A Phase 3, 12-week, Multicenter, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy, Safety, and Tolerability of 2 Fixed Doses of Brexpiprazole in the Treatment of Alzheimer's Agitation

A Phase 3, 12-week, Multicenter, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy, Safety, and Tolerability of 2 Fixed Doses of Brexpiprazole (OPC-34712) in the Treatment of Subjects With Agitation Associated With Dementia of the Alzheimer's Type

To compare the efficacy of 2 fixed doses of brexpiprazole with placebo in participants with agitation associated with dementia of the Alzheimer's type.

Study Overview

• Status: Completed
• Conditions: Nervous System Diseases; Alzheimer's Disease; Mental Disorder; Agitation Associated With; Alzheimer's Type
• Intervention / Treatment: Drug: Placebo Oral Tablet; Drug: Brexpiprazole, OPC-34712

Detailed Description

Behavioral symptoms, such as agitation, are core features in participants with Alzheimer's disease and related dementias and develop in the majority of dementia participants. The presence of agitation in participants with Alzheimer's disease places a significant burden not only on participants and their caregivers but also on the healthcare system.

This is a trial designed to assess the safety and efficacy of brexpiprazole in the treatment of participants with agitation associated with dementia of the Alzheimer's Type. The trial consists of a continuous 12-week double-blind treatment period with a 30-day follow-up. The trial population will include male and female participants between 55 and 90 years of age (inclusive) with a diagnosis of probable Alzheimer's disease, who are residing either in an institutionalized setting or in a non-institutionalized setting where the participant is not living alone.

• Study Type: Interventional
• Enrollment (Actual): 433
• Phase: Phase 3

Contacts and Locations

Study Locations

• Croatia
  • Rijeka, Croatia, 57000
  • Zadar, Croatia, 23000
  • Zagreb, Croatia, 10000
  • Zagreb, Croatia, 10090
• Germany
  • Achim, Germany, 28832
  • Berlin, Germany, 12209
  • Bielefeld, Germany, 33647
  • Bochum, Germany, 44791
  • Hamburg, Germany, 22083
  • Koln, Germany, 50935
  • Ostfildern, Germany, 73760
  • Westerstede, Germany, 26655
  • Saxony
    • Mittweida, Saxony, Germany, 09648
• Russian Federation
  • Ekaterinburg, Russian Federation, 620030
  • Samara, Russian Federation, 443016
  • Saratov, Russian Federation, 410060
  • St. Petersburg, Russian Federation, 192019
  • St. Petersburg, Russian Federation, 197341
  • St. Petersburg, Russian Federation, 190000
  • St. Petersburg, Russian Federation, 190005
  • St. Petersburg, Russian Federation, 191119
  • St. Petersburg, Russian Federation, 198510
  • Tonnel'nyy, Russian Federation, 357034
• Serbia
  • Belgrade, Serbia, 11000
  • Kovin, Serbia, 26220
  • Kragujevac, Serbia, 34000
  • Nis, Serbia, 18000
  • Novi Knezevac, Serbia, 23330
  • Novi Sad, Serbia, 21000
  • Vrsac, Serbia, 26300
• Spain
  • Barcelona, Spain, 08028
  • Getafe, Spain, 28905
  • Girona, Spain, 17190
  • Madrid, Spain, 28040
  • Madrid, Spain, 28034
  • Madrid, Spain, 28049
  • Pamplona, Spain, 31014
  • Salamanca, Spain, 37003
  • Valencia, Spain, 46026
  • Valencia, Spain, 46010
  • Zamora, Spain, 49021
• Ukraine
  • Kharkiv, Ukraine, 61068
  • Kherson, Ukraine, 73488
  • Kiev, Ukraine, 04080
  • Lviv, Ukraine, 79021
  • Odessa, Ukraine, 65006
  • Odessa, Ukraine, 67513
  • Poltava, Ukraine, 36013
• United States
  • Alabama
    • Tuscaloosa, Alabama, United States, 35404
  • Arizona
    • Phoenix, Arizona, United States, 85013
  • California
    • Bellflower, California, United States, 90706
    • Costa Mesa, California, United States, 92627
    • Downey, California, United States, 90706
    • Orange, California, United States, 92868
    • Redlands, California, United States, 92373
    • Yorba Linda, California, United States, 92886
  • Connecticut
    • Norwalk, Connecticut, United States, 06851
  • Florida
    • Coconut Creek, Florida, United States, 33024
    • Hialeah, Florida, United States, 33012
    • Hialeah, Florida, United States, 33013
    • Hialeah, Florida, United States, 33018
    • Lauderhill, Florida, United States, 33319
    • Miami, Florida, United States, 33137
    • Miami, Florida, United States, 33136
    • Miami, Florida, United States, 33126
    • Miami, Florida, United States, 33145
    • Miami, Florida, United States, 33122
    • Miami, Florida, United States, 33161
    • Miami, Florida, United States, 33174
    • Miami Springs, Florida, United States, 33166
    • Sarasota, Florida, United States, 34239
  • Georgia
    • Decatur, Georgia, United States, 30033
    • Suwanee, Georgia, United States, 30024
  • Massachusetts
    • Weymouth, Massachusetts, United States, 02190
  • Missouri
    • Saint Louis, Missouri, United States, 63141
    • Saint Louis, Missouri, United States, 63128
  • Nevada
    • Las Vegas, Nevada, United States, 89148
  • New Jersey
    • Manchester, New Jersey, United States, 08759
    • Mount Arlington, New Jersey, United States, 07856
    • Toms River, New Jersey, United States, 08755
  • North Carolina
    • Hickory, North Carolina, United States, 28601
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73118
  • Tennessee
    • Franklin, Tennessee, United States, 37064
  • Texas
    • Bedford, Texas, United States, 76022
  • Wisconsin
    • Waukesha, Wisconsin, United States, 53188

