Short-Term and Long-Term Safety Analyses of Brexpiprazole for Agitation Associated with Dementia due to Alzheimer's Disease: Timing and Duration of Adverse Events.

INTRODUCTION: Agitation symptoms are a common and burdensome aspect of Alzheimer's dementia. Historically, agitation has been managed using off-label treatments such as atypical antipsychotics, but this approach is associated with safety concerns in older, more vulnerable patients. Brexpiprazole is an atypical antipsychotic that has been recently approved in several countries for the treatment of agitation associated with dementia due to Alzheimer's disease. Previous analyses show that brexpiprazole was efficacious and generally well tolerated for up to 24 weeks. Building upon previous work, this post hoc analysis aimed to evaluate the timing and duration of treatment-emergent adverse events (TEAEs) during brexpiprazole treatment. METHODS: In a 12-week analysis, data were pooled from three phase 3, randomized, double-blind, placebo-controlled trials of brexpiprazole in participants with agitation associated with dementia due to Alzheimer's disease. In a separate 24-week analysis, brexpiprazole data were combined from a 12-week randomized trial and a 12-week active-treatment extension trial. The median time from starting treatment to first reporting a TEAE and the median duration of all TEAEs were determined. RESULTS: A total of 1043 participants received at least one dose of trial medication. Over 12 weeks, brexpiprazole 2 or 3 mg/day (the approved therapeutic dosages in the United States, N = 366) compared to placebo (N = 388) had similar time to first TEAE (32 days and 28 days, respectively), similar duration of all TEAEs (6 days and 4 days), and longer time to discontinuation due to adverse events (47 days and 30 days). Over 24 weeks (N = 163), the time to first TEAE on brexpiprazole 2 or 3 mg/day was 52 days, and the duration of all TEAEs was 3 days. Among participants who did not report a TEAE in the 12-week parent trial, TEAEs were rare throughout the 12-week extension trial. CONCLUSIONS: These exploratory analyses reinforce that brexpiprazole is generally well tolerated over 12 weeks, and also over 24 weeks among patients who tolerated the first 12 weeks of treatment. The results provide a practical clinical insight into the safety of brexpiprazole over time in patients with agitation associated with dementia due to Alzheimer's disease. TRIAL REGISTRATION: Post hoc analysis of NCT01862640, NCT01922258, NCT03548584, NCT03594123 (ClinicalTrials.gov). Alzheimer’s dementia is a brain disorder in which a person’s thinking and memory gradually worsen over time. Alzheimer’s dementia can also change a person’s behavior, with symptoms of agitation being common. Agitation may be non-aggressive, such as restlessness, repeating the same question, or pacing around the room, or aggressive, such as pushing or hitting. Agitation can worsen a person’s other symptoms and make life more difficult and distressing for their caregiver. Agitation requires separate treatment from those used for thinking and memory symptoms. Historically, medications such as antipsychotics have been used for agitation. However, some antipsychotics are linked to harmful side effects, such as stroke, heart failure, restlessness, dizziness, falls, sleepiness, and drowsiness. Brexpiprazole is an antipsychotic medicine that can treat agitation and that appears to be generally well tolerated. In clinical trials, few people taking brexpiprazole had a stroke, heart failure, restlessness, dizziness, falls, sleepiness, or drowsiness, and the numbers were similar to placebo (dummy drug). In this study, researchers investigated when and for how long these ‘adverse events’ occurred after starting brexpiprazole. The results showed that adverse events occurred at around the same time and lasted for about the same duration whether people took brexpiprazole or placebo. This means that the study reinforced the safety of brexpiprazole when treating agitation in people with Alzheimer’s dementia.