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Brexpiprazole AD Agitation

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

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Year of Publication: 2023

Authors: Lee D, Slomkowski M, Hefting N, ..., Grossberg GT

Journal: JAMA Neurology

Citation: JAMA Neurol. 2023;80(12):1307-1316. doi:10.1001/jamaneurol.2023.3810

Link: https://doi.org/10.1001/jamaneurol.2023.3810

Clinical Question

Is brexpiprazole an efficacious, safe, and well-tolerated treatment for agitation in patients with Alzheimer dementia?

Bottom Line

In patients with Alzheimer dementia, brexpiprazole 2 or 3 mg/d produced a statistically significant improvement in agitation (CMAI) versus placebo over 12 weeks and was generally well tolerated, supporting it as a treatment option for this vulnerable population.

        Major Points
        Brexpiprazole 2 or 3 mg/d significantly reduced CMAI total score vs placebo at week 12 (LSM difference −5.32; 95% CI −8.77 to −1.87; P=.003).
Cohen d effect size was 0.35.
Mean CMAI change: −22.6 (brexpiprazole) vs −17.3 (placebo) from efficacy-sample baselines of 80.6 and 79.2 respectively.
Completion rates were high and similar: 86.8% (brexpiprazole) and 88.9% (placebo).
No TEAE occurred at ≥5% incidence on brexpiprazole with greater frequency than placebo; headache was the only TEAE reaching 5% (6.6% vs 6.9%).
Discontinuations due to adverse events were similar (5.3% vs 4.3%).
One death occurred (3 mg group, cardiac failure) judged unrelated to brexpiprazole.

      

Design

Study Type: Phase 3, multicenter, double-blind, placebo-controlled, fixed-dose, parallel-arm randomized clinical trial

Randomization: 1

Blinding: Double-blind (patients, caregivers, investigators, and sponsor personnel including data analysts blinded)

Allocation: 2:1 brexpiprazole vs placebo; within brexpiprazole arm, further randomization 1:2 to 2 mg/d or 3 mg/d; fixed-block (block size 3) computer-generated, stratified by site

Enrollment Period: May 16, 2018 to June 1, 2022

Follow-up Duration: 12 weeks

Centers: 123

Countries: United States, Bulgaria, Hungary, Serbia, Slovakia, Spain, Ukraine

Sample Size: 345

Analyzed: 342

Analysis: Mixed model for repeated measures (MMRM) including all observed data; hierarchical testing to control type I error (primary at .035 two-sided gate to key secondary CGI-S)

Power Calculation: Details provided in eMethods (Supplement 2); not specified in source text

Registration: ClinicalTrials.gov NCT03548584

Inclusion Criteria

Age 55 to 90 years
Diagnosis of probable Alzheimer disease per NINCDS-ADRDA criteria
Previous CT or MRI consistent with Alzheimer disease
MMSE score of 5 to 22 at screening and baseline
Agitation meeting IPA provisional definition
Onset of agitation at least 2 weeks prior to screening
NPI or NPI-NH Agitation/Aggression domain score (frequency × severity) of 4 or greater at screening and baseline
Requiring pharmacotherapy for agitation in investigator's judgment after evaluation for reversible factors and trial of non-pharmacological interventions
Living in a care facility or community-based setting (not living alone)
Identified caregiver with sufficient contact to describe symptoms
Positivity for CMAI factor 1 (aggressive behavior) per defined frequency thresholds

Exclusion Criteria

Dementia or memory impairment due to a reason other than Alzheimer disease
Any clinically significant neurological, psychiatric (except as specified), or unstable medical condition
Use of antipsychotics, mood stabilizers, or anticonvulsants during the trial
Benzodiazepines beyond limited use in the first 4 weeks of double-blind treatment

Baseline Characteristics

Mean Age (years): 74.0 (SD 7.5)

Age Range: 56-90

Female: 195/345 (56.5%)

Male: 150/345 (43.5%)

Asian: 4 (1.2%)

Black: 12 (3.5%)

Hispanic: 108 (31.3%)

White: 329 (95.4%)

Moderate cognitive impairment (MMSE 13-18): 193 (55.9%)

Baseline CMAI (brexpiprazole): 80.4 (SD 16.7)

Baseline CMAI (placebo): 79.4 (SD 17.6)

On stable AD medications (brexpiprazole): 184 (81.4%)

On stable AD medications (placebo): 95 (81.9%)

Concomitant agitation medications, mostly lorazepam (brexpiprazole): 44 (19.5%)

Concomitant agitation medications, mostly lorazepam (placebo): 17 (14.7%)