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years to 90 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male and female participants 55 to 90 years of age, inclusive, at the time of informed consent.
• Participants who are residing at their current location for at least 14 days before screening and are expected to remain at the same location for the duration of the trial.
• Participants with a diagnosis of probable Alzheimer's disease according to National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association.
• Participants with a Mini-Mental State Exam score of 5 to 22, inclusive, at screening and baseline visits.
• Participants with onset of symptoms of agitation at least 2 weeks prior to the screening visit.
• Participants with a score of ≥ 4 on the agitation/aggression item of the Neuropsychiatric Inventory-Nursing Home at the screening and baseline visits.
• Participants who require pharmacotherapy for treatment of agitation per the investigator's judgment, after an evaluation for reversible factors (for example, pain, infection, polypharmacy) and a trial of nonpharmacological intervention.
• Participants must have a previous magnetic resonance imaging or computed tomography of the brain, which was performed after the onset of symptoms of dementia, with findings consistent with the diagnosis of Alzheimer's disease.

Exclusion Criteria:

• Participants with dementia or other memory impairment not due to Alzheimer's disease
• Participants with a history of stroke, well-documented transient ischemic attack, pulmonary or cerebral embolism.
• Participants who currently have clinically significant neurological, hepatic, renal, metabolic, hematological, immunological, cardiovascular, pulmonary, gastrointestinal, or psychiatric disorders.
• Participants who have been diagnosed with an Axis I disorder (Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision criteria)
• Participants with uncontrolled hypertension
• Participants with uncontrolled insulin-dependent diabetes mellitus
• Participants with epilepsy or a history of seizures
• Participants considered in poor general health based on the investigator's judgment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo; Matching placebo once daily	Drug: Placebo Oral Tablet; Once-daily, tablets
EXPERIMENTAL: Brexpiprazole 1 mg; Titrate up from 0.25 milligrams (mg)/day brexpiprazole to 1 mg/day brexpiprazole	Drug: Brexpiprazole, OPC-34712; Once-daily, tablets
EXPERIMENTAL: Brexpiprazole 2 mg; Titrate up from 0.25 mg/day brexpiprazole to 2 mg/day brexpiprazole	Drug: Brexpiprazole, OPC-34712; Once-daily, tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline In The Cohen-Mansfield Agitation Inventory (CMAI) Total Score After 12 Weeks Of Brexpiprazole Treatment	To compare the efficacy of 2 fixed doses (1 mg/day and 2 mg/day) of brexpiprazole with placebo in participants with agitation associated with dementia of the Alzheimer's type, by the assessment of CMAI after 12 weeks of treatment. The CMAI assesses the frequency of agitated behaviors in elderly persons, such as hitting, cursing, and restlessness. It consists of 29 items all rated on a 1 to 7 scale with 1 being the "best" rating and 7 being the "worst" rating. The minimum possible CMAI total score is 29, and the maximum possible CMAI total score is 203. A decrease in score indicates improvement in symptoms. To control the overall type I error at 0.05 level when making 2 comparisons of brexpiprazole doses versus placebo, statistical testing was carried out using a hierarchical testing procedure in the order of: 1) comparison of 2 mg/day brexpiprazole versus placebo, and 2) comparison of 1 mg/day brexpiprazole versus placebo.	