43.75%) compared to the sham group (one participant; 7.14%) reached the predefined response criteria (i.e. 30% reduction in YBOCS relative to baseline) after five weeks of treatment (c2 = 5.11, p < 0.05; Figure 2 lb). Calculating the response rate using the more restrictive criteria of 35%, we found that five participants (29.41%) from the HF group and one participant (7.14%) from the sham group were defined as responders (C2 1/4= 2.71, p < 0.10).
Analysis of the YBOCS scores during follow-up visits revealed a significant difference between the HF and sham groups at the 1 W FU visit (n = 11 and 13, respectively; t22 = 3.46, pc < 0.05). At this time point, 5 participants (45.45%; only one with less than 35% score reduction) of the HF group and 1 participant (7.69%) from the sham group were defined as responders (C2 1/4 = 4.53, p < 0.05). During the 1M FU, YBOCS scores continued to be stable, but significance was lost (n = 9 and 9, respectively; tie = 2.06, pc < 0.6). At this time point, 4 participants (44.44%; only one with less than 35% score reduction) of the HF group and none of the participant from the sham group were defined as responders (C2 1/4 = 5.14, p < 0.05).
Analysis of the CGIel scores revealed a significant main effect for Group (F 1^4 =10.55, p < 0.01; Figure 2lc). In accordance with this result, a significantly higher proportion of participants from the HF group (11 participants; 64.7%), compared to the sham group (one participant; 7.1%), reached the predefined response criteria after five weeks of treatment (C2 1/4 = 11.80, p < 0.001; Figure 2ld). Here again, there was a significant difference between the HF and sham groups in the 1 W FU 620 = 3.40, pc < 0.05), while 1M FU scores remain low but without a significant difference between the groups (tie = 2.23; pc = 0.23). During the 1 W FU, 7 participants (63.63%) of the HF group and 1 participant (7.69%) from the sham group were defined as responders (c2 = 8.39, p < 0.01); while during the 1M FU, 5 participants (55.55%) of the HF group and 3 participants (33.33%) from the sham group were defined as responders (C2 1/4 = 0.9, p < 0.35).
Stroop-EEG analysis
We excluded from the analysis patients who had more than 90% mistakes (2 from the HF group and 3 from the sham group), and patients who had no mistakes at all (1 from HF group and 2 from the sham group). Thus, the final ERN analysis included 13 participants from the HF group and 9 participants from the sham group, with no differences in behavioral mistake percentage at baseline (13 ± 3.4% and 8 ± 2.3%, respectively), or following treatment (14 ± 2% and 12 ± 2.5%, respectively). The ERN response expressed in the theta band (0-120 ms post response) was similar in both groups at baseline, but there was a shift towards increased ERN in the HF group, and decreased ERN in the sham group following treatment (Figure 22). Analysis of the theta power revealed a significant Group X Time X Response interaction (Fl; 20 = 4.11, p < 0.05); and post-hoc analysis revealed significant post treatment differences between the groups. Specifically, theta activity in response to a mistake following treatment was higher in the HF group when compared to that of the sham group (F 1.20 = 6.8, p > 0.01; Figure 23). Notably, the effect of treatment on ERN correlated with its effect on symptom severity in the HF group (r = 0.63, p < 0.01), but not in the sham group (1= -0.42, p < 0.26; Figure 24). Finally, a secondary analysis revealed gender differences in response to treatment, such that men were significantly more prone to respond than women (see Figure 27).
DISCUSSION
The present study is the first to explore the safety, tolerability, and efficacy of multiple sessions of DTMS in the treatment of OCD. The results indicate that HF stimulation over the mPFC and ACC is a safe and effective intervention for the alleviation of OCD symptoms in participants who failed to receive sufficient benefit from previous treatments. We found that compared to sham treatment, the response rate following HF treatment was significantly higher for up to one month, and that the reduction in symptoms severity was related to the magnitude of changes in the ERN response.
In this study, both HF and LF DTMS using the H7 coil turned out to be safe and overall well tolerated by OCD participants. No severe adverse events such as seizures occurred, and the most frequent side-effects included mild headaches during, or immediately following, stimulation; a pattern that is in line with a recent comprehensive review. In addition, response within the sham group was very low and in agreement with former sham-controlled TMS studies, implying that the obtained results are due to stimulation and are not merely a consequence of provocation-induced exposure therapy.
The fact that HF stimulation was superior over LF stimulation seems counterintuitive, as it would be expected that reducing excitability, rather than increasing it in the hyperactive mPFC and excitability, rather than increasing it in the hyperactive mPFC and ACC of OCD patients would induce a therapeutic effect.
