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

NCT03095066 | Completed Phase 2 Results FDA Drug

• 1 other identifier: 17-AVP-786-205
• Study Type: interventional
• Target: 168
• Locations: 1 country
• Sites: 54

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).

Conditions

Neurobehavioral Disinhibition

Keywords

aggression; agitation; irritability; non-penetrating brain injury; traumatic brain injury; TBI; AVP-786

Outcome Measures

Primary Outcomes (2)

• Stage 1: Change From Baseline in the Composite of the Clinical Impression Severity Scores on the Neuropsychiatric Inventory Clinician Rating Scale (NPI-C) Subscale of Aggression, Agitation, and Irritability/Lability (NPI-C-3)

  NPI-C is a retrospective informant/caregiver interview covering 12 neuropsychiatric symptom domains. These are collectively rated first by the informant/caregiver based on frequency (0-4);severity (0-3);informant/caregiver distress (0-5) \& then by the participant based on frequency (0-4), which the clinician then integrates into a (0-3) clinical impression severity rating. NPI-C-3= aggression, agitation, \& irritability/lability subscales. NPI-C agitation domain= sum of clinical impression severity scores for agitation questions 1-13 (score=0-39). NPI-C aggression domain= sum of clinician impression severity scores for aggression questions 1-8 (score=0-24). NPI-C irritability/lability domain= sum of clinician impression severity scores for irritability/lability questions 1-12 (score=0-36). NPI-C-3 composite score ranges from 0-99. Higher score= increased severity. Least square (LS) mean was analyzed using mixed effects model repeated measures (MMRM) analysis.

  Baseline to Week 6

• Stage 2: Change From Baseline in the Composite of the Clinical Impression Severity Scores on the NPI-C Subscale of NPI-C-3

  NPI-C is a retrospective informant/caregiver interview covering 12 neuropsychiatric symptom domains. These domains are collectively rated by the informant/caregiver based on frequency (0-4), severity (0-3) \& informant/caregiver distress (0-5), then by participant based on frequency (0-4), which is integrated by clinician into (0-3) clinical impression severity rating. NPI-C-3=aggression, agitation, \& irritability/lability subscales. NPI-C agitation domain=sum of clinical impression severity scores for agitation questions 1-13 (score=0-39). NPI-C aggression domain=sum of clinician impression severity scores for aggression questions 1-8 (score=0-24). NPI-C irritability/lability domain=sum of clinician impression severity scores for irritability/lability questions 1-12 (score= 0-36). NPI-C-3 composite score ranges from 0-99. Higher score=increased severity. LS mean was analyzed using MMRM analysis. Overall number analyzed=number of participants with data available for analysis.

  Week 7 to Week 12

Secondary Outcomes (8)

• Stage 1 and Stage 2: Change From Baseline in NPI-C Rating Scale Subscale Scores for Aggression

  Stage 1: Baseline to Week 6; Stage 2: Week 7 to Week 12

• Stage 1 and Stage 2: Change From Baseline in NPI-C Rating Scale Subscale Scores for Agitation

  Stage 1: Baseline to Week 6; Stage 2: Week 7 to Week 12

• Stage 1 and Stage 2: Change From Baseline in NPI-C Rating Scale Subscale Scores for Irritability/Lability

  Stage 1: Baseline to Week 6; Stage 2: Week 7 to Week 12

• Stage 1 and Stage 2: Change From Baseline in NPI-C Rating Scale Subscale Scores for Disinhibition

  Stage 1: Baseline to Week 6; Stage 2: Week 7 to Week 12

• Stage 1 and Stage 2: Change From Baseline in Modified Clinical Global Impression of Severity (mCGI-S) Scale Scores

  Stage 1: Baseline to Week 6; Stage 2: Week 7 to Week 12

Study Arms (8)

Overall Study: Stage 1 Placebo/Stage 2 Placebo or Stage 1 Placebo/Stage 2 AVP-786

PLACEBO COMPARATOR

Participants received AVP-786 matching placebo capsules, orally, twice daily (BID) during Weeks 1 to 6 of the Stage 1 treatment period. After Week 6 participants were classified as responders or non-responders and were re-randomized to receive either placebo, orally, BID or AVP-786 in a dose escalation schedule to reach the target dose of AVP-786-42.63/4.9, orally, BID during Week 7 to Week 12 of Stage 1 treatment period.

Drug: Placebo; Drug: AVP-786-42.63

Overall Study: Stage 1 AVP-786/Stage 2 AVP-786

EXPERIMENTAL

Participants received AVP-786-28/4.9 (deudextromethorphan 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: Placebo; Drug: AVP-786-28; Drug: AVP-786-42.63

Stage 1: Placebo

PLACEBO COMPARATOR

Participants received AVP-786 matching placebo capsules, orally, BID during Weeks 1 to 6 of the Stage 1 treatment period.

Drug: Placebo

Stage 1: Placebo Non-responders to Stage 2: Placebo

PLACEBO COMPARATOR

Participants who were randomized to receive placebo in Stage 1 and were classified as non-responders (responders" if modified Clinical Global Impression of Severity \[mCGI-S\] score is ≤ 3 at Day 43 and NPI-C-3 score has decreased by ≥ 25% from baseline. Participants who did not meet these criteria were considered "non-responders) after Week 6 were 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

Stage 1: Placebo Non-responders to Stage 2: AVP-786

EXPERIMENTAL

Participants who received placebo in Stage 1 and were 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 did not meet these criteria were considered "non-responders) after Week 6 were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1 i.e., AVP-786-28- 28/4.9 capsule, along with AVP-786 matching placebo capsule, orally, QD during Week 7 followed by AVP-786-28 -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; Drug: AVP-786-28; Drug: AVP-786-42.63

Stage 1: Placebo Responders to Stage 2: Placebo

PLACEBO COMPARATOR

Participants who were randomized to receive placebo in Stage 1 and were 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 were 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

Stage 1: Placebo Responders to Stage 2: AVP-786

EXPERIMENTAL

Participants who received placebo in Stage 1 and were 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 were re-randomized to receive AVP-786 in Stage 2 using the same dose escalation schedule used in Stage 1 i.e., AVP-786-28- 28/4.9 capsule, along with AVP-786 matching placebo capsule, orally, QD during Week 7 followed by AVP-786-28 -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; Drug: AVP-786-28; Drug: AVP-786-42.63

Stage 1: AVP-786

EXPERIMENTAL

Participants received AVP-786-28/4.9 (deudextromethorphan 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 6 of the Stage 1 treatment period.

Drug: Placebo; Drug: AVP-786-28; Drug: AVP-786-42.63

Interventions

Placebo DRUG

Administered as capsules

Overall Study: Stage 1 AVP-786/Stage 2 AVP-786; Overall Study: Stage 1 Placebo/Stage 2 Placebo or Stage 1 Placebo/Stage 2 AVP-786; Stage 1: AVP-786; Stage 1: Placebo; Stage 1: Placebo Non-responders to Stage 2: AVP-786; Stage 1: Placebo Non-responders to Stage 2: Placebo; Stage 1: Placebo Responders to Stage 2: AVP-786; Stage 1: Placebo Responders to Stage 2: Placebo

AVP-786-28 DRUG

28 mg of d6-DM and 4.9 mg of Q

Overall Study: Stage 1 AVP-786/Stage 2 AVP-786; Stage 1: AVP-786; Stage 1: Placebo Non-responders to Stage 2: AVP-786; Stage 1: Placebo Responders to Stage 2: AVP-786

AVP-786-42.63 DRUG

42.63 mg of d6-DM and 4.9 mg of Q

Overall Study: Stage 1 AVP-786/Stage 2 AVP-786; Overall Study: Stage 1 Placebo/Stage 2 Placebo or Stage 1 Placebo/Stage 2 AVP-786; Stage 1: AVP-786; Stage 1: Placebo Non-responders to Stage 2: AVP-786; Stage 1: Placebo Responders to Stage 2: AVP-786

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Otsuka Pharmaceutical Development & Commercialization, Inc.: lead

Study Sites (54)

Tuscaloosa Veterans Affairs Medical Center

Tuscaloosa, Alabama, 35404, United States

Location

Absolute Clinical Research Site#207

Phoenix, Arizona, 85051, United States

Location

Perseverance Research Center Site#152

Scottsdale, Arizona, 85254, United States

Location

ATP Clinical Research Site#150

Costa Mesa, California, 92626, United States

Location

Kaizen Brain Center #224

La Jolla, California, 92037, United States

Location

Sunwise Clinical Research, LLC Site#216

Lafayette, California, 94543, United States

Location

Torrance Clinical Research Institute Site#157

Lomita, California, 90717, United States

Location

Tibor Rubin VA Medical Center, SCIRE Biomedical Research Institute

Long Beach, California, 90822, United States

Location

Asclepes Research Centers - Panorama City Site #208

Panorama City, California, 91402, United States

Location

The Neurology Group

Pomona, California, 91767, United States

Location

Mountain Mind

Colorado Springs, Colorado, 80903, United States

Location

Mountain View Clinical Research, Inc. Site# 202

Denver, Colorado, 80209, United States

Location

Medical Center of the Rockies

Loveland, Colorado, 80538, United States

Location

Connecticut Clinical Research

Cromwell, Connecticut, 06416, United States

Location

Bradenton Research Center, Inc

Bradenton, Florida, 34205, United States

Location

Healthcare Innovative Institute, LLC Site# 173

Coral Springs, Florida, 33067, United States

Location

Science Connections, LLC Site#161

Doral, Florida, 33166, United States

Location

Design Neuroscience Center, PL

Doral, Florida, 33172, United States

Location

Alphab Global Research Site#163

Jupiter, Florida, 33458, United States

Location

Meridien Research

Maitland, Florida, 32751, United States

Location

Premier Clinical Research Institute, Inc.

Miami, Florida, 33122, United States

Location

Project 4 Research

Miami, Florida, 33125, United States

Location

Allied Biomedical Research Institute, Inc. Site#151

Miami, Florida, 33155, United States

Location

Health Synergy Clinical Research

Okeechobee, Florida, 34972, United States

Location

Roskamp Institute Clinic, Inc.

Sarasota, Florida, 34243, United States

Location

USF Dept of Psychiatry and Behavioral Neurosciences Site# 214

Tampa, Florida, 33613, United States

Location

Meridien Research Site# 108

Tampa, Florida, 33634, United States

Location

Hawaii Pacific Neuroscience Site#184

Honolulu, Hawaii, 96817, United States

Location

The University of Kentucky research foundation

Lexington, Kentucky, 40536, United States

Location

Baptist Health

Richmond, Kentucky, 40475, United States

Location

Sisu BHR Site#200

Springfield, Massachusetts, 01103, United States

Location

Neurobehavioral Medicine Group #222

Bloomfield Hills, Michigan, 48302, United States

Location

Millennium Psychiatric Associates, LLC

Creve Coeur, Missouri, 63141, United States

Location

Sharlin Health and Neurology

Ozark, Missouri, 65721, United States

Location

Clinical Research Professionals

St Louis, Missouri, 63141, United States

Location

JFK Johnson Rehabilitation Institute

Edison, New Jersey, 08820, United States

Location

The NeuroCognitive Insititute

Mount Arlington, New Jersey, 07856, United States

Location

New York University School of Medicine Site #122

New York, New York, 10016, United States

Location

Atrium Health - Carolinas Rehabilitation - Charlotte Site #166

Charlotte, North Carolina, 28203, United States

Location

New Hope Clinical Research Site#194

Charlotte, North Carolina, 28211, United States

Location

Carolina Headache Institute

Durham, North Carolina, 27713, United States

Location

Salisbury VAMC

Salisbury, North Carolina, 28144, United States

Location

Valley Medical Research

Centerville, Ohio, 45459, United States

Location

Cincinnati VA Medical Center

Cincinnati, Ohio, 45220, United States

Location

North Star Medical Research, LLC Site#154

Middleburg Heights, Ohio, 44130, United States

Location

IPS Research Site#196

Oklahoma City, Oklahoma, 73106, United States

Location

University of Pittsburgh

Pittsburgh, Pennsylvania, 15213, United States

Location

WJB Dorn VA-Wm. Jennings Bryan Dorn VA Medical Center

Columbia, South Carolina, 29205, United States

Location

University of Texas Southwestern Medical Site#140

Dallas, Texas, 75390, United States

Location

Polytrauma Rehabilitation Center S. Texas VA Health Care System Site# 146

San Antonio, Texas, 78229, United States

Location

Cedar Clinical Research #221

Draper, Utah, 84020, United States

Location

Virginia Commonwealth University #172

Richmond, Virginia, 23298, United States

Location

Virginia Commonwealth University Site#172

Richmond, Virginia, 23298, United States

Location

Salem Research Institute Site# 138

Salem, Virginia, 24153, United States

Location

MeSH Terms

Conditions

Aggression; Psychomotor Agitation; Brain Injuries, Traumatic

Condition Hierarchy (Ancestors)

Aberrant Motor Behavior in Dementia; Behavioral Symptoms; Behavior; Social Behavior; Dyskinesias; Neurologic Manifestations; Nervous System Diseases; Psychomotor Disorders; Neurobehavioral Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Brain Injuries; Brain Diseases; Central Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Wounds and Injuries

Results Point of Contact

• Title: Global Clinical Development
• Organization: Otsuka Pharmaceutical Development & Commercialization, Inc.

clinicaltransparency@otsuka-us.com

1-609-524-6788

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 23, 2017
• First Posted: March 29, 2017
• Study Start: May 30, 2017
• Primary Completion: August 22, 2022
• Study Completion: August 31, 2022
• Last Updated: October 29, 2025
• Results First Posted: October 29, 2025

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR
• Time Frame: Data will be available after marketing approval in global markets or beginning 1-3 years following article publication. There is no end date to the availability of the data.
• Access Criteria: Otsuka will share data on the Vivli data sharing platform which can be found here: https://vivli.org/ourmember/Otsuka/

Locations

US (54)