Baseline, Week 12/Early Termination (ET)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline In The Clinical Global Impression-Severity Of Illness (CGI-S) Score, As Related To Symptoms Of Agitation After 12 Weeks Of Brexpiprazole Treatment	To compare the efficacy of 2 fixed doses (1 mg/day and 2 mg/day) of brexpiprazole with placebo in participants with agitation associated with Alzheimer's dementia, by the assessment of CGI-S score after 12 weeks of treatment. The CGI-S was used to rate the severity of agitation. Scores were: 0 = not assessed; 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants. A decrease in score indicates improvement in symptoms.	Baseline, Week 12/ET

Collaborators and Investigators

• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
• Collaborators: H. Lundbeck A/S

Publications and helpful links

General Publications

• Grossberg GT, Kohegyi E, Mergel V, Josiassen MK, Meulien D, Hobart M, Slomkowski M, Baker RA, McQuade RD, Cummings JL. Efficacy and Safety of Brexpiprazole for the Treatment of Agitation in Alzheimer's Dementia: Two 12-Week, Randomized, Double-Blind, Placebo-Controlled Trials. Am J Geriatr Psychiatry. 2020 Apr;28(4):383-400. doi: 10.1016/j.jagp.2019.09.009. Epub 2019 Oct 1.

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 11, 2013
• Primary Completion (ACTUAL): March 15, 2017
• Study Completion (ACTUAL): March 15, 2017

Study Registration Dates

• First Submitted: May 22, 2013
• First Submitted That Met QC Criteria: May 22, 2013
• First Posted (ESTIMATE): May 24, 2013

Study Record Updates

• Last Update Posted (ACTUAL): December 31, 2020
• Last Update Submitted That Met QC Criteria: December 8, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: Alzheimer's Disease; Dementia; Agitation; OPC-34712; brexpiprazole; Cognitive Disorders
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Neurocognitive Disorders; Neurodegenerative Diseases; Dyskinesias; Psychomotor Disorders; Dementia; Tauopathies; Psychomotor Agitation; Mental Disorders; Nervous System Diseases; Alzheimer Disease; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Serotonin Agents; Dopamine Agonists; Dopamine Agents; Brexpiprazole
• Other Study ID Numbers: 331-12-283

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Anonymized Individual participant data (IPD) that underlie the results of this study will be shared with researchers to achieve aims pre-specified in a methodologically sound research proposal. Small studies with less than 25 participants are excluded from data sharing.
• IPD Sharing 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.
• IPD Sharing Access Criteria: Otsuka will share data on an Otsuka-owned remotely accessible data sharing platform with Python and R analytical software. Research requests should be directed to clinicaltransparency@Otsuka-us.com
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR