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

• ClinicalTrials.gov Identifier: NCT01922258
• Recruitment Status: Completed
• First Posted: August 14, 2013
• Last Update Posted: May 17, 2018
• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
• Collaborator: H. Lundbeck A/S
• Information provided by (Responsible Party): Otsuka Pharmaceutical Development & Commercialization, Inc.

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Agitation Associated With; Alzheimer's Disease; Alzheimer's Type; Mental Disorder; Nervous System Diseases	Drug: Brexpiprazole, OPC-34712	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 270 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: September 2013
• Actual Primary Completion Date: March 2017
• Actual Study Completion Date: March 2017

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Change in the Cohen-Mansfield Agitation Inventory (CMAI) total score [ Time Frame: Baseline to Week 12/Early Termination ]

Secondary Outcome Measures :

1. Change in the Clinical Global Impression Severity of Illness (CGI-S) score, as related to symptoms of agitation [ Time Frame: Baseline to Week 12/Early Termination ]

Other Outcome Measures:

1. Change in the CMAI subscale scores (aggressive behavior, physically nonaggressive behavior, verbally agitated behavior) [ Time Frame: Baseline to Week 12/Early Termination ]
2. Change in the NPI-NH total score, psychosis subscale score (delusions and hallucinations), individual item scores (eg, agitation/aggression, anxiety, irritability/lability), and occupational disruptiveness scores (individual item and total scores) [ Time Frame: Baseline to Week 12/Early Termination ]

   For institutionalized subjects.

   NPI-NH is an acronym for the Neuropsychiatric Inventory-Nursing Home Rating Scale.

3. Change in the NPI-NH total score, psychosis subscale score (delusions and hallucinations), individual item scores (eg, agitation/aggression, anxiety, irritability/lability), and in NPI distress scores (individual item and total scores) [ Time Frame: Baseline to Week 12/Early Termination ]
   For non-institutionalized subjects.
4. Clinical Global Impression-Improvement (CGI-I) score, as related to agitation [ Time Frame: Week 12/Early Termination ]
5. Clinical Global Impression-Efficacy Index (CGI-E) score, which is defined as the ratio of current therapeutic effect (as related to agitation) and severity of side effects [ Time Frame: Week 12/Early Termination ]
6. Change in the Modified Nursing Care Assessment Scale (M-NCAS) score (institutionalized subjects only) [ Time Frame: Baseline to Week 12/Early Termination ]
7. Change in the Quality of Life in Alzheimer's Disease (QoL-AD) score [ Time Frame: Baseline to Week 12/Early Termination ]
8. Change in the Nurses' Observation Scale for Geriatric Patients (NOSGER) score (institutionalized subjects only) [ Time Frame: Baseline to Week 12/Early Termination ]
9. Resource Utilization in Dementia (RUD) score [ Time Frame: Baseline to Week 12/Early Termination ]
10. Safety Variables [ Time Frame: Baseline to Week 12/Early Termination ]
    Safety variables to be examined will include: adverse events, physical examinations, neurological examinations, vital signs, body weight, waist circumference, clinical laboratory tests (hematology, serum chemistry, and urinalysis), electrocardiograms (ECGs), MMSE score, assessments of suicidality (Sheehan-STS), extrapyramidal symptoms (the Simpson Angus Scale [SAS], the Abnormal Involuntary Movement Scale [AIMS], the Barnes Akathisia Rating Scale [BARS]), adverse events of interest (eg, falls, sedation, diabetes, weight changes, QTc prolongation, or deaths), and change from baseline in body mass index (BMI).

Eligibility Criteria

• Ages Eligible for Study: 55 Years to 90 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

  Show 71 Study Locations

Sponsors and Collaborators

Otsuka Pharmaceutical Development & Commercialization, Inc.

H. Lundbeck A/S

Investigators

• Study Director: Eva Koheygi, MD; Otsuka Pharmaceutical Development and Commercialization, Inc.

More Information

• Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
• ClinicalTrials.gov Identifier: NCT01922258 History of Changes
• Other Study ID Numbers: 331-12-284
• First Posted: August 14, 2013
• Last Update Posted: May 17, 2018
• Last Verified: May 2018

Keywords provided by Otsuka Pharmaceutical Development & Commercialization, Inc.:

OPC-34712; brexpiprazole; Dementia; Alzheimer's Disease; Cognitive Disorders; Memory; Agitation

Additional relevant MeSH terms:

Brexpiprazole; Alzheimer Disease; Dementia; Psychomotor Agitation; Mental Disorders; Nervous System Diseases; Brain Diseases; Central Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Dyskinesias; Neurologic Manifestations; Psychomotor Disorders; Neurobehavioral Manifestations; Signs and Symptoms; Serotonin Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs; Dopamine Agonists; Dopamine Agents