Nevertheless, cumulative data suggest that the notion of excitatory HF vs. inhibitory LF stimulation is oversimplified. High- frequency stimulation, which is considered to be excitatory, can also disrupt neural activity, and was shown to be a more effective tool when attempting to induce long-term clinical effects. For example, in cigarette smokers high (but not low) frequency rTMS directed to the insula reduced cigarette consumption which mimics the effect of damage to this area. In addition, stimulation of the SMA with both LF and HF were shown to reduce YBOCS scores in OCD patients, and several other studies reported successful intervention by either HF or LF targeting the right, left or bilateral DLPFC or the left OFC, while others reported no difference between real or sham stimulation.
One mechanism that can explain the observed results is that neuromodulations induced by HF stimulation in the mPFC and ACC reinforced participants' ability to exert inhibitory control over their compulsive behavior. An additional factor that may contribute to the effect of stimulation is the state of the relevant neuronal circuit. Specifically, the DTMS procedure that was applied here may interfere with the dysfunctional information flow in the frontal-basal ganglia circuit, which is mediated by the ACC and was suggested to be a core pathology of OCD. According to this hypothesis, initiation of behavioral sequences that are stored in the PFC results in motivational distress that is only relieved upon completion of the sequences. However, in OCD participants, hyperactivation of the ACC retards the feeling of completion and generates the compulsive behavior. Accordingly, the protocol described herein may disrupt circuits associated with the feeling of incompleteness and may alter the dysfunctional monitoring activity. Consistent with this hypothesis, our results imply that the beneficial effect of the treatment was associated with modified theta activation over the mPFC and the ACC, which is considered to be the generator and the locus of the ERN response. Particularly, the HF treatment resulted with increased ERN theta activity that was correlated with reduction of symptom's severity. To the best of our knowledge, no TMS protocols or pharmacological interventions have shown such a change in ERN signal in OCD patients. Here again, the finding is somewhat counterintuitive considering that enhanced ERN is generally elicited in OCD participants in comparison to control, and that general hyper-activation of the ACC is commonly found in OCD participants. Patients treatment history
Table 100. Pharmacological characteristics of patients from High Frequency (HF), Low Frequency (LF)
Figure imgf000146_0001
Sham stimulation and blinding
Sham stimulation (randomized to mimic either HF and LF stimulation) was performed using a sham coil that is placed within the same helmet as the real coil, but induces only negligible electric fields in the brain. Participant were told that physical sensations may be induced by both real and sham coils. In addition, operators were blind to the type of treatment, which was determined by a magnetic card that was individually assigned following randomization using a computer program (Interactive Web Randomization System; Medpace's ClinTrak, USA)
The Stroop task
The Stroop task was administered using E-Prime software (Psychology Software Tools, Inc.) on a 17 inch computer screen, and included a response pad with four keys. During the task, the words‘red’,‘green’,’yellow’ and‘blue’ were presented with their respective color (congruent condition), or in one of the three other colors (incongruent condition), in a balanced manner (50- 50 chance). Participants were instructed to press the key associated with the color of the word while ignoring the word’s meaning.
EEG analysis
Continuous EEG data were filtered using 1 - 100 Hz band-pass and 50 Hz notch, and were segmented into trials that were time-locked to the participants' response (2 seconds epochs, 1 second before and 1 second after the participant response). The segmented data were baseline corrected (at -300 ms to -70 ms before the event), and noisy segments or were manually inspected and removed. Subsequently, the data were decomposed using Independent Component Analysis (ICA), in which eye blinks and horizontal eye movements were excluded. A second manual inspection was then performed and residual artifacts were removed. Excluded channels were replaced with spherical interpolation of the neighboring channels values. In order to analyze ERPs for the Stroop task, data were then gathered according to conditions (congruent/incongruent), divided by response type (correct/mistake) and filtered to the theta band (4-8 Hz). Since most of the mistakes (93%) were made within the incongruent trials, analysis was carried out solely for this condition. The ERN was computed as the amplitude difference between correct and mistake conditions, which generally range between 50-150 ms.
