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

Otsuka

Status and phase: Completed; Phase 2

Conditions: Neurobehavioral Disinhibition

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

Study type: Interventional

Funder types: Industry

Identifiers

NCT03095066

17-AVP-786-205

Details and patient eligibility

About

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).

Full 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.

Enrollment: 168 patients

Sex: All

Ages: 18 to 75 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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168 participants in 8 patient groups, including a placebo group

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

Placebo Comparator group

Description:

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.

Treatment:

Drug: AVP-786-42.63

Drug: Placebo

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

Experimental group

Description:

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.

Treatment:

Drug: AVP-786-28

Drug: AVP-786-42.63

Drug: Placebo

Stage 1: Placebo

Placebo Comparator group

Description:

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

Treatment:

Drug: Placebo

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

Placebo Comparator group

Description:

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.

Treatment:

Drug: Placebo

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

Experimental group

Description:

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.

Treatment:

Drug: AVP-786-28

Drug: AVP-786-42.63

Drug: Placebo

Stage 1: Placebo Responders to Stage 2: Placebo

Placebo Comparator group

Description:

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.

Treatment:

Drug: Placebo

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

Experimental group

Description:

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.

Treatment:

Drug: AVP-786-28

Drug: AVP-786-42.63

Drug: Placebo

Stage 1: AVP-786

Experimental group

Description:

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.

Treatment:

Drug: AVP-786-28

Drug: AVP-786-42.63

Drug: Placebo