Study to Assess the Efficacy, Safety, and Tolerability of AVP-786 for the Treatment of Neurobehavioral Disinhibition Including Aggression, Agitation, and Irritability in Participants With Traumatic Brain Injury

Study Overview
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Brief Summary
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This is a multicenter, randomized, placebo-controlled study to evaluate AVP-786 for the treatment of neurobehavioral disinhibition including aggression, agitation, and irritability in participants with traumatic brain injury (TBI).

Detailed Description
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Eligible participants for this study must have a diagnosis of neurobehavioral disinhibition including aggression, agitation, and irritability that persists after brain injury. This is a multicenter, randomized, 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 Neurobehavioral Disinhibition Including Aggression, Agitation, and Irritability in Patients With Traumatic Brain Injury (TBI).

Conditions
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Neurobehavioral Disinhibition

Intervention / Treatment
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* Drug: Placebo
* Drug: AVP-786-28
* Drug: AVP-786-42.63


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants with TBI Participants with neurobehavioral disinhibition symptoms that are present after trauma or after recovery of consciousness Score of ≥4 on the mCGI-S scale and the Agitation/Aggression or Irritability/Lability subscales of the Neuropsychiatric Inventory (NPI) scale at screening and baseline Participants with a reliable caregiver Exclusion Criteria: Participants with significant symptoms of a major depressive disorder Participants with a history of or current clinical symptoms of schizophrenia, schizoaffective disorder, bipolar disorder, antisocial personality disorder, or borderline personality disorder