However, in order to determine the optimal time window of the ERN signal for our sample, we calculated a combined ERN of all participants; an analysis revealed a time window of 0-120 ms post response. Within this time window, the amplitudes following correct and mistake responses were computed using an adaptive mean measure, which is a fixed time window (60 ms) surrounding the negative peak for each subject. In addition, we used a wavelet transform analysis to convert the data from a time to a frequency domain. Thus, the mean theta power from the Cz electrode, ranging between 0 and 120 ms post response, was converted to decibels (dB). The power spectral perturbation was expressed as a change from baseline (in dB). All EEG analysis was performed using MATLAB’s EEGLAB toolbox. Supplementary results
Interim analysis for the clinical effect of the treatment
In an attempt to maximize the clinical benefit to the participants, interim analysis was carried out midway through the experiment (n=7, 8, and 8 for the HF, LF, and sham groups, respectively).
We used a mixed model ANOVA with Group (HF, LF and sham) and Time (baseline and weeks 2-5) as independent variables and YBOCS scores as the dependent variable. This analysis revealed a near significant Group X Time interaction (F8, 80=1.81, p<0.08). Thereafter, we performed a 3X2 ANOVA analysis with Group (HF, LF and sham) and Time (Pre and Post treatment) to compare the effect of stimulation. This analysis revealed near significant effect for the HF (Fl, 20=5.38, p=0.055), but not the LF (Fl, 20=1.23, p=0.28) treatment (Figure 26).
Taking together with the fact that 2 out of 8 patients in the LF group demonstrated increased YBOCS score following treatment, and due to limitation of resources and slow recruitment rate, the LF arm of the study was omitted.
Secondary analysis
In the attempt to distinguish between responders and non-responders, we divided the HF group accordingly and compared the behavioral and electrophysiological data of these two subgroups. Surprisingly, despite the small sample size, we found statistically significant gender differences in response to the treatment, such that men were more prone to respond. More specifically, the rate of response was 66.66% (six out of nine) for men and
14.28% (one out of seven) for women (c =4.39, p<0.05; Figure 27). Calculating response rate using the more restrict criteria of -35%, we found that four men (44.44%) and one women (14.28%) were defined as responders (c2=2.80, r<0.10). No other differences that distinguished between these subgroups or between men and women were found. Despite the small sample size, these findings may suggest a role of gender in the neuronal pathophysiology of OCD, and to the best of our knowledge, this is the first time such gender differences are reported in this disorder. Further research is needed to validate this finding, and we encourage fellow investigators to revisit imaging and treatments data and to analyze for possible gender differences in their samples.
EXAMPLE 8
This example details an FDA-regulated multi-center double-blind randomized controlled study, wherein 99 participants received 29 daily sessions of repetitive high-frequency or sham stimulation using a unique deep TMS coil which is designed to stimulate the medial prefrontal and the anterior cingulate cortices. In addition, to specifically affect the relevant neuronal pathways and increase the chance of response, all stimulation sessions were conducted following a tailored and personalized symptoms provocation. Our experiment demonstrates that, compare to sham, real stimulation greatly reduces symptom severity by the end of the treatment, with response rates that remained significantly different for at least an additional month. We discuss several potential mechanisms involving TMS-induced neuroadaptation which could account for these significant therapeutic effects.
These results provide a thorough experimental examination of behaviorally tailored exposure along with the use of deep TMS stimulation for OCD, and to the best of our knowledge is the first to report an enduring effect on OCD refractory patients. Notably, the study led to FDA clearance of the treatment.
Objective: Obsessive Compulsive Disorder (OCD) is a chronic and disabling disorder that often unsatisfactorily responds to pharmacological and psychological treatments. Converging evidence suggests that patients with OCD suffer from dysfunction of the cortical-striatal-thalamic-cortical circuit. Here, we validated the therapeutic effect in a large double-blind, sham-controlled, FDA-regulated, multicenter study.
Methods: At 11 centers, 99 treatment-resistant OCD patients (age 22-68) were randomly allocated to either high-frequency (20Hz) or sham dTMS, and were daily treated for six weeks following individualized symptom provocation. Clinical response to treatment was determined using the Yale-Brown-Obsessive-Compulsive Scale (Y-BOCS), and the primary efficacy end-point was the change in this scale from baseline to post treatment. Additional measures were response rates at post-treatment and following another month of follow up. Results: Reduction of Y-BOCS scores in patients who received active dTMS treatment was significantly larger than that of patients who received sham treatment (-6.0 vs. -3.3, p=0.0l), with response rates of 38.1% and 11.1%, respectively. Significant differences between groups were maintained at follow-up.
Conclusion: High-frequency dTMS over the mPFC and ACC significantly improves OCD symptoms and represent a novel therapeutic intervention for patients who do not satisfactorily respond to adequate pharmacological and psychological interventions.
