Efficacy and safety of brexpiprazole in adolescents with schizophrenia: a multicountry, randomised, double-blind, placebo-controlled, phase 3 trial with an active reference

Abstract

Background: New treatment options are needed for adolescent schizophrenia, partly due to an unfavourable risk-benefit profile of current options. This trial aimed to evaluate the short-term efficacy and safety of brexpiprazole in adolescents with schizophrenia.

Methods: This multicountry, randomised, double-blind, parallel-arm, placebo-controlled, phase 3 trial with an active reference was done at 62 outpatient sites in ten countries. Eligible patients were aged 13-17 years with a primary DSM-5 diagnosis of schizophrenia and a Positive and Negative Syndrome Scale (PANSS) total score ≥80 at screening and baseline. Patients were randomly assigned (1:1:1) to oral brexpiprazole 2-4 mg/day, placebo, or aripiprazole 10-20 mg/day (active reference). Patients, investigators, and sponsor personnel were masked to treatment assignment. The primary efficacy endpoint was change from baseline to week 6 in PANSS total score (in randomly assigned patients who took at least one dose of study drug and had baseline and post-baseline PANSS evaluations). Safety was assessed in randomly assigned patients who took at least one dose of study drug. People with lived experience of schizophrenia were not involved in the research or writing process. The trial was registered with ClinicalTrials.gov, NCT03198078, and is complete.

Findings: Between June 29, 2017, and Feb 23, 2023, 376 patients were screened, and 316 patients were randomly assigned to brexpiprazole (n=110), placebo (n=104), or aripiprazole (n=102). The mean age of patients was 15·3 years (SD 1·5). 166 (53%) of 316 patients were female and 150 (47%) were male. Of 316 patients, seven (2%) were American Indian or Alaskan Native, two (1%) were Asian, 21 (7%) were Black or African American, 204 (65%) were White, and 81 (26%) were other, as reported using US Census Bureau classifications. Mean doses of brexpiprazole and aripiprazole at last visit were 3·0 mg (SD 0·9) and 13·9 mg (4·7), respectively. Least squares mean change from baseline to week 6 in PANSS total score was -22·8 (SE 1·5) with brexpiprazole and -17·4 (1·6) with placebo (least squares mean difference -5·33 [95% CI -9·55 to -1·10]; p=0·014). The corresponding PANSS total score change at week 6 with aripiprazole was -24·0 (SE 1·6; least squares mean difference versus placebo -6·53 [95% CI -10·8 to -2·21]; p_nominal=0·0032, not adjusted for multiple testing). Treatment-emergent adverse events were reported in 44 (40%) of 110 patients in the brexpiprazole group, 42 (40%) of 104 in the placebo group, and 53 (52%) of 102 in the aripiprazole group. The most common (incidence ≥5%) treatment-emergent adverse events were headache (n=7) and nausea (n=7) with brexpiprazole and somnolence (n=11), fatigue (n=8), and akathisia (n=7) with aripiprazole. Serious treatment-emergent adverse events were reported by one (1%) of 110 patients in the brexpiprazole group, three (3%) of 104 in the placebo group, and one (1%) of 102 in the aripiprazole group. No deaths were reported.

Interpretation: In adolescents with schizophrenia, brexpiprazole 2-4 mg/day was associated with greater reduction in symptom severity than placebo over 6 weeks. The safety profile of brexpiprazole in adolescents was consistent with trials in adult patients. These results add to the body of evidence for brexpiprazole in adolescents with schizophrenia and might help to inform treatment selection in clinical practice.

Funding: Otsuka Pharmaceutical Development & Commercialization and H Lundbeck.