Efficacy and Safety of Brexpiprazole for the Treatment of Agitation in Alzheimer's Dementia: Two 12-Week, Randomized, Double-Blind, Placebo-Controlled Trials.

Abstract

OBJECTIVE:

To assess the efficacy, safety, and tolerability of brexpiprazole in patients with agitation in Alzheimer's dementia (AAD).

DESIGN:

Two 12-week, randomized, double-blind, placebo-controlled, parallel-arm studies (NCT01862640; NCT01922258).

SETTING:

Study 1: 81 sites in 7 countries. Study 2: 62 sites in 9 countries.

PARTICIPANTS:

Patients with AAD (Study 1: 433 randomized; Study 2: 270 randomized) in a care facility or community-based setting. Stable Alzheimer disease medications were permitted.

INTERVENTION:

Study 1 (fixed dose): brexpiprazole 2 mg/day, brexpiprazole 1 mg/day, or placebo (1:1:1) for 12 weeks. Study 2 (flexible dose): brexpiprazole 0.5-2 mg/day or placebo (1:1) for 12 weeks.

MEASUREMENTS:

Cohen-Mansfield Agitation Inventory (CMAI) (Total score range: 29-203; higher scores indicate more frequent agitated behaviors), and Clinical Global Impression - Severity of illness (CGI-S) as related to agitation. Safety was also assessed.

RESULTS:

In Study 1, brexpiprazole 2 mg/day demonstrated statistically significantly greater improvement in CMAI Total score from baseline to Week 12 than placebo (adjusted mean difference, -3.77; confidence limits, -7.38, -0.17; t(316) = -2.06; p = 0.040; MMRM). Brexpiprazole 1 mg/day did not show meaningful separation from placebo (0.23; -3.40, 3.86; t(314) = 0.12; p = 0.90; MMRM). In Study 2, brexpiprazole 0.5-2 mg/day did not achieve statistical superiority over placebo (-2.34; -5.49, 0.82; t(230) = -1.46; p = 0.15; MMRM). However, a benefit was observed in post hoc analyses among patients titrated to the maximum brexpiprazole dose of 2 mg/day compared with similarly titrated placebo patients (-5.06; -8.99, -1.13; t(144) = -2.54; p = 0.012; MMRM). On the CGI-S, a greater numerical improvement than placebo was demonstrated for brexpiprazole 2 mg/day in Study 1 (-0.16; -0.39, 0.06; t(337) = -1.42; nominal p = 0.16; MMRM), and a greater improvement for brexpiprazole 0.5-2 mg/day in Study 2 (-0.31; -0.55, -0.06; t(222) = -2.42; nominal p = 0.016; MMRM). In Study 1, treatment-emergent adverse events (TEAEs) with incidence ≥5% among patients receiving brexpiprazole 2 mg/day were headache (9.3% versus 8.1% with placebo), insomnia (5.7% versus 4.4%), dizziness (5.7% versus 3.0%), and urinary tract infection (5.0% versus 1.5%). In Study 2, TEAEs with incidence ≥5% among patients receiving brexpiprazole 0.5-2 mg/day were headache (7.6% versus 12.4% with placebo) and somnolence (6.1% versus 3.6%). In both studies, the majority of TEAEs were mild or moderate in severity.

CONCLUSIONS:

Brexpiprazole 2 mg/day has the potential to be efficacious, safe, and well tolerated in the treatment of AAD.

• Authors: George T Grossberg, Eva Kohegyi, Victor Mergel, Mette Krog Josiassen, Didier Meulien, Mary Hobart, Mary Slomkowski, Ross A Baker, Robert D McQuade, Jeffrey L Cummings
• Journal: The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry (Am J Geriatr Psychiatry) Vol. 28 Issue 4 Pg. 383-400 (04 2020) ISSN: 1545-7214 [Electronic] England
• PMID: 31708380 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Quinolones
• Thiophenes
• brexpiprazole

Topics

• Aged
• Aged, 80 and over
• Alzheimer Disease (diagnosis, drug therapy)
• Female
• Headache (etiology)
• Humans
• Internationality
• Male
• Middle Aged
• Psychiatric Status Rating Scales
• Psychomotor Agitation (diagnosis, drug therapy)
• Quinolones (administration & dosage, adverse effects)
• Sleep Initiation and Maintenance Disorders (etiology)
• Thiophenes (administration & dosage, adverse effects)
• Treatment Outcome