Trial Outcomes & Findings for 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 (NCT NCT03095066)

Last Updated: 2025-10-29

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

168 participants

Primary outcome timeframe

Baseline to Week 6

Results posted on

2025-10-29

Participant Flow

Participants took part in this study at 67 investigative sites in the United States from 30 May 2017 to 31 August 2022. A total of 467 participants were screened of which 168 participants were randomized to receive placebo or AVP-786.

Study was conducted in 2 Stages. Participants randomized to receive placebo in Stage 1 were re-randomized after Week 6 to receive either placebo or AVP-786 in Stage 2. As pre-specified in protocol, participants randomized to 'AVP-786' arm were not re-randomized after Week 6 and continued receiving AVP-786 in the same arm throughout 12 weeks of study. Study is presented in 3 stages: Overall Study, Stage 1 \& Stage 2.

Participant milestones

Participant milestones
Measure	Overall Study: Stage 1 Placebo/Stage 2 Placebo or Stage 1 Placebo/Stage 2 AVP-786 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.	Overall Study: Stage 1 AVP-786/Stage 2 AVP-786 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.	Stage 1: Placebo Participants received AVP-786 matching placebo capsules, orally, BID during Weeks 1 to 6 of the Stage 1 treatment period.	Stage 1: Placebo Non-responders to Stage 2: Placebo 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.	Stage 1: Placebo Non-responders to Stage 2: AVP-786 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.	Stage 1: Placebo Responders to Stage 2: Placebo 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.	Stage 1: Placebo Responders to Stage 2: AVP-786 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.	Stage 1 and 2: AVP-786 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. Participants who completed Stage 1, continued to receive AVP-786-42.63/4.9 (d6-DM 42.63 mg/Q 4.9 mg) capsules, orally, BID during Weeks 7 to 12 of the Stage 2 treatment period.
Overall Study (Baseline to Week 12) STARTED	83	85	0	0	0	0	0	0
Overall Study (Baseline to Week 12) COMPLETED	58	68	0	0	0	0	0	0
Overall Study (Baseline to Week 12) NOT COMPLETED	25	17	0	0	0	0	0	0
Stage 1 (Baseline to Week 6) STARTED	0	0	83	0	0	0	0	85
Stage 1 (Baseline to Week 6) COMPLETED	0	0	68	0	0	0	0	71
Stage 1 (Baseline to Week 6) NOT COMPLETED	0	0	15	0	0	0	0	14
Stage 2 (Week 7 to Week 12) STARTED	0	0	0	22	17	16	13	71
Stage 2 (Week 7 to Week 12) COMPLETED	0	0	0	20	13	14	11	68
Stage 2 (Week 7 to Week 12) NOT COMPLETED	0	0	0	2	4	2	2	3

