Study to Assess the Efficacy, Safety, and Tolerability of AVP-786 for the Treatment of Intermittent Explosive Disorder

Study Overview
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Brief Summary
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This is a multicenter, randomized, double-blind, placebo-controlled study to evaluate AVP-786 for the treatment of Intermittent Explosive Disorder (IED).

Detailed Description
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Eligible participants for this study must have a diagnosis of current IED. This is a multicenter, randomized, double-blind, placebo-controlled study, consisting of up to 12 weeks of treatment.

Official Title
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A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Assess the Efficacy, Safety, and Tolerability of AVP-786 (Deudextromethorphan Hydrobromide [d6-DM]/Quinidine Sulfate [Q]) for the Treatment of Intermittent Explosive Disorder (IED)

Conditions
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Intermittent Explosive Disorder

Intervention / Treatment
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* Drug: AVP-786
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of current Intermittent Explosive Disorder (IED) according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria, as solicited by the Structured Clinical Interview for DSM-5, Clinical Trials Version At least 3 IED days (at least 1 IED episode each day, as recorded by the participant) per week for the 2 consecutive weeks directly preceding baseline with 70% compliance during that time frame, as assessed by the investigator Score ≥ 12 on the Life History of Aggression scale at screening Score ≥ 6 on the Overt Aggression Scale - Modified Total Irritability at screening and baseline Score ≥ 4 on the modified Clinical Global Impression of Severity for IED at screening and baseline Exclusion Criteria: Diagnosis of major depressive disorder within 6 months of screening Significant symptoms of a depressive disorder or a Patient Health Questionnaire-9 score ≥ 10 at screening Met only the DSM-5 A2 criterion for IED Lifetime history of schizophrenia, schizoaffective disorder, bipolar disorder, antisocial personality disorder, neurocognitive disorder, or mental retardation (DSM-5 criteria) Recurrent IED episodes that are better explained by another mental disorder or attributable to another medical condition (e.g., head trauma, Alzheimer's disease) or to the physiological effect of a substance (e.g., a drug of abuse, a medication) (DSM-5 criteria)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AVP-786<br>Participants were to receive AVP-786-28 (deudextromethorphan hydrobromide [d6-DM] 28 milligrams [mg]/quinidine sulfate [Q] 4.9 mg) once daily (OD) for the first 7 days, followed by AVP-786-28 twice daily (BID) for the next 7 days. Beginning on Day 15, participants were to receive AVP-786-42.63 (d6-DM 42.63 mg/Q 4.9 mg) BID for 10 weeks. | Drug: AVP-786<br>* oral capsules<br>|
| Placebo Comparator: Placebo<br>Participants were to receive placebo BID for 12 weeks. | Drug: Placebo<br>* oral capsules<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Overt Aggression Scale - Modified for Outpatient Use (OAS-M) Total Aggression Score at Week 12 | The OAS-M is a clinical-administered instrument designed to assess various manifestations of aggressive behavior through 2 domains: aggression and irritability. The OAS-M aggression domain includes 4 items: verbal assault, assault against objects, assault against others, and assault against self. The rater determines the frequency of each response (item) during the past week, and the frequency of each item is multiplied by the severity level (0 to 5), producing a raw score. This raw score is multiplied by severity weight for that item (verbal assault x 1, assault against objects x 2, assault against others x 3, and assault against self x 3). Each response is scored using a 6-point scale (0 = no events to 5 = most severe form of assault within that category). The weighted individual item scores are added to obtain the OAS-M Total Aggression score. Higher scores indicate increased aggression. | Baseline; Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the OAS-M Total Irritability Score at Week 12 | The OAS-M is a clinical-administered instrument designed to assess various manifestations of aggressive behavior through 2 domains: aggression, and irritability. The OAS-M irritability domain includes 2 global assessment items: global subjective irritability and global overt irritability. Each response is scored using a 6-point scale (0 = not at all to 5 = extreme). The 2 scores are added to create the OAS-M Total Irritability score (range = 0 to 10). Higher scores indicate increased irritability. | Baseline; Week 12 | 
| Change From Baseline in the OAS-M Individual Items for Aggression at Week 12 | The OAS-M is a clinical-administered instrument designed to assess various manifestations of aggressive behavior through 2 domains: aggression and irritability. The OAS-M aggression domain includes 4 items: verbal assault, assault against objects, assault against others, and assault against self. The rater determines the frequency of each response (item) during the past week, and the frequency of each item is multiplied by the severity level (0 to 5), producing a raw score. This raw score is multiplied by severity weight for that item (verbal assault x 1, assault against objects x 2, assault against others x3, and assault against self x 3). Each response is scored using a 6-point scale (0 = no events to 5 = most severe form of assault). Higher scores indicate increased aggression. | Baseline; Week 12 | 
| Change From Baseline in the OAS-M Individual Items for Irritability at Week 12 | The OAS-M is a clinical-administered instrument designed to assess various manifestations of aggressive behavior through 2 domains: aggression and irritability. The OAS-M irritability domain includes 2 items: global subjective irritability and global overt irritability. Each response is scored using a 6-point scale (0 = not at all; 5 = extreme). Higher scores indicate increased irritability. | Baseline; Week 12 | 
| Change From Baseline in the Number of Intermittent Explosive Disorder (IED) Days Documented by Participants at Week 12 | The IED episodes were to be documented by the participants each evening before bedtime. | Baseline; Week 12 | 
