Topline results announced from two phase III trials of brexpiprazole as combination therapy with sertraline for the treatment of post-traumatic stress disorder in adults

The first trial (NCT04124614) was a phase III, randomized, double-blind, 2-arm, flexible dose trial to evaluate the efficacy, safety, and tolerability of brexpiprazole (2 - 3 mg/day) as combination therapy with sertraline in 416 randomized adult subjects with PTSD. The second trial (NCT04174170) was a phase III, randomized, double-blind, 3-arm, fixed dose trial to evaluate the efficacy, safety, and tolerability of brexpiprazole (2 or 3 mg/day) as combination therapy with sertraline in 553 randomized adult subjects with PTSD.

The primary endpoint for both trials was the change in the Clinician-Administered PTSD Scale (CAPS-5) total score for brexpiprazole + sertraline combination therapy versus sertraline + placebo at week 10 in patients diagnosed with PTSD according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). The first trial met its primary endpoint by demonstrating improvements from baseline on the primary endpoint of CAPS-5 for patients receiving brexpiprazole 2-3 mg/day + sertraline combination therapy being statistically significantly greater than for those receiving sertraline + placebo (p<0.05).

The second phase III trial missed its primary endpoint (p>0.05) .

Overall, the safety and tolerability results were consistent with the profile of brexpiprazole as observed in the clinical trials for schizophrenia, agitation associated with dementia due to Alzheimer’s disease (AADAD), and adjunctive treatment of major depressive disorder (MDD). The most common treatment emergent adverse events in patients receiving combination therapy of brexpiprazole + sertraline versus sertraline + placebo (incidence at least 2% and greater than sertraline + placebo) were dyspepsia, fatigue, weight increased, akathisia and somnolence. Discontinuations due to adverse events occurred in 3.7% of patients treated with brexpiprazole + sertraline combination therapy and 7.6% of patients receiving sertraline + placebo.

Full trial results are not yet available. Further prespecified and exploratory analyses of this data set will be conducted to further assess brexpiprazole as combination therapy with sertraline for the treatment of PTSD. The trial results are planned to be submitted for scientific publication.

“The results from the first trial indicate that brexpiprazole in combination with sertraline provides improvement of symptoms for people living with PTSD, whereas the second trial did not meet its primary endpoint,” said John Kraus, M.D., Ph.D., executive vice president and chief medical officer, Otsuka Pharmaceutical Development & Commercialization, Inc. “We will fully analyze these results and will discuss our findings with the FDA to determine next steps.”

“PTSD is a serious mental health disorder with a wide range of symptoms with no new therapeutic options in more than 20 years,” Dr. Johan Luthman, executive vice president and head of Research & Development at Lundbeck. “The two trials constitute one of the largest clinical development programs ever conducted in PTSD. We will analyze the dataset to further determine the potential of brexpiprazole as combination therapy with sertraline in comprehensively addressing symptoms across the PTSD core domains.”

About the trials: Trials 331-201-00071 (NCT04124614) and 331-201-00072 (NCT04174170) were designed to evaluate the efficacy, safety and tolerability of brexpiprazole and sertraline combination treatment in adults with PTSD. The trial populations included male and female patients, aged 18-65 years (inclusive), with a diagnosis of PTSD according to the DSM-5 and confirmed by the Mini International Neuropsychiatric Interview. The trials consisted of a 1-week double-blind placebo run-in period followed by 11-weeks of double-blind randomized treatment for a continuous 12-week double-blind treatment period with a 21-day follow-up].

Trial 331-201-00071 was a 2-arm, double-blind, flexible-dose trial in which patients were randomized to receive either flexible-dose brexpiprazole 2-3 mg/day plus sertraline 150 mg/day or sertraline 150 mg/day plus placebo during the 11-week randomized treatment period.

Trial 331-201-00072 was a 3-arm, double-blind, fixed-dose trial in which patients were randomized to receive either fixed-dose brexpiprazole 2 mg/day plus sertraline 150 mg/day, brexpiprazole 3 mg/day plus sertraline 150 mg/day, or sertraline 150 mg/day plus placebo during the 11-week randomized treatment period. The primary outcome in both trials was the change from randomization to week 10 in the CAPS-5 total score in those patients that met blinded criteria at the week 1 visit of the trial.

About CAPS-5: The Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) is a structured interview designed to assess PTSD diagnostic status and symptoms severity as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). The interview consists of 30 items, with a higher score indicating a worse outcome.