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
- Conditions
- Neurobehavioral Disinhibition
- Interventions
- Drug: PlaceboDrug: AVP-786-28Drug: AVP-786-42.63
- Registration Number
- NCT03095066
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 168
- 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
- 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 & 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)
Tuscaloosa Veterans Affairs Medical Center
🇺🇸Tuscaloosa, Alabama, United States
Absolute Clinical Research Site#207
🇺🇸Phoenix, Arizona, United States
Perseverance Research Center Site#152
🇺🇸Scottsdale, Arizona, United States
ATP Clinical Research Site#150
🇺🇸Costa Mesa, California, United States
Kaizen Brain Center #224
🇺🇸La Jolla, California, United States
Sunwise Clinical Research, LLC Site#216
🇺🇸Lafayette, California, United States
Torrance Clinical Research Institute Site#157
🇺🇸Lomita, California, United States
Tibor Rubin VA Medical Center, SCIRE Biomedical Research Institute
🇺🇸Long Beach, California, United States
Asclepes Research Centers - Panorama City Site #208
🇺🇸Panorama City, California, United States
The Neurology Group
🇺🇸Pomona, California, United States
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