| Change From Baseline in the Number of IED Days as Assessed by the Investigator at Week 12 | The IED episodes were to be documented by the participants each evening before bedtime and reviewed by the Investigator post dose. | Baseline; Week 12 | 
| Change From Baseline in the Number of IED Episodes at Week 12 | The IED episodes were to be documented by the participants each evening before bedtime. If the participant indicated that he/she experienced an IED episode, he/she was to document the number of episodes. | Baseline; Week 12 | 
| Change From Baseline in the Severity of IED Episodes at Week 12 | The IED episodes were to be documented by the participants each evening before bedtime. If the participant indicated that he/she experienced an IED episode, he/she was to document the number of episodes and to rate the severity of the worst episode (0 = not severe at all to 10 = worst severity imaginable). | Baseline; Week 12 | 
| Change From Baseline in the Severity of Distress From Episodes at Week 12 | The IED episodes were to be documented by the participants each evening before bedtime. If the participant indicated that he/she experienced an IED episode, he/she was to document the number of episodes and to rate the severity of distress experienced by the episode(s) (0 = no distress to 10 = worst distress imaginable). | Baseline; Week 12 | 
| Change From Baseline in the OAS-M: Number of Discrete IED Episodes at Week 12 | The OAS-M is a clinical-administered instrument designed to assess various manifestations of aggressive behavior through 2 domains: aggression, and irritability. The OAS-M includes information regarding the number of Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) A1 aggressive episodes, and the number of DSM-5 A2 aggressive episodes experienced by the participants during the past week. The number of discrete IED episodes is calculated after an interview with the participant. Episodes identified as discrete are separated by at least 30 minutes; episodes separated by less than 30 minutes are considered a single episode. | Baseline; Week 12 | 
| Change From Baseline in the Modified Clinical Global Impression of Severity (mCGI-S) Score for IED at Week 12 | The mCGI-S is a modified version of the CGI-S scale that provides a global evaluation of the participant's IED symptoms (e.g., aggression, anger, and irritability). The mCGI-S scale measures the severity of the participant's symptoms from the clinician's perspective in the context of other participants with IED. The mCGI-S responses are scored on a 7- point scale (1 = normal, not at all ill; 2 = borderline ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 7 = among the most extremely ill participants). | Baseline; Week 12 | 
| Change From Baseline in the Modified Clinical Global Impression of Change (mCGI-C) Score for IED at Week 12 | The mCGI-C is a modified version of the CGI-C scale. The clinician rates the overall global change in the participant's IED symptoms (e.g., aggression, anger, and irritability) from Baseline at the scheduled double- blind visits. The mCGI-C responses are scored using a 7-point scale (1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; 7 = very much worse). | Baseline; Week 12 | 
| Change From Baseline in the Modified Patient Global Impression of Severity (mPGI-S) Score for IED at Week 12 | The mPGI-S is a single-question scale. Participants rate the overall global severity of their IED symptoms (e.g., aggression, anger, and irritability) using a 7-point scale (1 = normal, no symptoms; 2 = borderline symptoms; 3 = mild symptoms; 4 = moderately bad symptoms; 5 = markedly bad symptoms; 6 = severely bad symptoms; 7 = extremely bad symptoms). | Baseline; Week 12 | 
| Change From Baseline in the Modified Patient Global Impression of Change (mPGI-C) Score for IED at Week 12 | The mPGI-C is a single-question scale. Participants rate the overall global change in their IED symptoms (e.g., aggression, anger, and irritability) from Baseline at the scheduled double-blind visits. The mPGI- C responses are scored using a 7-point scale (1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; 7 = very much worse). | Baseline; Week 12 | 
| Change From Baseline in the Sheehan Disability Scale (SDS) Score at Week 12 | The SDS is a 3-item, participant-rated questionnaire used to evaluate impairments in the domains of work/school, social life or leisure activities, and family life or home responsibility. Participants rate the degree of impairment in work/school, social life or leisure activities, and family life or home responsibility as a result of IED symptoms using a visual analogue scale (0 = no impairment; 1, 2, 3 = mildly; 4, 5, 6 = moderately; 7, 8, 9 = markedly; 10 = extremely). Only those score categories with at least one participant with event are reported. | Baseline; Week 12 | 
| Change From Baseline in the Short-Form 12-Item Health Survey (SF-12) Score at Week 12 | The SF-12 is a 12-item, participant self-rated questionnaire used to measure the general health status and quality of life. The SF-12 includes questions to measure the effects of health on physical functioning, role limitations due to physical health, bodily pain, general health perception, vitality, social functioning, role limitations due to emotional problems, and mental health. Scores range from 0 to 100. Higher scores indicate better health status. | Baseline; Week 12 | 
| Change From Baseline in the State-Trait Anger Expression Inventory-2 (STAXI-2) Score at Week 12 | The STAXI-2 is a 57-item, participant self-rated scale used to measure the intensity of anger as an emotional state (state anger) and the disposition to experience angry feelings as a personality trait (trait anger). The STAXI-2 includes a measure of state anger, trait anger, anger expression-out, anger expression-in, anger control-out and anger control, and the anger expression index (an overall measure of the expression and control of anger). The state anger items are scored using a 4-point scale (1 = not at all to 4 = very much so) to assess the intensity of anger feelings at a particular moment. The other scales are scored using a 4- point scale to assess how frequently angry feelings are experienced, expressed, suppressed, or controlled (1 = almost never to 4 = almost always). | Baseline; Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AVP-786, Intermittent Explosive Disorder