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

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).

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).

Study Overview

• Status: Completed
• Conditions: Neurobehavioral Disinhibition
• Intervention / Treatment: Drug: AVP-786-28; Drug: AVP-786-42.63; Drug: Placebo

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 Type: Interventional
• Enrollment (Actual): 168
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Tuscaloosa, Alabama, United States, 35404
      • Tuscaloosa Veterans Affairs Medical Center
  • Arizona
    • Phoenix, Arizona, United States, 85051
      • Absolute Clinical Research Site#207
    • Scottsdale, Arizona, United States, 85254
      • Perseverance Research Center Site#152
  • California
    • Costa Mesa, California, United States, 92626
      • ATP Clinical Research Site#150
    • La Jolla, California, United States, 92037
      • Kaizen Brain Center #224
    • Lafayette, California, United States, 94543
      • Sunwise Clinical Research, LLC Site#216
    • Lomita, California, United States, 90717
      • Torrance Clinical Research Institute Site#157
    • Long Beach, California, United States, 90822
      • Tibor Rubin VA Medical Center, SCIRE Biomedical Research Institute
    • Panorama City, California, United States, 91402
      • Asclepes Research Centers - Panorama City Site #208
    • Pomona, California, United States, 91767
      • The Neurology Group
  • Colorado
    • Colorado Springs, Colorado, United States, 80903
      • Mountain Mind
    • Denver, Colorado, United States, 80209
      • Mountain View Clinical Research, Inc. Site# 202
    • Loveland, Colorado, United States, 80538
      • Medical Center of the Rockies
  • Connecticut
    • Cromwell, Connecticut, United States, 06416
      • Connecticut Clinical Research
  • Florida
    • Bradenton, Florida, United States, 34205
      • Bradenton Research Center, Inc
    • Coral Springs, Florida, United States, 33067
      • Healthcare Innovative Institute, LLC Site# 173
    • Doral, Florida, United States, 33166
      • Science Connections, LLC Site#161
    • Doral, Florida, United States, 33172
      • Design Neuroscience Center, PL
    • Jupiter, Florida, United States, 33458
      • Alphab Global Research Site#163
    • Maitland, Florida, United States, 32751
      • Meridien Research
    • Miami, Florida, United States, 33122
      • Premier Clinical Research Institute, Inc.
    • Miami, Florida, United States, 33125
      • Project 4 Research
    • Miami, Florida, United States, 33155
      • Allied Biomedical Research Institute, Inc. Site#151
    • Okeechobee, Florida, United States, 34972
      • Health Synergy Clinical Research
    • Sarasota, Florida, United States, 34243
      • Roskamp Institute Clinic, Inc.
    • Tampa, Florida, United States, 33613
      • USF Dept of Psychiatry and Behavioral Neurosciences Site# 214
    • Tampa, Florida, United States, 33634
      • Meridien Research Site# 108
  • Hawaii
    • Honolulu, Hawaii, United States, 96817
      • Hawaii Pacific Neuroscience Site#184
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • The University of Kentucky research foundation
    • Richmond, Kentucky, United States, 40475
      • Baptist Health
  • Massachusetts
    • Springfield, Massachusetts, United States, 01103
      • Sisu BHR Site#200
  • Michigan
    • Bloomfield Hills, Michigan, United States, 48302
      • Neurobehavioral Medicine Group #222
  • Missouri
    • Creve Coeur, Missouri, United States, 63141
      • Millennium Psychiatric Associates, LLC
    • Ozark, Missouri, United States, 65721
      • Sharlin Health and Neurology
    • Saint Louis, Missouri, United States, 63141
      • Clinical Research Professionals
  • New Jersey
    • Edison, New Jersey, United States, 08820
      • JFK Johnson Rehabilitation Institute
    • Mount Arlington, New Jersey, United States, 07856
      • The NeuroCognitive Insititute
  • New York
    • New York, New York, United States, 10016
      • New York University School of Medicine Site #122
  • North Carolina
    • Charlotte, North Carolina, United States, 28203
      • Atrium Health - Carolinas Rehabilitation - Charlotte Site #166
    • Charlotte, North Carolina, United States, 28211
      • New Hope Clinical Research Site#194
    • Durham, North Carolina, United States, 27713
      • Carolina Headache Institute
    • Salisbury, North Carolina, United States, 28144
      • Salisbury VAMC
  • Ohio
    • Centerville, Ohio, United States, 45459
      • Valley Medical Research
    • Cincinnati, Ohio, United States, 45220
      • Cincinnati VA Medical Center
    • Middleburg Heights, Ohio, United States, 44130
      • North Star Medical Research, LLC Site#154
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73106
      • IPS Research Site#196
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh
  • South Carolina
    • Columbia, South Carolina, United States, 29205
      • WJB Dorn VA-Wm. Jennings Bryan Dorn VA Medical Center
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Site#140
    • San Antonio, Texas, United States, 78229
      • Polytrauma Rehabilitation Center S. Texas VA Health Care System Site# 146
  • Utah
    • Draper, Utah, United States, 84020
      • Cedar Clinical Research #221
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University #172
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University Site#172
    • Salem, Virginia, United States, 24153
      • Salem Research Institute Site# 138

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Stage 1: Placebo; 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; Administered as capsules
Experimental: AVP-786; 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; 28 mg of d6-DM and 4.9 mg of Q; Drug: AVP-786-42.63; 42.63 mg of d6-DM and 4.9 mg of Q
Placebo Comparator: Stage 1: Placebo Non-responders to Stage 2: 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.	Drug: Placebo; Administered as capsules
Experimental: Stage 1: Placebo Non-responders to Stage 2: AVP-786; 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: AVP-786-28; 28 mg of d6-DM and 4.9 mg of Q; Drug: AVP-786-42.63; 42.63 mg of d6-DM and 4.9 mg of Q; Drug: Placebo; Administered as capsules
Placebo Comparator: Stage 1: Placebo Responders to Stage 2: 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.	Drug: Placebo; Administered as capsules
Experimental: Stage 1: Placebo Responders to Stage 2: AVP-786; 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: AVP-786-28; 28 mg of d6-DM and 4.9 mg of Q; Drug: AVP-786-42.63; 42.63 mg of d6-DM and 4.9 mg of Q; Drug: Placebo; Administered as capsules

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): May 30, 2017
• Primary Completion (Actual): August 22, 2022
• Study Completion (Actual): August 31, 2022

Study Registration Dates

• First Submitted: March 23, 2017
• First Submitted That Met QC Criteria: March 23, 2017
• First Posted (Actual): March 29, 2017

Study Record Updates

• Last Update Posted (Actual): September 29, 2023
• Last Update Submitted That Met QC Criteria: September 26, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: irritability; TBI; traumatic brain injury; agitation; aggression; AVP-786; non-penetrating brain injury
• Additional Relevant MeSH Terms: Behavioral Symptoms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Wounds and Injuries; Neurobehavioral Manifestations; Dyskinesias; Psychomotor Disorders; Craniocerebral Trauma; Trauma, Nervous System; Aggression; Psychomotor Agitation; Brain Injuries; Brain Injuries, Traumatic
• Other Study ID Numbers: 17-AVP-786-205

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Anonymized Individual participant data (IPD) that underlie the results of this study will be shared with researchers to achieve aims pre-specified in a methodologically sound research proposal. Small studies with less than 25 participants are excluded from data sharing
• IPD Sharing 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.
• IPD Sharing Access Criteria: Otsuka will share data on the Vivli data sharing platform which can be found here: https://vivli.org/ourmember/Otsuka/
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No