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Stage 1: Placebo<br>Participants will receive AVP-786 matching placebo capsules, orally, twice daily (BID) during Weeks 1 to 6 of the Stage 1 treatment period. | Drug: Placebo<br>* Administered as capsules<br>|
| Experimental: AVP-786<br>Participants will receive AVP-786-28/4.9 (deudextromethorpan hydrobromide [d6-DM] 28 milligrams (mg)/quinidine sulfate [Q] 4.9 mg) capsule, along with AVP-786 matching placebo capsule, orally, once daily (QD) during Week 1 followed by AVP-786-28/4.9 capsule, orally, BID during Week 2, and AVP-786-42.63/4.9 (d6-DM 42.63 mg/Q 4.9 mg) capsules (target dose), orally, BID during Weeks 3 to 12 of the treatment period. | Drug: AVP-786-28<br>* 28 mg of d6-DM and 4.9 mg of Q<br>Drug: AVP-786-42.63<br>* 42.63 mg of d6-DM and 4.9 mg of Q<br>|
| Placebo Comparator: Stage 1: Placebo Non-responders to Stage 2: Placebo<br>Participants who will be randomized to receive placebo in Stage 1 and will be classified as non-responders (responders if modified Clinical Global Impression of Severity [mCGI-S] score is ≤ 3 at Day 43 and Neuropsychiatric Inventory Clinician (NPI-C)-3 score has decreased by ≥ 25% from baseline. Participants who will not meet these criteria will be considered non-responders) after Week 6 will be re-randomized to continue receiving AVP-786 matching placebo capsules, orally, BID during Weeks 7 to 12 of the Stage 2 treatment period. | Drug: Placebo<br>* Administered as capsules<br>|
| Experimental: Stage 1: Placebo Non-responders to Stage 2: AVP-786<br>Participants who will be randomized randomized to receive placebo in Stage 1 and will be classified as non-responders (responders if mCGI-S score is ≤ 3 at Day 43 and NPI-C-3 score has decreased by ≥ 25% from baseline. Participants who will not meet these criteria will be considered non-responders) after Week 6 will be re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1 i.e., AVP-786-28/4.9 capsule, along with AVP-786 matching placebo capsule, orally, QD during Week 7 followed by AVP-786-28/4.9 capsule, orally, BID during Week 8, and AVP-786-42.63/4.9 capsules, orally, BID, during Weeks 9 to 12 of the Stage 2 treatment period. | Drug: Placebo<br>* Administered as capsules<br>Drug: AVP-786-28<br>* 28 mg of d6-DM and 4.9 mg of Q<br>Drug: AVP-786-42.63<br>* 42.63 mg of d6-DM and 4.9 mg of Q<br>|
| Placebo Comparator: Stage 1: Placebo Responders to Stage 2: Placebo<br>Participants who will be randomized to receive placebo in Stage 1 and will be classified as responders (responders if mCGI-S score is ≤ 3 at Day 43 and NPI-C-3 score has decreased by ≥ 25% from baseline) after Week 6 will be re-randomized to continue receiving AVP-786 matching placebo capsules, orally, BID during Weeks 7 to 12 of the Stage 2 treatment period. | Drug: Placebo<br>* Administered as capsules<br>|
| Experimental: Stage 1: Placebo Responders to Stage 2: AVP-786<br>Participants who will be randomized to receive placebo in Stage 1 and will be classified as responders (responders if mCGI-S score is ≤ 3 at Day 43 and NPI-C-3 score has decreased by ≥ 25% from baseline) after Week 6 will be re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1 i.e., AVP-786-28/4.9 capsule, along with AVP-786 matching placebo capsule, orally, QD during Week 7 followed by AVP-786-28/4.9 capsule, orally, BID during Week 8, and AVP-786-42.63/4.9 capsules, orally, BID, during Weeks 9 to 12 of the Stage 2 treatment period. | Drug: Placebo<br>* Administered as capsules<br>Drug: AVP-786-28<br>* 28 mg of d6-DM and 4.9 mg of Q<br>Drug: AVP-786-42.63<br>* 42.63 mg of d6-DM and 4.9 mg of Q<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline to Week 12 in the Composite of the Clinical Impression Severity Scores on the Neuropsychiatric Inventory Clinician Rating Scale (NPI-C) Subscales of Aggression, Agitation, and Irritability/Lability (NPI-C-3) | The NPI-C can be used to rate the presence of neuropsychiatric symptoms across 14 domains. The scores for each item within an individual domain/subscale range from 0 to 3, with a higher score indicating increased severity. The NPI-C-3 is comprised of the aggression, agitation, and irritability/lability subscales. The scores for the three subscales are summed to create the total NPI-C-3 composite score, which ranges from 0 to 99, with a higher score indicating increased severity. | Baseline; Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline to Week 12 in Modified Clinical Global Impression of Change (mCGI-C) Raw Scores | The mCGI-C will be used to assess the clinician's general impression of the participant's treatment response. The mCGI-C is a 7-point (1 to 7) modified version of the CGI-C scale. A higher score represents worsening of symptoms. | Baseline; Week 12 | 
| Change from Baseline to Week 12 in NPI-C Rating Scale Subscales Scores for Aggression, Agitation, Irritability/Lability, and Disinhibition | The NPI-C is used to rate the presence of neuropsychiatric symptoms across 14 domains. The scores for each item within an individual domain/subscale range from 0 to 3, with a higher score indicating increased severity. | Baseline; Week 12 | 
| Change from Baseline to Week 12 in Modified Clinical Global Impression of Severity (mCGI-S) Scale Scores | The mCGI-S will be used to assess the clinician's view of the participant's severity of aggression, agitation, and irritability symptoms. The mCGI-S is a 7-point (1 to 7) modified version of the CGI-S scale. In all cases, a higher score represents increased severity. | Baseline; Week 12 | 
| Change from Baseline to Week 12 in Patient Global Impression of Severity (PGI-S) Scores | The PGI-S is a single-question scale that specifically assesses the severity of symptoms of neurobehavioral disinhibition, including aggression, agitation, and irritability, 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; or 7, extremely ill. | Baseline; Week 12 | 
| Change from Baseline to Week 12 in Patient Global Impression of Change (PGI-C) Raw Scores | The PGI-C is a 7-point (1 to 7) scale used to assess the participant's assessment of treatment response. A higher score indicates worsening of the symptoms. | Baseline; Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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aggression, agitation, irritability, non-penetrating brain injury, traumatic brain injury, TBI, AVP-786