Methods
Study Design and Timeline
The study was conducted at 11 sites: 9 in the United States, 1 in Israel, and 1 in Canada. The study was approved by local institutional review boards and was registered at clinicaltrials.gov (NCT02229903). It consisted of three phases: a 3-week screening phase (Pre), a 6-weeks treatment phase (Post; consisted of five weeks of daily treatments and 4 treatments during the sixth week to a total of 29 treatments), and a 4-weeks follow-up phase (FU).
Patients
One hundred patients were recruited using web advertisements and referrals from local physicians. Eligibility criteria included: 22-68 years old, DSM-IV confirmed diagnosis of OCD, treated in an outpatient setting, and Y-BOCS score >20. Serotonin reuptake inhibitors (SRIs), anti-depressants, and D2 or D2-5HT2 antagonist medications were allowed, but doses could not be changed for at least 2 months prior to enrollment and throughout the study. The main exclusion criteria included any primary Axis I diagnosis other than OCD, severe neurological impairment, and increased risk of seizures. All patients provided written informed consent after receiving a complete description of the study.
Eligible Subjects were randomized into the study by center. After subjects met the eligibility criteria, they were equally allocated (with a 1 : 1 ratio) to one of the 2 treatment groups (Sham or Active dTMS), based on a stratified randomization scheme using the SAS (version 9.4) random number generator. A central Interactive Web-Based Randomization System (IWRS) was developed for the current study and was validated according to the IEEE Standard for Software Development and Test Documentation. Site users entered the IWRS by using their user identification (ID) and password provided by the CRO. The system recognized the user site automatically by the unique user identification. Users were then asked to enter the requested subject details (eligibility code, subject's initials, subject's ID, Date of Birth and Motor Threshold level). Based on this information, the IWRS assigned a unique subject randomization code, which determined the treatment assignment for the subject. The unique subject randomization code matched one of the pre-programmed treatment cards maintained at the clinical site. The operator was then asked to take the treatment card with the same randomization code from the box of pre-programmed treatment cards and to complete the subject ID on the card label and place the treatment card inside the subject's Operator Binder.
Assessments
Clinical severity rating scales included the Y-BOCS, Hamilton Depression Rating Scale (HDRS-21), Sheehan Disability Scale (SDS), Clinical Global Impression - Severity (CGI-S), and CGI - Improvement (CGI-I). Safety evaluations included monitoring of adverse events, vital signs assessment, physical and neurological examinations, urine pregnancy tests, and the Scale for Suicidal Ideation (SSI). All raters underwent a uniform training program and certification for the administration of the rating scales.
Personalized symptoms provocation
Following previous studies, a 3-5 minutes individualized symptom provocation was performed before each treatment in order to activate the relevant neuronal pathways. The provocations were designed in a multi-step process to ensure they were tailored for every patient in a similar fashion. They were created in a ninety -minute session by the certified Y-BOCS rater(varing degrees) and site PI (psychiatrist) for each patient during the first assessment meeting, based on the main obsessions and compulsions the patient described during that meeting and submitted to the central expert rater for prior to randomization. The steps were as follows: Detailed Y- BOCS symptom checklist, draft symptom list, complete Y-BOCS severity measure, create hierarchy, develop internal provocations, develop external provocations, and review with the dTMS operators. The patient’s OCD symptomology was collected using the detailed Y -BOCS symptom checklist. The main current OCD symptoms were annotated during the interview to focus on during YBOCS scoring and for creation of provocations. The obsession (such as did I cause harm?) and compulsion (reviewing or checking) that cause the most symptoms, are focused on in detailed fashion to create provocations in an individualized hierarchal fashion, using the most troubling symptoms. In the initial session, ten provocations are designed, five internal and five external. The series of five internal provocations are meant to have escalating difficulty relevant to the individual, generating doubt in the patient by asking questions such as: Is it possible that... ? How can you be sure? Similarly, with the series of five external provocations which are created by using props: Such as a news article opened to a picture of a fire or an accident, leaving an iron plugged in while taking the patient to another room, exposing the patient to a potential contaminant etc. After the provocation, patients are asked regarding the degree of their symptomology on a self-reported visual analog scale (VAS) ranging from 1-10. If it is too low (1-3) they are exposed to a higher severity provocation, including a combined internal-external provocation (a prop with a question). If it is too high (8-10) they are allowed to calm down and if absolutely necessary even perform their compulsion. dTMS treatment is initiated only when they are moderately provoked (4-7) and not performing compulsions.
The tailored provocation was administered prior to each treatment session, after the coil was in the treatment position and lasted between 3-5 minutes. The provocations were delivered by the TMS operators (BA or BS), who were trained about OCD (so as not to give reassurance and strengthen compulsions) and about the patients specific symptomology. The operators had a list of ten provocations to use as a guide, not to be read verbatim. Additionally, they were not to use themselves as a target of the provocation which could ruin the therapeutic alliance. The operator would start with the lowest provocation on the hierarchy, and ask the VAS. If it was too low, they would go to a higher provocation. The provocations used for each treatment, and the outcome self- reported distress score on a 1 to 10 visual analog scale (VAS) were recorded on the case report forms (CRFs).
During the eighteen-minute dTMS session, they are reminded to focus on their thoughts (rather than watch a TV show or read) and not perform compulsions (physical or mental).
Deep TMS intervention
dTMS was administered using a Magstim Rapid2 TMS (The Magstim Co. Ltd., Whitland, Carmarthenshire, United Kingdom) stimulator equipped with a unique H shaped coil design. The H-coil version used in this study was the H7 (HAC) (Brainsway LTD, Jerusalem, Israel). As shown in computer simulations and in electric field measurements in a head model filled with saline solution, when the H7 coil is placed 4 cm anterior to the foot motor cortex and used at 100% of the leg resting motor threshold (RMT), it stimulates the dorsal mPFC-ACC bilaterally. Approximately 70 cm3 of the neuronal volume are stimulated above neuronal activation threshold (100 V/m). Maps of the H7 coil field distribution are shown in Figure 28.
The subjects’ RMT was determined prior to the first treatment and at the beginning of each week by ascertaining the coil position that elicited the minimal involuntary contractions of the feet. The motor threshold was determined visually, but EMG could be used as well. The resting MT was defined as the minimum stimulator output resulting in either foot or toe movement for 3/6 trials. The Active treatment group received 20 Hz dTMS at 100% of RMT, with 2 second pulse trains and 20 second inter-train intervals for a total of 50 trains and 2000 pulses per session. The Sham group received treatment with identical technical parameters, that induced scalp sensations but without penetration of the electric field into the brain, as previously described. Subjects were told that face or hand twitching might occur during applications of protocols of either Sham or Active treatments.
Blinding
Patients, operators, and raters were blinded to the treatment condition (Active or Sham). Each patient was assigned a magnetic card that determined which coil in the helmet would be activated following placement of the helmet over the mPFC-ACC location, and raters were not allowed to be present while treatments were administered. After the first treatment, patients were asked to guess which treatment they were assigned to (Active/Sham) by choosing one of the following answers: 1. Strong belief I received active treatment, 2. Moderate belief I received active treatment, 3.1 do not know, 4. Moderate belief I received Sham treatment, 5. Strong belief I received Sham treatment.
Primary and secondary efficacy objectives
The primary outcome measure of the study was the change in Y -BOCS scores from Pre to Post treatment. The secondary outcome measures were the change in Y-BOCS scores from Pre to FU, full response rates (reduction of > 30% from baseline) and partial response rates (reduction of > 20% from baseline) at Post-treatment, and the change from Pre to Post treatment in CGI-I, CGI-S, and SDS scores. Exploratory outcome measures included the change in HDRS-21 score from Pre to Post treatment and from Pre to FU.
Sample size and power analysis
In the dTMS-OCD pilot study, the mean reduction from baseline to week 5 in YBOCS score was -6.7 points with a standard deviation (SD) of 3.86 points in the Active treatment group, and -1.0 point with a SD of 2.88 points in the control group. A more conservative difference of 3 points between groups was used to calculate the sample size, assuming a standard deviation of 4.0 points. The analysis revealed that a total of 78 subjects (39 per group) would provide a power of approximately 90% at a 5% significance level. The minimum sample size was increased by 20% to 49 subjects per group (for a total of 98 subjects) to account for potential drop outs.
Statistical Analysis
Study Analysis Sets
The intent-to-treat (ITT) analysis set includes all patients randomized to the study who received at least one Active/Sham treatment (even if found to be mistakenly enrolled). The modified intent-to-treat (mITT) analysis set includes all patients randomized to the study who received at least one Active/Sham treatment and met the study eligibility criteria enrollment.