Arms

Field	Brexpiprazole 2 or 3 mg/d	Control
N	228	117
Intervention	Oral brexpiprazole 2 mg/d or 3 mg/d (1:2 ratio within arm), taken once daily for 12 weeks; stable background AD medications permitted	Matching oral placebo tablets once daily for 12 weeks
Duration	12 weeks	12 weeks

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Change in Cohen-Mansfield Agitation Inventory (CMAI) total score from baseline to week 12 for brexpiprazole 2 or 3 mg vs placebo	Primary	Baseline 79.2; mean change −17.3 (n=116)	Baseline 80.6; mean change −22.6 (n=225)	Cohen d 0.35; LSM difference −5.32	0.003
Change from baseline to week 12 in CGI-S score as related to agitation (key secondary, tested if primary significant at .035 level)	Secondary	n=225 (brexpiprazole) vs 116 (placebo); baseline 4.7 vs 4.7; LS mean change −1.2 vs −0.9; LS mean difference −0.27 (95% CI −0.47 to −0.07); P=.008; Cohen d 0.31
CMAI factor scores, CGI-I score, CMAI/CGI-I response rates (tested at nominal .05, no multiplicity adjustment)	Secondary	CMAI factor 1 (aggressive behavior) difference −1.95 (95% CI −3.28 to −0.63), P=.004, Cohen d 0.33; CMAI factor 2 (physically non-aggressive) difference −1.41 (−2.68 to −0.14), P=.03, d=0.25; CMAI factor 3 (verbally agitated) difference −1.24 (−2.21 to −0.28), P=.01, d=0.29; CGI-I week-12 score (LOCF) 2.7 vs 3.0, difference −0.33 (−0.57 to −0.09), P=.007; Response-rate ratios (brexpiprazole/placebo): CMAI ≥20% improvement 1.41 (1.15 to 1.72), P<.001; CMAI ≥30% 1.62 (1.18 to 2.23), P=.002; CMAI ≥40% 1.62 (1.00 to 2.61), P=.03; improvement in agitation status 1.47 (1.14 to 1.89), P=.002; CGI-I very much/much improved 1.32 (1.03 to 1.69), P=.02
Exploratory: NPI-NH total score, CMAI total score by dose, CGI-S score by dose	Secondary	NPI-NH total score: n=215 vs 111; baseline 37.7 vs 36.6; LS mean change −17.3 vs −12.7; difference −4.60 (95% CI −7.33 to −1.88); P=.001; Cohen d 0.39. Both 2-mg and 3-mg dose subgroups showed similar improvement vs placebo on CMAI total score with nominal significance; on CGI-S, nominal significance vs placebo was reached for the 3-mg dose
Any TEAE	Safety	Brexpiprazole: 92/226 (40.7%) · Placebo: 36/116 (31.0%)
Discontinuation due to adverse events	Safety	Brexpiprazole: 12/226 (5.3%) · Placebo: 5/116 (4.3%)
Headache (only TEAE ≥5% on brexpiprazole)	Safety	Brexpiprazole: 15 (6.6%) · Placebo: 8 (6.9%)
Mean (SD) body weight change at week 12	Safety	Brexpiprazole: +0.3 (2.8) kg (n=196) · Placebo: 0.0 (2.0) kg (n=104)
Weight gain ≥7% from baseline	Safety	Brexpiprazole: 3/196 (1.5%) · Placebo: 0/104 (0%)
Death	Safety	Brexpiprazole: 1 (3 mg subgroup; cardiac failure, considered unrelated to brexpiprazole) · Placebo: 0
Any cardiovascular TEAE	Adverse	Brexpiprazole 2 (0.9%); Placebo 1 (0.9%)
Any cerebrovascular TEAE	Adverse	Brexpiprazole 0; Placebo 0
Any extrapyramidal symptom-related TEAE	Adverse	Brexpiprazole 8 (3.5%); Placebo 0
Any somnolence/sedation TEAE	Adverse	Brexpiprazole 9 (4.0%); Placebo 1 (0.9%)
Any accident or injury TEAE (including fall)	Adverse	Brexpiprazole 5 (2.2%); Placebo 4 (3.4%)
Any metabolism and nutrition disorder TEAE	Adverse	Brexpiprazole 3 (1.3%); Placebo 2 (1.7%)
Severity	Adverse	Majority of TEAEs mild or moderate

Subgroup Analysis

Prespecified subgroup analyses of the primary efficacy end point by region, sex, race, age, dementia severity, and psychosis status (details in eFigure 4, Supplement 2).

