A Trial to Evaluate the Safety, Efficacy, and Tolerability of Brexpiprazole in Treating Agitation Associated With Dementia of the Alzheimer's Type

NCT03548584 | Completed Phase 3 Results FDA Drug

• 1 other identifier: 331-14-213
• Study Type: interventional
• Target: 345
• Locations: 1 country
• Sites: 1

Brief Summary

This study compares the efficacy of 2 doses of brexpiprazole with placebo in participants with agitation associated with dementia of the Alzheimer's type.

Conditions

Agitation Associated With Alzheimer's Dementia; Alzheimer Dementia

Keywords

Agitation

Outcome Measures

Primary Outcomes (1)

• Change From Baseline to Week 12 in the CMAI Total Score

  The CMAI score is used to assess the frequency of manifestations of agitated behaviors in participants. The CMAI consists of 29 agitated behaviors that are rated on a 7-point scale of frequency across four subscales of aggressive behavior, physically nonaggressive behavior, verbally agitated behavior and hiding and hoarding as: 1=never; 2=less than once a week; 3=once or twice a week; 4=several times a week; 5=once or twice a day; 6=several times a day; 7=several times an hour. The CMAI total score ranges from 29 to 203. Higher scores indicate worsening of the condition. A negative change from baseline indicates improvement. Mixed model repeated measures (MMRM) was used for the analysis. As prespecified in the statistical analysis plan (SAP), data for this outcome measure was analyzed and reported in a combined way for brexpiprazole 2 and 3 mg.

  Baseline and Week 12

Secondary Outcomes (8)

• Change From Baseline to Week 12 in the Clinical Global Impression Severity of Illness (CGI-S) Score, as Related to Agitation

  Baseline and Week 12

• Change From Baseline to Week 12 in CMAI Subscale Scores

  Baseline and Week 12

• Change From Baseline in CMAI Total Score for Each Trial Visit During the Double-blind Treatment Period

  Baseline, Weeks 2, 4, 6, 8, 10, and 12

• Change From Baseline in CGI-S for Each Trial Visit During the Double-Blind Treatment Period

  Baseline, Weeks 2, 4, 6, 8, 10, and 12

• Clinical Global Impressions-Improvement (CGI-I) Score at Each Trial Visit During the Double-Blind Treatment Period

  Baseline, Weeks 2, 4, 6, 8, 10, and 12

Study Arms (3)

Brexpiprazole 2 mg

EXPERIMENTAL

Participants followed a titration schedule, to gradually increase their dose from 0.5 milligrams per day (mg/day) in the starting to 2 mg/day from Day 15. Participants continued to receive brexpiprazole 2 milligrams (mg), once daily until Week 12.

Drug: Brexpiprazole

Brexpiprazole 3 mg

EXPERIMENTAL

Participants followed a titration schedule, to gradually increase their dose from 0.5 mg/day in the starting to 3 mg/day from Day 29. Participants continued to receive brexpiprazole 3 mg, once daily until Week 12.

Drug: Brexpiprazole

Placebo

PLACEBO COMPARATOR

Participants received matching placebo, once daily for 12 weeks.

Other: Placebo

Interventions

Brexpiprazole DRUG

Oral tablets

Also known as: OPC-34712

Brexpiprazole 2 mg; Brexpiprazole 3 mg

Placebo OTHER

Oral tablets

Placebo

Eligibility Criteria

• Age: 55 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants with a diagnosis of probable Alzheimer's disease.
• Participants with a diagnosis of agitation
• Participants with a MMSE score of 5 to 22, inclusive, at screening and baseline visits.
• Participants with a previous MRI or CT scan of the brain, that was performed after the onset of symptoms of dementia, with findings consistent with a diagnosis of Alzheimer's disease.
• Participants who are residing at their current location for at least 28 days before screening and are expected to remain at the same location for the duration of the trial.
• Institutionalized participants with an identified caregiver who has sufficient contact (minimum of 2 hours per day for 4 days per week) to describe the participant's symptoms and has direct observation of the participant's behavior. Non-institutionalized participants may not be living alone and must have an identified caregiver who has sufficient contact (minimum of 2 hours per day for 4 days per week) to describe the participant's symptoms and has direct observation of the participant's behavior.
• Participants with onset of symptoms of agitation at least 2 weeks prior to screening visit.
• Participants will and able to discontinue all prohibited concomitant medications to meet protocol required washouts prior to and during the trial period.

You may not qualify if:

• Participants with dementia or other memory impairment not due to Alzheimer's disease.
• Participants with a history of stroke, well-documented transient ischemic attack, or pulmonary or cerebral embolism.
• Participants who had an insufficient response, based on the investigator's judgment, to 2 or more previous antipsychotic medications.
• Participants who have been diagnosed with an Axis I disorder.
• Participants who currently have clinically significant neurological, hepatic, renal, metabolic, hematological, immunological, cardiovascular, pulmonary, gastrointestinal, or psychiatric disorders.
• Participants with uncontrolled hypertension or symptomatic hypotension, or orthostatic hypotension.
• Participants with diabetes mellitus (insulin-dependent and non-insulin-dependent) may be eligible for the trial if their condition is stable and well-controlled.

