Troriluzole (BHV-4157) in Adult Participants With Obsessive Compulsive Disorder

• Troriluzole (Drug): Troriluzole, 140 mg capsules once daily (QD) orally for the first 4 weeks and 200 mg (140 mg+ 60 mg capsules QD) for an additional 8 weeks
• Placebo (Drug): Matching capsule once daily (QD)

Primary outcomes

• Change From Baseline in the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) Total Score [Baseline, Week 12]: The Y-BOCS is a clinician-administered scale used extensively in research and clinical practice to both rate severity of obsessive compulsive disorder (OCD) and to monitor improvement during treatment. It is designed to rate the severity of obsessions and compulsions as well as the type of symptoms in patients with OCD. The scale consists of 10 items; the first 5 items assess obsessions, and the last 5 items assess compulsions. Subscale scores can be calculated for obsessions and compulsions, each on a scale of 0 to 20. A total score ranging from 0 to 40 can then be correlated to overall severity. The higher the number on the Y-BOCS, the more severe the symptoms.

Secondary outcomes

• Number of Participants With Adverse Events (AEs), Serious AEs (SAEs) and AEs Leading to Study Drug Discontinuation in the DB Randomization Phase [Up to 12 weeks]: An AE is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in participants or clinical investigation participants administered an investigational (medicinal) product and that does not necessarily have a causal relationship with this treatment. An SAE was defined as any event that met any of the following criteria at any dose: death; life-threatening; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect in the offspring of a participant who received study drug; other important medical events that may not have resulted in death, been life-threatening, or required hospitalization, or, based upon appropriate medical judgment, may have jeopardized the participant and may have required medical or surgical intervention to prevent other serious outcomes.
• Number of Participants With Adverse Events (AEs), Serious AEs (SAEs) and AEs Leading to Study Drug Discontinuation in the Open-Label Extension Phase [Up to 192 weeks]: An AE is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in participants or clinical investigation participants administered an investigational (medicinal) product and that does not necessarily have a causal relationship with this treatment. An SAE was defined as any event that met any of the following criteria at any dose: death; life-threatening; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect in the offspring of a participant who received study drug; other important medical events that may not have resulted in death, been life-threatening, or required hospitalization, or, based upon appropriate medical judgment may, have jeopardized the participant and may have required medical or surgical intervention to prevent other serious outcomes.
• Number of Participants With Clinically Significant Laboratory Abnormalities During the DB Randomization Phase [Up to 12 weeks]: Clinically significant laboratory abnormalities were defined as Grade 3 or 4 laboratory test results according to numeric laboratory test criteria found in Common Technical Criteria for Adverse Events Version 5.0 (2017) if available; otherwise, according to Division of Acquired Immune Deficiency Syndrome Table for Grading the Severity of Adult and Pediatric Adverse Events Corrected Version 2.1 (2017). Laboratory tests of clinical interest for troriluzole included absolute neutrophil count < 500 per mm\^3, alanine aminotransferase or aspartate aminotransferase > 3x upper limit of normal (ULN), and total bilirubin ≥ 2x ULN (Laboratory results were presented in US units).
• Change From Baseline in Functional Disability Assessed Using the Sheehan Disability Scale (SDS) Total Score [Baseline, Week 12]: The SDS was assessed in 3 domains: work/school (0-10), social life (0-10), and family life (0-10). The score from each domain was summed into a single dimensional measure of global functional impairment that ranges from 0 (unimpaired) to 30 (highly impaired). If the participant has not worked or studied for reasons unrelated to OCD, then the total score was considered as missing.
• Change From Baseline in Clinical Global Impression of Severity Scale (CGI-S) Score [Baseline, Week 12]: Measures severity of illness at the time of assessment compared with start of treatment. Scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill patients).
• Change From Baseline in the Y-BOCS Obsessions Sub-Scale Score [Baseline, Week 12]: The Y-BOCS Obsessions Sub-scale consists of the last 5 items on the Y-BOCS and is measured on a scale of 0 to 20. A higher score on the Y-BOCS corresponds to greater symptom severity.

Other outcomes

• Change From Baseline in the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) Total Score at Weeks 4 and 8 [Baseline, Week 4 and Week 8]: The Y-BOCS is a clinician-administered scale used extensively in research and clinical practice to both rate severity of obsessive compulsive disorder (OCD) and to monitor improvement during treatment. It is designed to rate the severity of obsessions and compulsions as well as the type of symptoms in patients with OCD. The scale consists of 10 items; the first 5 items assess obsessions, and the last 5 items assess compulsions. Subscale scores can be calculated for obsessions and compulsions, each on a scale of 0 to 20. A total score ranging from 0 to 40 can then be correlated to overall severity. The higher the number on the Y-BOCS, the more severe the symptoms.

Sex: All, ages: 18 Years to 65 Years

Inclusion Criteria:

1. Primary diagnosis of OCD as per the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5).
2. Participants must be currently experiencing non-response or inadequate response to their current standard of care (SOC) medication defined as:

   1. Participant Yale-Brown Obsessive Compulsive Scale total score must be ≥ 19 at screening and Baseline, reflecting moderate or severe OCD symptoms.
   2. Participants must currently be on a SSRI, clomipramine, venlafaxine or desvenlafaxine.
3. Determined by the investigator to be medically stable at baseline/randomization as assessed by medical history, physical examination, laboratory test results, and electrocardiogram testing. Participants must be physically able and expected to complete the trial as designed;
4. Minimum of 6 years of education or equivalent and sufficiently fluent in English to complete necessary scales and understand consent forms;
5. Participants must have adequate hearing, vision, and language skills to perform neuropsychiatric testing and interviews as specified in the protocol;
6. Participants must be able to understand and agree to comply with the prescribed dosage regimens and procedures; report for regularly scheduled office visits; and reliably communicate with study personnel about adverse events and concomitant medications;
7. It is required that all women of child-bearing potential (WOCBP) who are sexually active agree to use two methods of contraception for the duration of the study (i.e. beginning 30 days prior to baseline and extending to 30 days after the last dose of study drug).
8. WOCBP must have a negative serum pregnancy test at screening and a negative urine pregnancy test prior to dosing at Baseline;
9. It is required that men who are sexually active with WOCBP agree to use 2 methods of contraception for the duration of the study (beginning at first treatment and extending to 90 days after the last dose of study drug).
10. The duration of the subject's OCD disease was to be ≥ 1 year.
11. In addition, subjects had to be on stable doses of other psychotropic medication for at least 12 weeks prior to screening.
12. Subjects had to have a Clinical Global Impression of Severity Scale (CGI-S) score of ≥ 4 at screening and baseline.

Exclusion Criteria:

1. Participants should be excluded with a history of more than 2 previous failed treatment trials of SSRIs, clomipramine, venlafaxine, or desvenlafaxine (not including the current SSRI trial) given for an adequate duration at an adequate dose as defined by the following criteria taken from the Massachusetts General Hospital Treatment Response Questionnaire for OCD (MGH-TRQ-OCD) as follows:

   1. Treatment failure / non-response: As per the MGH-TRQ-OCD, there has been minimal or no meaningful clinical benefit as perceived by the participant despite an adequate dose and duration of treatment;
   2. Adequate duration: At least 10 weeks of treatment with SSRI, clomipramine, venlafaxine, or desvenlafaxine
   3. Adequate dose: Defined by the the United States Prescribing Information labeling.
2. Evidence at screening or baseline of any medical or psychiatric condition other than OCD that could predominantly explain or contribute significantly to the subjects' symptoms or that could confound assessment of OCD symptoms
3. Mini Mental State Examination (MMSE) score of < 24 at Screening
4. Current or prior history, per DSM-5 criteria, of bipolar I or II disorder, schizophrenia or other psychotic disorders, schizoaffective disorder, autism or autistic spectrum disorders, borderline personality disorder, antisocial personality disorder, body dysmorphic disorder, hoarding disorder (symptoms of hoarding disorder as part of the OCD diagnosis are allowed, but a primary diagnosis of hoarding disorder is excluded); a current diagnosis of Tourette's disorder is also excluded;
5. Any eating disorder within the last 12 months;
6. Acute suicidality or suicide attempt or self-injurious behavior in the last 6 months;
7. History of psychosurgery, Deep Brain Stimulation (DBS) or Electroconvulsive Therapy (ECT).
8. Transcranial Magnetic Stimulation (TMS) is prohibited within 3 months prior to screening and during the study.
9. Participants who may have received a non-biological investigational agent in any clinical trial within 30 days, or a biological agent within 90 days prior to screening are excluded.
10. Creatinine ≥ 2 mg/dL.
11. Course of treatment for participants with localized cancers (without metastatic spread) is 5 years prior to screening.
12. QTcF (Fridericia) interval ≥ 470 msec during the screening or baseline period or uncontrolled arrhythmia or frequent premature ventricular contraction (PVCs) (> 5/minute) or Mobitz Type II second or third degree atrioventricular (AV) block or left bundle branch block, or right bundle branch block with a QRS duration ≥ 150 msec or intraventricular conduction defect with a QRS duration ≥150 msec or evidence of acute or sub-acute myocardial infarction or ischemia and added or other electrocardiogram findings that, in the investigator's opinion, would preclude participation in the study.
13. Previous treatment with riluzole

Participant flow

Outcome results

• Change From Baseline in the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) Total Score (Primary), Least squares mean, Scores on a scale: Troriluzole - Randomization Phase -5.91 (-7.05 to -4.77); Placebo - Randomization Phase -4.91 (-6.03 to -3.79) (p 0.2202)
• Number of Participants With Adverse Events (AEs), Serious AEs (SAEs) and AEs Leading to Study Drug Discontinuation in the DB Randomization Phase (Secondary), Number, participants: Troriluzole - Randomization Phase 61; Placebo - Randomization Phase 61
• Number of Participants With Adverse Events (AEs), Serious AEs (SAEs) and AEs Leading to Study Drug Discontinuation in the Open-Label Extension Phase (Secondary)
• Number of Participants With Clinically Significant Laboratory Abnormalities During the DB Randomization Phase (Secondary), Number, participants: Troriluzole - Randomization Phase 0; Placebo - Randomization Phase 0
• Change From Baseline in Functional Disability Assessed Using the Sheehan Disability Scale (SDS) Total Score (Secondary), Least squares mean, Scores on a scale: Troriluzole - Randomization Phase -4.68 (-6.01 to -3.36); Placebo - Randomization Phase -3.68 (-4.96 to -2.39)
• Change From Baseline in Clinical Global Impression of Severity Scale (CGI-S) Score (Secondary), Least squares mean, Scores on a scale: Troriluzole - Randomization Phase -0.67 (-0.84 to -0.50); Placebo - Randomization Phase -0.59 (-0.76 to -0.42)
• Change From Baseline in the Y-BOCS Obsessions Sub-Scale Score (Secondary), Least squares mean, Scores on a scale: Troriluzole - Randomization Phase -2.91 (-3.53 to -2.28); Placebo - Randomization Phase -2.55 (-3.16 to -1.93)
• Change From Baseline in the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) Total Score at Weeks 4 and 8 (Other pre specified), Least squares mean, Scores on a scale: Troriluzole - Randomization Phase -3.40 (-4.26 to -2.53); Placebo - Randomization Phase -2.93 (-3.78 to -2.08) (p 0.4508)

Adverse events

Time frame: Randomization Phase: Maximum duration: 12 weeks

Other adverse events by term

Limitations and caveats: The provided results are from the DB Randomization Phase as the Open-Label Extension phase is still on-going.

• Study Protocol (PDF, 2022-10-13)
• Statistical Analysis Plan (PDF, 2020-06-11)