Reasons for withdrawal

Reasons for withdrawal
Measure	Overall Study: Stage 1 Placebo/Stage 2 Placebo or Stage 1 Placebo/Stage 2 AVP-786 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.	Overall Study: Stage 1 AVP-786/Stage 2 AVP-786 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.	Stage 1: Placebo Participants received AVP-786 matching placebo capsules, orally, BID during Weeks 1 to 6 of the Stage 1 treatment period.	Stage 1: Placebo Non-responders to Stage 2: Placebo 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.	Stage 1: Placebo Non-responders to Stage 2: AVP-786 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.	Stage 1: Placebo Responders to Stage 2: Placebo 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.	Stage 1: Placebo Responders to Stage 2: AVP-786 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.	Stage 1 and 2: AVP-786 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. Participants who completed Stage 1, continued to receive AVP-786-42.63/4.9 (d6-DM 42.63 mg/Q 4.9 mg) capsules, orally, BID during Weeks 7 to 12 of the Stage 2 treatment period.
Overall Study (Baseline to Week 12) Adverse Event	3	6	0	0	0	0	0	0
Overall Study (Baseline to Week 12) Lost to Follow-up	6	1	0	0	0	0	0	0
Overall Study (Baseline to Week 12) Non-compliance With Study Drug	2	1	0	0	0	0	0	0
Overall Study (Baseline to Week 12) Physician Decision	0	1	0	0	0	0	0	0
Overall Study (Baseline to Week 12) Protocol Deviation	1	2	0	0	0	0	0	0
Overall Study (Baseline to Week 12) Trial Site Terminated by Sponsor	1	0	0	0	0	0	0	0
Overall Study (Baseline to Week 12) Withdrawal by Subject	4	4	0	0	0	0	0	0
Overall Study (Baseline to Week 12) Reason not Specified	8	2	0	0	0	0	0	0
Stage 1 (Baseline to Week 6) Adverse Event	0	0	2	0	0	0	0	6
Stage 1 (Baseline to Week 6) Lost to Follow-up	0	0	3	0	0	0	0	1
Stage 1 (Baseline to Week 6) Non-compliance With Study Drug	0	0	2	0	0	0	0	1
Stage 1 (Baseline to Week 6) Withdrawal by Subject	0	0	2	0	0	0	0	3
Stage 1 (Baseline to Week 6) Trial Site Terminated by Sponsor	0	0	1	0	0	0	0	0
Stage 1 (Baseline to Week 6) Reason Not Specified	0	0	5	0	0	0	0	2
Stage 1 (Baseline to Week 6) Physician Decision	0	0	0	0	0	0	0	1
Stage 2 (Week 7 to Week 12) Adverse Event	0	0	0	0	0	1	0	0
Stage 2 (Week 7 to Week 12) Lost to Follow-up	0	0	0	0	1	0	2	0
Stage 2 (Week 7 to Week 12) Protocol Deviation	0	0	0	0	1	0	0	2
Stage 2 (Week 7 to Week 12) Withdrawal by Subject	0	0	0	0	2	0	0	1
Stage 2 (Week 7 to Week 12) Reason Not Specified	0	0	0	2	0	1	0	0

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Overall Study: Placebo n=83 Participants Participants received AVP-786 matching placebo capsules, orally, 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.	Overall Study: AVP-786 n=85 Participants Participants received AVP-786-28/4.9 (d6-DM 28 mg/ Q 4.9 mg) capsule, along with AVP-786 matching placebo capsule, orally, 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.	Total n=168 Participants Total of all reporting groups
Age, Continuous	47.5 years STANDARD_DEVIATION 13.54 • n=5 Participants	46.8 years STANDARD_DEVIATION 13.93 • n=7 Participants	47.1 years STANDARD_DEVIATION 13.70 • n=5 Participants
Sex: Female, Male Female	27 Participants n=5 Participants	27 Participants n=7 Participants	54 Participants n=5 Participants
Sex: Female, Male Male	56 Participants n=5 Participants	58 Participants n=7 Participants	114 Participants n=5 Participants
Race/Ethnicity, Customized White	68 Participants n=5 Participants	79 Participants n=7 Participants	147 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	10 Participants n=5 Participants	3 Participants n=7 Participants	13 Participants n=5 Participants
Race/Ethnicity, Customized Asian	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized Other	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized Hispanic or Latino	25 Participants n=5 Participants	27 Participants n=7 Participants	52 Participants n=5 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	58 Participants n=5 Participants	58 Participants n=7 Participants	116 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline to Week 6

Population: Modified intent-to-treat (mITT) population. Stage 1: Participants randomized in Stage 1 who took at least 1 dose of study medication \& had at least 1 post-baseline NPI-C-3 composite score efficacy assessment in Stage 1. Overall number analyzed=participants with data available for analysis.

Outcome measures

Outcome measures
Measure	Stage 1: Placebo n=64 Participants Participants received AVP-786 matching placebo capsules, orally, BID during Weeks 1 to 6 of the Stage 1 treatment period.	Stage 1: AVP-786 n=61 Participants 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.	Stage 1: Placebo Non-responders; to Stage 2: Placebo Participants who were randomized to receive 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 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 Participants who were randomized to receive 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-786-28/4.9 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: 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)	-18.7 score on a scale Standard Error 1.74	-20.4 score on a scale Standard Error 1.73	—	—

PRIMARY outcome

Timeframe: Week 7 to Week 12

Population: mITT population. Stage 2: participants randomized into Stage 2 with at least 1 NPI-C-3 efficacy assessment in Stage 2. As pre-specified in protocol, data for placebo non-responders re-randomized into Stage 2 was used to estimate \& report Stage 2 efficacy. Hence only these Stage 2 arms are reported for the OM.

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.