Brexpiprazole and Sertraline Combination Treatment in Posttraumatic Stress Disorder: A Phase 3 Randomized Clinical Trial

Abstract

Importance: New pharmacotherapy options are needed for posttraumatic stress disorder (PTSD).

Objective: To investigate the efficacy, safety, and tolerability of brexpiprazole and sertraline combination treatment (brexpiprazole + sertraline) compared with sertraline + placebo for PTSD.

Design, setting, and participants: This was a parallel-design, double-blind, randomized clinical trial conducted from October 2019 to August 2023. The study had a 1-week, placebo run-in period followed by an 11-week, double-blind, randomized, active-controlled, parallel-arm period (with 21-day follow-up) and took place at 86 clinical trial sites in the US. Adult outpatients with PTSD were enrolled (volunteer sample).

Interventions: Oral brexpiprazole 2 to 3 mg per day (flexible dose) + sertraline 150 mg per day or sertraline 150 mg per day + placebo (1:1 ratio) for 11 weeks.

Main outcomes and measures: The primary end point was change in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total score (which measures the severity of 20 PTSD symptoms) from randomization (week 1) to week 10 for brexpiprazole + sertraline vs sertraline + placebo. Safety assessments included adverse events.

Results: A total of 1327 individuals were assessed for eligibility. After 878 screen failures, 416 participants (mean [SD] age, 37.4 [11.9] years; 310 female [74.5%]) were randomized. Completion rates were 137 of 214 participants (64.0%) for brexpiprazole + sertraline and 113 of 202 participants (55.9%) for sertraline + placebo. At week 10, brexpiprazole + sertraline demonstrated statistically significant greater improvement in CAPS-5 total score (mean [SD] at randomization, 38.4 [7.2]; LS mean [SE] change, -19.2 [1.2]; n = 148) than sertraline + placebo (randomization, 38.7 [7.8]; change, -13.6 [1.2]; n = 134), with LS mean difference, -5.59 (95% CI, -8.79 to -2.38; P < .001). All key secondary and other efficacy end points were also met. Treatment-emergent adverse events with incidence of 5% or greater for brexpiprazole + sertraline (and corresponding incidences for sertraline + placebo) were nausea (25 of 205 [12.2%] and 23 of 196 [11.7%]), fatigue (14 of 205 [6.8%] and 8 of 196 [4.1%]), weight increase (12 of 205 [5.9%] and 3 of 196 [1.5%]), and somnolence (11 of 205 [5.4%] and 5 of 196 [2.6%]). Discontinuation rates due to adverse events were 8 of 205 participants (3.9%) for brexpiprazole + sertraline and 20 of 196 participants (10.2%) for sertraline + placebo.

Conclusions and relevance: Results of this randomized clinical trial show that brexpiprazole + sertraline combination treatment statistically significantly improved PTSD symptoms vs sertraline + placebo, indicating its potential as a new efficacious treatment for PTSD. Brexpiprazole + sertraline was tolerated by most participants, with a safety profile consistent with that of brexpiprazole in approved indications.

Trial registration: ClinicalTrials.gov Identifier: NCT04124614.

Figure 1.. Participant Disposition

^aA total of 449 distinct patients, as 1 patient was enrolled twice. After each enrollment, this patient discontinued before randomization (1 withdrawal by participant and 1 lost to follow-up). ^bAggregated reasons for discontinuation were as follows: (1) withdrawal by participant + lost to follow-up + adverse event: 23.8% (51 of 214 participants) for brexpiprazole + sertraline and 34.2% (69 of 202 participants) for sertraline + placebo; (2) lost to follow-up + adverse event: 11.7% (25 of 214 participants) for brexpiprazole + sertraline and 23.3% (47 of 202 participants) for sertraline + placebo. ^cIncluding 1 participant who reported an adverse event of fatigue (start day 39; resolved day 44), discontinued trial medication on day 60, and discontinued the trial due to withdrawal of consent on day 75. ^dThe efficacy sample was enriched for participants with Clinician-Administered Posttraumatic Stress Disorder (PTSD) Scale for DSM-5 (CAPS-5) total score ≥27 at the randomization visit (week 1) and <50% improvement in CAPS-5 total score from baseline (day 0) to week 1.

Figure 2.. Change in Clinician-Administered Posttraumatic Stress Disorder (PTSD) Scale for DSM-5 (CAPS-5) Total Score (Primary End Point), Clinical Global Impression–Severity of Illness (CGI-S) and Brief Inventory of Psychosocial Function (B-IPF) Scores and CAPS-5 Response Rate

Mean CAPS-5 total score at randomization (week 1): brexpiprazole + sertraline, 38.4; sertraline + placebo, 38.7. Mean CGI-S score at randomization (week 1): brexpiprazole + sertraline, 4.6; sertraline + placebo, 4.6. Mean B-IPF score at baseline (day 0): brexpiprazole + sertraline, 64.8; sertraline + placebo, 63.5. Mixed model for repeated measures (A-C); last observation carried forward, Cochran-Mantel-Haenszel general association test (D); efficacy sample. ^aP < .05 vs sertraline + placebo (nominal P values with no adjustment for multiplicity). ^bP < .01 vs sertraline + placebo (nominal P values with no adjustment for multiplicity). ^cFor sertraline + placebo, n = 95 at week 8 and n = 79 at week 12. For brexpiprazole + sertraline, n = 101 at week 8 and n = 87 at week 12. ^dFor sertraline + placebo, n = 128 at week 3 and n = 137 at weeks 4 onward. For brexpiprazole + sertraline, n = 141 at week 3 and n = 149 at weeks 4 onward. ^eP < .001 vs sertraline + placebo (nominal P values with no adjustment for multiplicity).