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

Study Overview
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Brief Summary
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To compare the efficacy of flexible dosing of brexpiprazole with placebo in subjects with agitation associated with dementia of the Alzheimer's type

Detailed Description
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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.

Official Title
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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

Conditions
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Agitation Associated With, Alzheimer's Disease, Alzheimer's Type, Mental Disorder, Nervous System Diseases

Intervention / Treatment
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* Drug: Brexpiprazole, OPC-34712


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Matching Placebo Once-Daily | Drug: Brexpiprazole, OPC-34712<br>* Flexible dose of 0.5 to 2 mg/day or placebo tablets for up to 12 weeks<br>|
| Experimental: Brexpiprazole (flexible dose range 0.5 to 2 mg)<br>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<br>* Flexible dose of 0.5 to 2 mg/day or placebo tablets for up to 12 weeks<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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OPC-34712, brexpiprazole, Dementia, Alzheimer's Disease, Cognitive Disorders, Agitation