Safety and Tolerability Study of Flexible Dosing of Brexpiprazole in the Treatment of Subjects With Agitation Associated With Dementia of the Alzheimer's Type

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

To compare the efficacy of flexible dosing of brexpiprazole with placebo in subjects 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: Brexpiprazole, OPC-34712

Detailed Description

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

This is a trial designed to assess the safety and efficacy of flexible dosing of brexpiprazole in the treatment of subjects with agitation associated with dementia of the Alzheimer's type. The trial consists of a 12-week double-blind treatment period with a 30-day follow-up. The trial population will include male and female subjects 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 subject is not living alone.

• Study Type: Interventional
• Enrollment (Actual): 270
• Phase: Phase 3

Contacts and Locations

Study Locations

• Bulgaria
  • Burgas, Bulgaria, 8000
  • Kardzhali, Bulgaria, 6600
  • Pazardzhik, Bulgaria, 4400
  • Ruse, Bulgaria, 7003
  • Sofia, Bulgaria, 1431
  • Sofia, Bulgaria, 1113
  • Sofia, Bulgaria, 1154
  • Varna, Bulgaria, 9020
  • Veliko Tarnovo, Bulgaria, 5000
• Canada
  • Kentville, Canada, B4N 4K9
  • British Columbia
    • Penticton, British Columbia, Canada, V2A 4M4
• Finland
  • Kuopio, Finland, 70210
  • Turku, Finland, 20520
• France
  • Bourg en Bresse, France, 01012
  • Douai, France, 59500
  • Elancourt, France, 78990
  • Limoges, France, 87042
  • Nice, France, 06100
  • Toulouse, France, 31059
• Russian Federation
  • Ekaterinburg, Russian Federation, 620030
  • Saratov, Russian Federation, 410060
  • St. Petersburg, Russian Federation, 197341
  • St. Petersburg, Russian Federation, 190005
  • St. Petersburg, Russian Federation, 195176
  • St. Petersburg, Russian Federation, 188820
  • Stavropol Region
    • Tonnel'nyy, Stavropol Region, Russian Federation, 357034
• Slovenia
  • Ljubljana, Slovenia, 1000
  • Maribor, Slovenia, 2000
  • Sempeter pri Gorici, Slovenia, 5290
• Ukraine
  • Donetsk, Ukraine, 83037
  • Kharkiv, Ukraine, 61068
  • Kharkov, Ukraine, 61068
  • Kherson, Ukraine, 73488
  • Kiev, Ukraine, 04080
  • Kiev, Ukraine, 04114
  • Lviv, Ukraine, 79021
  • Poltava, Ukraine, 36013
  • Simferopol, Ukraine, 95006
  • Vinnytsia, Ukraine, 21005
• United Kingdom
  • Crewe, United Kingdom, CW1 2ER
  • Manchester, United Kingdom, M8 5RB
  • Margate, United Kingdom, CT20 1JY
  • Torpoint, United Kingdom, PL11 2TB
• United States
  • California
    • Imperial, California, United States, 92251
    • Lakewood, California, United States, 08755
    • Long Beach, California, United States, 90806
    • Long Beach, California, United States, 90822
    • Panorama City, California, United States, 91402
    • Universal City, California, United States, 91950
  • Colorado
    • Denver, Colorado, United States, 80209
  • Florida
    • Bradenton, Florida, United States, 34205
    • Miami, Florida, United States, 33165
    • Miami, Florida, United States, 33176
    • Miami, Florida, United States, 33142
    • Orange City, Florida, United States, 32763
  • Georgia
    • Atlanta, Georgia, United States, 30331
    • Smyrna, Georgia, United States, 30080
  • Hawaii
    • Honolulu, Hawaii, United States, 96817
  • Indiana
    • Indianapolis, Indiana, United States, 46256
  • Massachusetts
    • Quincy, Massachusetts, United States, 02169
    • South Dartmouth, Massachusetts, United States, 02747
  • Michigan
    • Ann Arbor, Michigan, United States, 48105
  • New York
    • Brooklyn, New York, United States, 11214
    • Buffalo, New York, United States, 14215
    • New Hyde Park, New York, United States, 11040
  • North Carolina
    • Charlotte, North Carolina, United States, 28270
    • Raleigh, North Carolina, United States, 27609
  • Texas
    • Austin, Texas, United States, 78757
    • Dallas, Texas, United States, 75231
    • Dallas, Texas, United States, 75243
  • Vermont
    • Woodstock, Vermont, United States, 05091

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 subjects 55 to 90 years of age, inclusive, at the time of informed consent.
• Subjects 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.
• Subjects with diagnosis of probable Alzheimer's disease according to NINCDS-ADRDA criteria.
• Subjects with a MMSE score of 5 to 22, inclusive, at screening and baseline visits.
• Subjects with onset of symptoms of agitation at least 2 weeks prior to the screening visit.
• Subjects with a total score greater than or equal to 4 on the agitation aggression item of the NPI-NH or NPI/NPI-NH at the screening and baseline visits.
• Subjects who require pharmacotherapy for the treatment of agitation per the investigator's judgement, after an evaluation of reversible factors (eg, pain, infection, polypharmacy) and a trial of nonpharmacological interventions.
• Subjects must have a previous MRI or CT scan 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:

• Subjects with dementia or other memory impairment not due to Alzheimer's disease.
• Subjects with history of stroke, well-documented transient ischemic attack, or pulmonary or cerebral embolism.
• Subjects who currently have clinically significant neurological, hepatic, renal, metabolic, hematological, immunological, cardiovascular, pulmonary, gastrointestinal, or psychiatric disorders.
• Subjects who have been diagnosed with an Axis I disorder (DSM-IV-TR criteria).
• Subjects with uncontrolled hypertension.
• Subjects with uncontrolled insulin-dependent diabetes mellitus (IDDM)
• Subjects with epilepsy or a history of seizures.
• Subjects 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 Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Matching Placebo Once-Daily	Drug: Brexpiprazole, OPC-34712; Flexible dose of 0.5 to 2 mg/day or placebo tablets for up to 12 weeks
Experimental: Brexpiprazole (flexible dose range 0.5 to 2 mg); Titrate up from 0.25 mg/day brexpiprazole to 1 mg/day brexpiprazole. After achieving 1 mg/day target dose may be increased or decreased based on efficacy and tolerability. Allowable flexible doses will be 0.5 mg/day, 1 mg/day, or 2 mg/day.	Drug: Brexpiprazole, OPC-34712; Flexible dose of 0.5 to 2 mg/day or placebo tablets for up to 12 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to Week 12/Early Termination in the Cohen-Mansfield Agitation Inventory (CMAI) Total Score	The CMAI is widely used in clinical research for evaluation of agitation associated with Alzheimer's dementia, with reliability and validity in both institutionalized and noninstitutionalized participants. It consists of 29 items, all rated on a 1 to 7 scale (1=Never and 7=Several times in an hour), with 1 being the "best" rating and 7 being the "worst" rating. The total score is the sum of ratings for all 29 items. The possible total scores range from 29 to 203. The total score will be unevaluable if less than 24 of the 29 items are recorded. If 24 to 28 of the 29 items are recorded, the total score will be the mean of the recorded items multiplied by 29 and rounded to the first decimal place. The mean change from baseline (Day 0) to week 12 in the CMAI total score is reported. Statistical comparison of interest was brexpiprazole flexible dose versus placebo, analyzed using a mixed-effect model repeated measure approach. A decrease in score indicates improvement in symptoms.	From screening to week 12/early termination

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in the Clinical Global Impression Severity of Illness (CGI-S) Score, as Related to Symptoms of Agitation	The severity of agitation for each participant was rated using the CGI-S. The investigator (or designee) answered the following question: "Considering your total clinical experience with this particular population, how mentally ill (as related to agitation) was the participant at the observation period?" Response choices 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. The score 0 (= not assessed) was set to missing. The CGI-S was therefore a 7-point scale (1-7). The primary analysis used a mixed-effect model repeated measure approach.	From screening to week 12/early termination

Collaborators and Investigators

• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
• Collaborators: H. Lundbeck A/S
• Investigators: Study Director: Eva Koheygi, MD, Otsuka Pharmaceutical Development and Commercialization, Inc.

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): September 1, 2013
• Primary Completion (Actual): March 1, 2017
• Study Completion (Actual): March 1, 2017

Study Registration Dates

• First Submitted: August 12, 2013
• First Submitted That Met QC Criteria: August 12, 2013
• First Posted (Estimate): August 14, 2013

Study Record Updates

• Last Update Posted (Actual): November 20, 2020
• Last Update Submitted That Met QC Criteria: November 4, 2020
• Last Verified: November 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; Tauopathies; Psychomotor Agitation; Mental Disorders; Dementia; 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: 331-12-284

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; ICF; CSR