Statistical analyses were performed using SAS (SAS Institute, Cary NC, USA). The principal statistical analysis was performed using a Repeated Measures Analysis (RMA) of covariance approach (SAS® MIXED procedure). The principal statistical analysis consisted of a comparison between the treatment groups' slopes, derived from the time by treatment interaction term from the RMA model. The analysis aimed to compare the Y-BOCS slopes of change from baseline between study arms included the following fixed effects: time from randomization, treatment group, time by treatment interaction, use of SRIs and any other drugs, and/or psychotherapeutic behavioral interventions at enrollment, and baseline Y-BOCS score. The individual subject intercept and the time effects were also included in the model as random effects (random intercept and slope model). The adjusted mean changes from baseline in Y-BOCS scores to 6 weeks post randomization were estimated from the model (LS Means) for each group, as well as the difference between the adjusted means, and are presented together with 95% confidence intervals. Binary efficacy and other categorical measures are compared between the study groups at week 6 (Post treatment) and week 10 (FU) with a chi-squared test or Fisher’s exact test.
Missing data
The primary outcome measure was not evaluated for patients who dropped out prior to randomization. Patients who dropped out after one or more treatments and have data available for the analysis (i.e., at least one post baseline assessment) of continuous variables were analyzed with a repeated measures analysis of variance model using PROC mixed in SAS, which can handle missing data at random. At the Post visit we did not expect a high proportion of drop outs, and thus any missing data at Post-treatment can be considered missing at random. Therefore, for this evaluation, no imputation of missing data was considered beyond the model estimates. Nevertheless, in a case where the missing at random assumption prove to be incorrect at other time points, a sensitivity analysis using other methods for data imputation, such as Fast Observed Carried Forward (FOCF), was performed. In the case of binary variables (such as response and remission rates at Post-treatment and FU), the FOCF method was used. Baseline characteristics of patients who dropped out were assessed by study group to evaluate the potential for differential drop out.
Results
A total of 100 OCD subjects were enrolled in the study (demographic characteristics and drop outs of the ITT analysis are presented in Supplementary Table 101). The ITT sample included 99 randomized patients, whereas the mITT sample included 94 randomized patients (Figure 29).
Baseline Assessment Scale Values
Table 101 shows the distribution of baseline values of all assessment scale data represented in the efficacy analyses, including the Y-BOCS, CGI -I, CGI-S, SDS and HDRS-21 scores. No statistically significant differences were found between the study groups with respect to the baseline efficacy assessment scale data, or to the primary, secondary and exploratory efficacy end-point variables. The baseline HDRS-21 score mean was 10.1 (5.74) and 10.7 (5.47) in the Active and Sham group (respectively), indicating that the patients were not depressed.
Figure imgf000154_0001
Table 101. Demographic data and Baseline measurements of clinical Assessments (ITT)
(*) t-test; Y-BOCS- Yale Brown Obsessive Compulsive Scale; CGI-I- Clinical Global Impression - Improvement; CGI - S- Clinical Global Impression - Severity; SDS- Sheehan Disability Scale; HDRS-21- Hamilton Depression Rating Scale
Primary efficacy analysis
The primary efficacy analysis was conducted on the mITT set. The Y-BOCS score decreased significantly in both the Active (-6.0 points, 95% Cl: [4.0;8. l]) and Sham (-3.3 points, 95% Cl: [l .2;5.3]) groups. The slopes difference between the two groups was statistically significant at Post treatment (2.8 points, p = 0.01) for an effect size of 0.69 (Figure 30). Secondary efficacy analysis
The effect was also present at FU (4 weeks after the end of the treatment), were Y-BOCS score decreased by - 6.5 points (95% Cl: [4.3; 8.7]) in the Active group and by -4.1 points (95% Cl: [l .9;6.2]) in the Sham group (p=0.03) for an effect size of 0.62. Full response rate (YBOCS reduction>30%) at Post treatment in the Active group was 38.1% (n\N= 16\42) versus 11.1% (n\N=5\45) in the Sham group (p=0.003; Figure 31).
The full response rate at FU in the Active group was 45.2% (n\N= 19\42) versus 17.8% (n\N= 8\45) in the Sham group (p=0.0057, chi-squared test). The partial response rate at FU in the Active group was 59.5% (n\N= 25\42) versus 42.2% (n\N= l9\45) in the Sham group (p=0T059, chi-squared test).
The CGI-I categorical analyses demonstrated a significant difference between the Active and Sham groups at Post treatment. Within the Active group, 49% of the subjects (n\N= 20\4l) reported feelings of a moderate to “very much” clinical improvement as compared to only 21% (n\N= 9\43) of the subjects in the Sham group (p=0.0H2; Figure 32).
The CGI-S score was also found to be statistically significant at Post treatment, with higher rates of patients rated‘improved’ in the Active group (61%, n\N= 25\4l) as compared to the Sham group (32.6%, n\N= l4\43; p=0.022l). The positive CGI-I and CGI-S results were also present at the FU visit (CGI-I: 49%, n\N= l9\39 vs. 27.5%, n\N= 11\40) and CGI-S: 64%, n\N= 25\39 vs. 45%, n\N= 18\40), although not statistically significant.
SDS scores decreased by 3.8 points (95% Cl: [l.5;6.1]) in the Active group and by 3.0 points (95% Cl: [0.8;5.3]) in the Sham group from baseline to Post treatment, with no statistically significant difference between the groups.
Exploratory analysis
The majority of patients did not suffer from co-morbid MDD (mean HDRS-21 score at baseline in each treatment group was 10), and in both groups HDRS-21 scores decreased by 2.1 points from Pre to Post treatment with no significant difference.
Blinding Assessment
The most frequent answer of subjects in both groups was that they did not know which treatment they received (44% of subjects in the Active group and 47% of the subjects in the Sham group). Forty-four percentage of the Active group and 31% of the Sham group subjects correctly guessed (had a moderate to strong belief) their assigned treatment, while 12% from the Active group and 22% from the Sham group mistakenly guessed (had a moderate to strong belief) their assigned treatment. Thus, most of the study’s subjects, (66% of the Active group and 69% of the Sham group) were not aware of wrongly guessed the type of treatment they received. In addition, the answer to the treatment type question was not found to correlate with the actual treatment that was received (p=0. l043).
Adverse Events and drop outs
35 subjects (73%) in the Active group and 35 subjects (69%) in the Sham group reported adverse events, with no statistically significant difference (chi-square p-value: 0.6393). The adverse events reported in the study are typical to TMS studies, with the most frequent event of headaches (37.5% of the subjects who received Active treatment and 35.3% of the subjects who received Sham treatment), which did not statistically differ between the treatment groups.
One serious adverse event was reported in the study. After receiving 2 treatments, a subject in the Active group reported having significant suicidal thoughts, which he indicated that had preceded the beginning of the treatment sessions but had neglected to mention prior to study commencement. The investigator and subject decided that hospital admission would be appropriate. The subject claimed his suicidal thoughts/urges were related to escalating problems with his family and not to the study treatments.
The dropout rate was 10% for both groups (Active group: 5\48; Sham group: 5\5 l) with no significant difference between groups.
Discussion
This is the first FDA regulated study of dTMS that explored the safety, tolerability, and efficacy of dTMS in OCD. The results indicate that dTMS stimulation over the mPFC and ACC is a safe and effective intervention for improving OCD symptoms in patients who failed to receive sufficient benefit from treatments with SRIs and CBT. The reduction in Y-BOCS scores was significantly greater at Post treatment and remained significant at FU in the Active as compared to the Sham group. In addition, the positive effect of the treatment was evident as higher response rate and a greater CGI-I and CGI-S results following Active as compared to Sham treatment. The response in the Sham group was low and in agreement with former Sham -controlled TMS studieS. The high-frequency dTMS using the H7 coil was well tolerated by OCD patients. No severe adverse events such as seizures occurred and the most frequent side-effects included mild headaches during, or immediately following, stimulation; a pattern that is in line with a recent comprehensive review.
In a recent meta-analysis based on 17 studies, SRI’s were found to be superior to placebo treatment with an average of the weighted mean difference of 3.2 points change in Y-BOCS score over 10 - 13 weeks. In this regard, our study showed the same effect (a delta of 2.8 points in Y-BOCS between the Active and Sham groups) in a shorter time (6 weeks). Furthermore, the patients that were recruited to this study were non responders to different SRIs and CBT, which imply that dTMS and SRI’s recruit different neuronal mechanism. Our study also included integration of tailored Obsessive-Compulsive exposures as part of the treatment. As described herein, personalized obsessive-compulsive symptom provocation exposures were used at the beginning of each treatment in order to activate the pathological circuitry.
As described herein, the amplitude of the theta frequency band (4-8 Hz) in response to a Stroop task correlated with the amplitude of the change in the Y-BOCS. Corroborating such measures at baseline could be used to predict response and choose the subjects that are most likely to respond favorably to the six-week treatment course described herein.