Sponsors & Collaborators

• Otsuka Pharmaceutical Development & Commercialization, Inc.: lead
• H. Lundbeck A/S: collaborator

Study Sites (1)

For additional information regarding sites, contact 844-687-8522

Los Angeles, California, 90036, United States

Location

Related Publications (7)

• Cummings JL, Chumki SR, Chang D, Zhang Z, Brubaker M, Hefting N, Such P, Wang D, Grossberg GT. Efficacy of Brexpiprazole in Participants with Agitation Associated with Dementia Due to Alzheimer's Disease: Pooled Analysis of Randomized Controlled Trials. Clin Drug Investig. 2026 Jan 27. doi: 10.1007/s40261-025-01517-9. Online ahead of print.

  PMID: 41591746 DERIVED

• Shah A, Kalu U, Chen D, Slomkowski M, Hobart M, Such P, Grossberg GT. Brexpiprazole side-effect profile in people with agitation in Alzheimer's dementia: a plain language summary. Curr Med Res Opin. 2026 Jan 14:1-3. doi: 10.1080/03007995.2025.2608578. Online ahead of print.

  PMID: 41533472 DERIVED

• Grossberg GT, Sabbagh MN, Chumki SR, Wang D, Such P, Zhang Z, Palma AM, Cummings JL. Efficacy of Brexpiprazole on Neuropsychiatric Symptoms and Impact on Caregivers: Pooled Neuropsychiatric Inventory (NPI) Analysis in Patients With Agitation Associated With Dementia due to Alzheimer's Disease. J Geriatr Psychiatry Neurol. 2025 Dec 24:8919887251407124. doi: 10.1177/08919887251407124. Online ahead of print.

  PMID: 41439450 DERIVED

• Stroud J, Cummings JL, Chumki SR, Such P, Wang D, Palma AM, Zhang Z, Brubaker M, Grossberg GT. Brexpiprazole for agitation in clinically relevant patient subgroups: a post hoc analysis of efficacy and safety in patients with agitation associated with dementia due to Alzheimer's disease. Curr Med Res Opin. 2025 Aug;41(8):1523-1534. doi: 10.1080/03007995.2025.2552278. Epub 2025 Sep 5.

  PMID: 40847656 DERIVED

• Shah A, Estilo A, Sheridan PL, Kalu U, Chen D, Chang D, Slomkowski M, Lee D, Hefting N, Hobart M, Behl S, Such P, Brubaker M, Grossberg GT. Safety and Tolerability of Brexpiprazole in Participants with Agitation Associated with Dementia due to Alzheimer's Disease: Pooled Analysis of Three Randomized Trials and an Extension Trial. CNS Drugs. 2025 Oct;39(10):1011-1023. doi: 10.1007/s40263-025-01200-9. Epub 2025 Jul 19.

  PMID: 40681915 DERIVED

• Meunier J, Creel K, Loubert A, Larsen KG, Aggarwal J, Hefting N, Oberdhan D. Defining a clinically meaningful within-patient change threshold for the Cohen-Mansfield Agitation Inventory in Alzheimer's dementia. Front Neurol. 2024 Jul 23;15:1379062. doi: 10.3389/fneur.2024.1379062. eCollection 2024.

  PMID: 39108660 DERIVED

• Lee D, Slomkowski M, Hefting N, Chen D, Larsen KG, Kohegyi E, Hobart M, Cummings JL, Grossberg GT. Brexpiprazole for the Treatment of Agitation in Alzheimer Dementia: A Randomized Clinical Trial. JAMA Neurol. 2023 Dec 1;80(12):1307-1316. doi: 10.1001/jamaneurol.2023.3810.

  PMID: 37930669 DERIVED

MeSH Terms

Conditions

Alzheimer Disease; Psychomotor Agitation

Interventions

brexpiprazole

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Dyskinesias; Neurologic Manifestations; Psychomotor Disorders; Neurobehavioral Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Aberrant Motor Behavior in Dementia; Behavioral Symptoms; Behavior

Results Point of Contact

• Title: Director of Clinical Trials
• Organization: Otsuka Pharmaceutical Co., LTD.

CL_OPCJ_RDA_Team@otsuka.jp

+81-3-6361-7366

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 7, 2018
• First Posted: June 7, 2018
• Study Start: May 16, 2018
• Primary Completion: May 23, 2022
• Study Completion: June 1, 2022
• Last Updated: September 18, 2023
• Results First Posted: September 18, 2023

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR
• Time Frame: Data will be available after marketing approval in global markets, or beginning 1-3 years following article publication. There is no end date to the availability of the data.
• Access Criteria: Otsuka will share data on the Vivli data sharing platform which can be found here: https://vivli.org/ourmember/Otsuka/

Locations

US (1)