Criticisms

Predominantly White population (95.4%) and limited Black representation (3.5%) may limit generalizability
Modest effect size (Cohen d 0.35) raises questions about clinical meaningfulness
Concomitant lorazepam use during the first 4 weeks may have affected agitation outcomes
Sponsor-employed authors (Otsuka, Lundbeck) involved in design, conduct, and analysis

Funding

Otsuka Pharmaceutical Development & Commercialization and H. Lundbeck (sponsors)

Based on: Brexpiprazole AD Agitation (JAMA Neurology, 2023)

Authors: Lee D, Slomkowski M, Hefting N, ..., Grossberg GT

Citation: JAMA Neurol. 2023;80(12):1307-1316. doi:10.1001/jamaneurol.2023.3810

Content summarized and formatted by NeuroTrials.ai.

Brexpiprazole AD Agitation

(2023)

Objective

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

Study Summary

• Brexpiprazole 2 or 3 mg/d reduced CMAI total score significantly more than placebo at week 12 (mean change −22.6 vs −17.3; LSM difference −5.32; 95% CI −8.77 to −1.87; P=.003)
• Cohen d effect size 0.35
• No TEAE had ≥5% incidence with brexpiprazole and greater than placebo; discontinuations due to AEs were 5.3% (brexpiprazole) vs 4.3% (placebo)

Intervention

Oral brexpiprazole 2 mg/d or 3 mg/d vs placebo for 12 weeks

Inclusion Criteria

Age 55-90 years; probable Alzheimer disease (NINCDS-ADRDA); MMSE 5-22; IPA-defined agitation with onset ≥2 weeks prior to screening; NPI/NPI-NH Agitation/Aggression domain score ≥4; CMAI factor 1 (aggressive behavior) positivity; living in care facility or community-based setting; identified caregiver

Study Design

Arms: Brexpiprazole 2 or 3 mg/d (n=228) vs Placebo (n=117)

Patients per Arm: Brexpiprazole 228; Placebo 117

Outcome

• Primary: CMAI total score change from baseline to week 12 — brexpiprazole −22.6 vs placebo −17.3; LSM difference −5.32 (95% CI −8.77 to −1.87); P=.003
• Cohen d effect size 0.35
• Headache was the only TEAE with ≥5% incidence on brexpiprazole (6.6% vs 6.9% placebo); one death in 3 mg group, considered unrelated to drug

Bottom Line

Major Points

Brexpiprazole 2 or 3 mg/d significantly reduced CMAI total score vs placebo at week 12 (LSM difference −5.32; 95% CI −8.77 to −1.87; P=.003).
Cohen d effect size was 0.35.
Mean CMAI change: −22.6 (brexpiprazole) vs −17.3 (placebo) from efficacy-sample baselines of 80.6 and 79.2 respectively.
Completion rates were high and similar: 86.8% (brexpiprazole) and 88.9% (placebo).
No TEAE occurred at ≥5% incidence on brexpiprazole with greater frequency than placebo; headache was the only TEAE reaching 5% (6.6% vs 6.9%).
Discontinuations due to adverse events were similar (5.3% vs 4.3%).
One death occurred (3 mg group, cardiac failure) judged unrelated to brexpiprazole.

Study Design

Study Type: Phase 3, multicenter, double-blind, placebo-controlled, fixed-dose, parallel-arm randomized clinical trial
Randomization: Yes
Blinding: Double-blind (patients, caregivers, investigators, and sponsor personnel including data analysts blinded)
Sample Size: 345
Follow-up: 12 weeks
Centers: 123
Countries: United States, Bulgaria, Hungary, Serbia, Slovakia, Spain, Ukraine

Primary Outcome

Definition: Change in Cohen-Mansfield Agitation Inventory (CMAI) total score from baseline to week 12 for brexpiprazole 2 or 3 mg vs placebo

Control	Intervention	HR/OR	P-value
Baseline 79.2; mean change −17.3 (n=116)	Baseline 80.6; mean change −22.6 (n=225)	- (−8.77 to −1.87)	0.003

Limitations & Criticisms

Predominantly White population (95.4%) and limited Black representation (3.5%) may limit generalizability
Modest effect size (Cohen d 0.35) raises questions about clinical meaningfulness
Concomitant lorazepam use during the first 4 weeks may have affected agitation outcomes
Sponsor-employed authors (Otsuka, Lundbeck) involved in design, conduct, and analysis

Citation

JAMA Neurol. 2023;80(12):1307-1316. doi:10.1001/jamaneurol.2023.3810

View Original Publication →

Brexpiprazole AD Agitation

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

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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