The efficacy of brexpiprazole in the treatment of adults with schizophrenia was demonstrated in two 6-week randomized, double-blind, placebo-controlled, fixed-dose clinical studies in patients who met DSM-IV-TR criteria for schizophrenia.

In both studies, Study 3 (NCT01396421) and Study 4 (NCT01393613), patients were randomized to brexpiprazole 2 mg or 4 mg once per day or placebo. Patients in the brexpiprazole groups initiated treatment at 1 mg once daily on Days 1 to 4. The brexpiprazole dosage was increased to 2 mg on Days 5 to 7. The dosage was then either maintained at 2 mg once daily or increased to 4 mg once daily, depending on treatment assignment, for the 5 remaining weeks.

The primary efficacy endpoint of both studies was the change from baseline to Week 6 in the Positive and Negative Syndrome Scale (PANSS) total score. The PANSS is a 30-item scale that measures positive symptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items), and general psychopathology (16 items), each rated on a scale of 1 (absent) to 7 (extreme); the total PANSS scores range from 30 (best) to 210 (worst).

In Study 3, brexpiprazole at both 2 mg once daily and 4 mg once daily was superior to placebo on the PANSS total score. In Study 4, brexpiprazole 4 mg once daily was superior to placebo on the PANSS total score (Table 13). Figure 5 shows the time course of response based on the primary efficacy measure (change from baseline in PANSS total score) in Study 3.

Examination of population subgroups based on age, sex and race did not suggest differential responsiveness.

Table 13: Change in PANSS Total Score from Baseline at Week 6 in Adult Patients in Studies of Schizophrenia (Study 3 and Study 4)

Figure 5: Change from Baseline in PANSS Total Score by Study Visit (Week) in Adult Patients with Schizophrenia (Study 3)

The safety and efficacy of brexpiprazole as maintenance treatment in adults with schizophrenia aged 18 to 65 years were demonstrated in the maintenance phase of a randomized withdrawal study (Study 5, NCT01668797). Patients were stabilized for at least 12 weeks on 1 mg/day to 4 mg/day of brexpiprazole (N=202). They were then randomized in the double-blind treatment phase to either continue brexpiprazole at their achieved stable dose (N=97), or to switch to placebo (N=105).

The primary endpoint in Study 5 was time from randomization to impending relapse during the double-blind phase, defined as: 1) Clinical Global Improvement score of ≥ 5 (minimally worse) and an increase to a score > 4 on PANSS conceptual disorganization, hallucinatory behavior, suspiciousness, or unusual thought content items, with either a ≥ 2 increase on a specific item or ≥ 4 point increase on the combined four PANSS items, 2) hospitalization due to worsening of psychotic symptoms, 3) current suicidal behavior, or 4) violent/aggressive behavior.

A pre-specified interim analysis demonstrated a statistically significantly longer time to relapse in patients randomized to the brexpiprazole group compared to placebo-treated patients. The study was subsequently terminated early because maintenance of efficacy had been demonstrated. The Kaplan-Meier curves of the cumulative proportion of patients with relapse during the double-blind treatment phase for brexpiprazole and placebo groups are shown in Figure 6. The key secondary endpoint, the proportion of patients who met the criteria for impending relapse, was statistically significantly lower in brexpiprazole-treated patients compared with placebo group.

Figure 6: Kaplan-Meier Estimation of Percent Impending Relapse in Study 5

Note: A total of 202 patients were randomized. Among them, one patient in the placebo group did not take investigational medicinal product and one patient in the brexpiprazole group did not have post-randomization efficacy evaluations. These two patients were excluded from the efficacy analysis.