Brexpiprazole for the Treatment of Agitation in Alzheimer Dementia: A Randomized Clinical Trial

Abstract

Importance: Agitation is a prevalent, distressing, and burdensome manifestation of Alzheimer dementia in need of an efficacious, safe, and well-tolerated treatment.

Objective: To confirm the efficacy, safety, and tolerability of brexpiprazole in patients with agitation in Alzheimer dementia.

Design, setting, and participants: This randomized clinical trial was a 12-week, double-blind, placebo-controlled, fixed-dose, parallel-arm trial that ran from May 2018 to June 2022 at 123 clinical trial sites in Europe and the United States. Participants included patients with agitation in Alzheimer dementia in a care facility or community-based setting. Stable Alzheimer disease medications were permitted.

Interventions: In this 2-arm trial, patients were randomized to receive oral brexpiprazole or placebo (2:1 ratio) for 12 weeks. Within the brexpiprazole arm, patients were further randomized to receive fixed doses of 2 mg/d or 3 mg/d in a 1:2 ratio.

Main outcomes and measures: The primary end point was change in Cohen-Mansfield Agitation Inventory total score (which measures the frequency of 29 agitated behaviors) from baseline to week 12 for brexpiprazole, 2 or 3 mg, vs placebo. Safety was assessed by standard measures, including treatment-emergent adverse events.

Results: A total of 345 patients were randomized to receive brexpiprazole (n = 228) or placebo (n = 117); completion rates were 198 (86.8%) for brexpiprazole and 104 (88.9%) for placebo. Mean (SD) age was 74.0 (7.5) years, and 195 of 345 patients were female (56.5%). Patients receiving brexpiprazole, 2 or 3 mg (n = 225), demonstrated statistically significantly greater improvement than those taking placebo (n = 116) in Cohen-Mansfield Agitation Inventory total score from baseline to week 12 (brexpiprazole baseline, 80.6, mean change, -22.6; placebo baseline, 79.2, mean change, -17.3; least-squares mean difference, -5.32; 95% CI, -8.77 to -1.87; P = .003; Cohen d effect size, 0.35). No treatment-emergent adverse events had an incidence of 5% or more with brexpiprazole and greater incidence than placebo. The proportion of patients who discontinued because of adverse events was 12 of 226 (5.3%) for brexpiprazole and 5 of 116 (4.3%) for placebo.

Conclusions and relevance: In this study, patients with Alzheimer dementia who took brexpiprazole, 2 or 3 mg, showed a statistically significant improvement vs placebo in agitation over 12 weeks. Brexpiprazole was generally well tolerated over 12 weeks in this vulnerable patient population.

Trial registration: ClinicalTrials.gov Identifier: NCT03548584.

Figure 1.. Patient Disposition

^aDefined as a patient who provided informed consent but was not randomized. The top 5 categories of screen failure were blinded Cohen-Mansfield Agitation Inventory (CMAI) factor 1 criterion, investigator or sponsor discretion, unstable diabetes, abnormal test results (laboratory tests, vital signs, electrocardiograms), and Mini-Mental State Examination score. ^bIn the brexpiprazole group, the efficacy sample comprised 226 patients who took at least 1 dose of study drug and who had a baseline and postbaseline CMAI measurement. However, 1 patient was excluded from efficacy analyses because their only postbaseline CMAI measurement was outside of the visit window.

Figure 2.. Change From Baseline in Cohen-Mansfield Agitation Inventory (CMAI) Total Score (Primary End Point) and Clinical Global Impression–Severity of Illness (CGI-S) Score as Related to Agitation (Key Secondary End Point): Efficacy Sample

Baseline mean CMAI total scores: brexpiprazole, 80.6; placebo, 79.2. Baseline mean CGI-S scores: brexpiprazole, 4.7; placebo, 4.7. Footnotes indicate nominal P values with no adjustment for multiplicity. ^aP < .01 vs placebo, mixed model for repeated measures. ^bP < .001 vs placebo, mixed model for repeated measures.