Claims

In the claims
1. A method for treating a subject afflicted with obsessive compulsive disorder, the method comprising:
(i) inducing a personalized provocation related to at least one of obsessions or compulsions of the subject and
(ii) stimulating brain structures in at least one of an anterior cingulate cortex (ACC) or a medial prefrontal cortex (mPFC) of the subject’s brain after the inducing, wherein the stimulating bilaterally stimulates brain structures in at least one of the ACC or the mPFC of the subject’s brain, wherein the stimulating comprises applying deep transcranial magnetic stimulation (dTMS) to the subject’s skull such that brain structures in at least one of the ACC or the mPFC of the subject’s brain is stimulated, wherein the dTMS is delivered repetitively and at a high frequency comprising at least 5Hz.
2. The method of claim 1, wherein the stimulation is applied immediately after the inducing the personalized provocation; up to 5 minutes after the inducing the personalized provocation; or up to 30 minutes after the inducing the personalized provocation.
3. The method of claim 1, wherein the stimulation is applied 3-5 minutes after the inducing the personalized provocation.
4. The method of any of the preceding claims, wherein the provocation is designed to achieve a score of between 4 to 7 on a 1 to 10 visual analog scale (VAS) self-report and wherein the stimulation is given after a score of 4 to 7 is achieved.
5. The method of any of the preceding claims, wherein the subject is instructed to focus his/her thoughts on the provocation during the stimulation session.
6. The method of any of the preceding claims, wherein the high frequency ranges from 5-25Hz.
7. The method of any of the preceding claims, wherein the high frequency ranges from l8-22Hz.
8. The method of any of the preceding claims, wherein the high frequency is about 20Hz or is 20Hz.
9. The method of any of the preceding claims, wherein the stimulating is effectuated at a stimulation intensity between 80% and 120% of the leg resting motor threshold (RMT).
10. The method of any of the preceding claims, wherein the stimulating is effectuated at a stimulation intensity of 100% of the leg resting motor threshold (RMT).
11. The method of any of the preceding claims, wherein the high frequency is 20Hz dTMS at a stimulation intensity of 100% of leg resting motor threshold (RMT) at a frequency of 2 second pulse trains and 20 second inter-train intervals for a total of 50 trains and 2000 pulses per session.
12. The method of any of the preceding claims, wherein the stimulating of brain structures in at least one of the ACC or the mPFC is sufficient to stimulate interconnecting fibers of the at least one of the ACC or the mPFC of the subject’s brain.
13. The method of any of the preceding claims, wherein the stimulating of brain structures in at least one of the ACC or the mPFC is sufficient to stimulate brain structures in the at least one of the ACC or the mPFC, without a significant increase of electrical fields induced in superficial cortical regions of the subject’s brain.
14. The method of any of the preceding claims, wherein the deep TMS is delivered to each subject’s skull position relative to a location on each subject’s skull identified as corresponding to a stimulation point that stimulates a muscle of the subject’s leg at leg resting motor threshold (RMT).
15. The method of claim 14, wherein the deep TMS is delivered to each subject’s skull 2 cm to 7 cm anterior to the stimulation point that stimulates the muscle of the subject’s leg.
16. The method of claim 14, wherein the deep TMS is delivered to each subject’s skull 4 cm anterior to the stimulation point that stimulates the muscle of the subject’s leg.
17. The method of any one of claims 14-16, wherein the muscle is the tibialis muscle.
18. The method of any of the preceding claims, wherein when the stimulation intensity is 100% of the leg resting motor threshold (RMT) the deep TMS stimulates approximately 70 cm3 of target neuronal volume above neuronal activation threshold.
19. The method of any of the preceding claims, wherein the subject afflicted with obsessive compulsive disorder is selected based on the subject’s baseline amplitude of theta frequency band during and/or following a Stroop task.
20. The method of claim 19, wherein the baseline amplitude of the theta frequency band ranges from 4-8 Hz.
21. The method of any of the preceding claims, wherein the subject afflicted with obsessive compulsive disorder is selected based on the subject’s lack of responsiveness to at least one of serotonin reuptake inhibitors or cognitive behavioral therapy.
22. The method of any of the preceding claims, wherein the stimulation is given in 29 sessions during six weeks.
23. The method of any of the preceding claims, wherein the stimulation is given in between 20 and 30 sessions during between four to six weeks.
24. A device for treating a subject afflicted with obsessive compulsive disorder, wherein the device is as set forth in Figure 33 and wherein the device is configured to deliver deep transcranial magnetic stimulation (dTMS) to the subject’s skull such that brain structures in at least one of the ACC or the mPFC of the subject’s brain is stimulated and wherein the dTMS is delivered repetitively and at a high frequency comprising at least 5Hz.
25. The device of claim 24, wherein the subject has undergone induction of a personalized provocation related to at least one of obsessions or compulsions of the subject.
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