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

Phase 2

Completed

• Conditions: Neurobehavioral Disinhibition
• Interventions: Drug: Placebo; Drug: AVP-786-28; Drug: AVP-786-42.63

• Registration Number: NCT03095066
• Lead Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2017-03-23
• Study First Submitted QC: 2017-03-23
• Study First Posted: 2017-03-29
• Study Start: 2017-05-30
• Primary Completion: 2022-08-22
• Study Completion: 2022-08-31
• Disposition First Submitted: 2023-08-22
• Disposition First Posted: 2023-08-28
• Status Verified: 2023-09
• Last Update Submitted: 2023-09-26
• Last Update Posted: 2023-09-29

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 168

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Stage 1: Placebo	Placebo	Participants will receive AVP-786 matching placebo capsules, orally, twice daily (BID) during Weeks 1 to 6 of the Stage 1 treatment period.
AVP-786	AVP-786-28	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.
AVP-786	AVP-786-42.63	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.
Stage 1: Placebo Non-responders to Stage 2: Placebo	Placebo	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.
Stage 1: Placebo Non-responders to Stage 2: AVP-786	Placebo	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.
Stage 1: Placebo Non-responders to Stage 2: AVP-786	AVP-786-28	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.
Stage 1: Placebo Non-responders to Stage 2: AVP-786	AVP-786-42.63	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.
Stage 1: Placebo Responders to Stage 2: Placebo	Placebo	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.
Stage 1: Placebo Responders to Stage 2: AVP-786	Placebo	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.
Stage 1: Placebo Responders to Stage 2: AVP-786	AVP-786-28	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.
Stage 1: Placebo Responders to Stage 2: AVP-786	AVP-786-42.63	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.

Primary Outcome Measures

Name	Time	Method
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)	Baseline; Week 12	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.

Secondary Outcome Measures

Name	Time	Method
Change from Baseline to Week 12 in Modified Clinical Global Impression of Change (mCGI-C) Raw Scores	Baseline; Week 12	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.
Change from Baseline to Week 12 in NPI-C Rating Scale Subscales Scores for Aggression, Agitation, Irritability/Lability, and Disinhibition	Baseline; Week 12	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.
Change from Baseline to Week 12 in Modified Clinical Global Impression of Severity (mCGI-S) Scale Scores	Baseline; Week 12	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.
Change from Baseline to Week 12 in Patient Global Impression of Severity (PGI-S) Scores	Baseline; Week 12	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.
Change from Baseline to Week 12 in Patient Global Impression of Change (PGI-C) Raw Scores	Baseline; Week 12	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.

Trial Locations

Locations (54)

Design Neuroscience Center, PL; 🇺🇸 Doral, Florida, United States

Meridien Research; 🇺🇸 Maitland, Florida, United States

Neurobehavioral Medicine Group #222; 🇺🇸 Bloomfield Hills, Michigan, United States

JFK Johnson Rehabilitation Institute; 🇺🇸 Edison, New Jersey, United States

Salisbury VAMC; 🇺🇸 Salisbury, North Carolina, United States

Science Connections, LLC Site#161; 🇺🇸 Doral, Florida, United States

Baptist Health; 🇺🇸 Richmond, Kentucky, United States

Sisu BHR Site#200; 🇺🇸 Springfield, Massachusetts, United States

The NeuroCognitive Insititute; 🇺🇸 Mount Arlington, New Jersey, United States

Tibor Rubin VA Medical Center, SCIRE Biomedical Research Institute; 🇺🇸 Long Beach, California, United States

Connecticut Clinical Research; 🇺🇸 Cromwell, Connecticut, United States

WJB Dorn VA-Wm. Jennings Bryan Dorn VA Medical Center; 🇺🇸 Columbia, South Carolina, United States

Mountain Mind; 🇺🇸 Colorado Springs, Colorado, United States

Bradenton Research Center, Inc; 🇺🇸 Bradenton, Florida, United States

Torrance Clinical Research Institute Site#157; 🇺🇸 Lomita, California, United States

Medical Center of the Rockies; 🇺🇸 Loveland, Colorado, United States

The University of Kentucky research foundation; 🇺🇸 Lexington, Kentucky, United States

Roskamp Institute Clinic, Inc.; 🇺🇸 Sarasota, Florida, United States

Alphab Global Research Site#163; 🇺🇸 Jupiter, Florida, United States

Clinical Research Professionals; 🇺🇸 Saint Louis, Missouri, United States

Cedar Clinical Research #221; 🇺🇸 Draper, Utah, United States

University of Pittsburgh; 🇺🇸 Pittsburgh, Pennsylvania, United States

Premier Clinical Research Institute, Inc.; 🇺🇸 Miami, Florida, United States

Project 4 Research; 🇺🇸 Miami, Florida, United States

Absolute Clinical Research Site#207; 🇺🇸 Phoenix, Arizona, United States

Mountain View Clinical Research, Inc. Site# 202; 🇺🇸 Denver, Colorado, United States

Carolina Headache Institute; 🇺🇸 Durham, North Carolina, United States

Cincinnati VA Medical Center; 🇺🇸 Cincinnati, Ohio, United States

IPS Research Site#196; 🇺🇸 Oklahoma City, Oklahoma, United States

Polytrauma Rehabilitation Center S. Texas VA Health Care System Site# 146; 🇺🇸 San Antonio, Texas, United States

USF Dept of Psychiatry and Behavioral Neurosciences Site# 214; 🇺🇸 Tampa, Florida, United States

Meridien Research Site# 108; 🇺🇸 Tampa, Florida, United States

Tuscaloosa Veterans Affairs Medical Center; 🇺🇸 Tuscaloosa, Alabama, United States

Perseverance Research Center Site#152; 🇺🇸 Scottsdale, Arizona, United States

ATP Clinical Research Site#150; 🇺🇸 Costa Mesa, California, United States

Sunwise Clinical Research, LLC Site#216; 🇺🇸 Lafayette, California, United States

Kaizen Brain Center #224; 🇺🇸 La Jolla, California, United States

The Neurology Group; 🇺🇸 Pomona, California, United States

Asclepes Research Centers - Panorama City Site #208; 🇺🇸 Panorama City, California, United States

Healthcare Innovative Institute, LLC Site# 173; 🇺🇸 Coral Springs, Florida, United States

Health Synergy Clinical Research; 🇺🇸 Okeechobee, Florida, United States

Allied Biomedical Research Institute, Inc. Site#151; 🇺🇸 Miami, Florida, United States

Millennium Psychiatric Associates, LLC; 🇺🇸 Creve Coeur, Missouri, United States

New Hope Clinical Research Site#194; 🇺🇸 Charlotte, North Carolina, United States

Valley Medical Research; 🇺🇸 Centerville, Ohio, United States

Sharlin Health and Neurology; 🇺🇸 Ozark, Missouri, United States

Atrium Health - Carolinas Rehabilitation - Charlotte Site #166; 🇺🇸 Charlotte, North Carolina, United States

New York University School of Medicine Site #122; 🇺🇸 New York, New York, United States

North Star Medical Research, LLC Site#154; 🇺🇸 Middleburg Heights, Ohio, United States

University of Texas Southwestern Medical Site#140; 🇺🇸 Dallas, Texas, United States

Salem Research Institute Site# 138; 🇺🇸 Salem, Virginia, United States

Hawaii Pacific Neuroscience Site#184; 🇺🇸 Honolulu, Hawaii, United States

Virginia Commonwealth University #172; 🇺🇸 Richmond, Virginia, United States

Virginia Commonwealth University Site#172; 🇺🇸 Richmond, Virginia, United States