Aripiprazole in the Treatment of Patients With Psychosis Associated With Dementia of Alzheimer's Type

Otsuka Pharmaceutical Development & Commercialization, Inc.232 enrolled

Overview

The primary objective of the study is to compare the efficacy of aripiprazole with placebo in patients with psychosis associated with Alzheimer's dementia.

Open label Extension Phase: The 130-week Extension Phase was conducted to provide information regarding long-term safety and efficacy of aripiprazole in participants who were diagnosed at the onset of the Acute Phase with psychotic symptoms associated with dementia of the Alzheimer's type who responded to treatment in the 10-week Acute Phase of this study. Treatment beyond 140 week: A country-specific amendment for France, allowed participants treated with aripiprazole who, according to the investigator's opinion, showed improvement at the Week 140 visit to continue treatment beyond 140 weeks. The termination was to be determined by clinical benefit to he participant. Study design: Acute Phase: Randomized, double-blind, placebo-controlled, flexible-dose, parallel-group study. Extension Phase: Open label; flexible-dose.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

232

Conditions

Dementia, Alzheimer Type

Interventions

Aripiprazole (BMS-337039)DRUG

Acute Phase: Oral, Tablets (1 and 5 mg), Week 1-2: 2 mg, Week 3-4: 2 - 5 mg, Week 5-6: 2 - 10 mg, Weeks 7-10: 2 - 15 mg, Once daily, 10 weeks Extension Phase: Oral, Tablets (1 and 5 mg), Week 11: 2 mg, Weeks 12-13: 2 - 5 mg, Weeks 14-15: 2 - 10 mg, Weeks 16-140: 2 - 15 mg, Once daily, 130 weeks

PlaceboDRUG

Acute Phase: Oral, Tablets, 0 mg, Once daily, 10 Weeks

Eligibility

Sex: ALLMin age: 55 YearsMax age: 95 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Non-institutionalized patients with a diagnosis of Alzheimer's disease as defined by Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition (DSM-IV) criteria with symptoms of delusions or hallucinations, which have been present, at least intermittently for one month or longer * Mini Mental State Examination (MMSE) score of 6 to 24 points * Patients capable of self locomotion or locomotion with the aid of an assistive device * Patients with an identified caregiver or proxy For Extension Phase: Eligible patients were males and females who had completed the 10-week Acute Phase in either treatment group; had a Week 10 Total Score of ≥ 6 on the NPI; and were, in the judgment of the investigator, deemed suitable for participation in the long-term trial. Treatment beyond 140 weeks: All subjects who completed the extension phase of CN138-006 in any French Investigational Site may be considered eligible for entry until they are no longer receiving clinical benefit, per the investigator's judgment Exclusion Criteria: * Patients with an Axis I (DSM IV) diagnosis of: * delirium * amnestic disorders * bipolar disorder * schizophrenia or schizoaffective disorder * mood disorder with psychotic features * Patients with reversible causes of dementia * Patients with psychotic symptoms continuously present since prior to the onset of the symptoms of dementia * Patients with psychotic symptoms that are better accounted for by another general medical condition or by direct physiological effects of a substance * Patients with a current major depressive episode with psychotic symptoms of hallucinations or delusions * Patients with a diagnosis of dementia related to infection with the human immunodeficiency virus * Patients with substance-induced persistent dementia * Patients with dementia due to vascular causes, multi-infarct, head trauma, Pick's disease, Parkinson's disease, frontal or temporal dementia, Lewy body dementia, or any specific non-Alzheimer's type dementia * Patients with seizure disorders * Patients who have been refractory to neuroleptics used to treat psychotic symptoms in the past when treated for an adequate period with a therapeutic dose, unless permission is obtained from Bristol-Myers Squibb * Patients who have met DSM-IV criteria for any significant substance use disorder within the 6 months prior to the start of screening

Outcomes

Primary Outcomes

Change From Baseline in Neuropsychiatric Inventory (NPI) Psychosis Subscale Score at Week 10 in Acute Phase

The NPI is a questionnaire that quantifies behavioral changes in dementia. For each of 12 behavioral domains there are 4 scores: Frequency (scale:1=occasionally to 4=very frequently), Severity (scale:1=Mild to 3=Severe), Total (frequency x severity), Caregiver distress (scale: 0=not at all distressing to 5=extremely distressing).The NPI Psychosis Subscale consists of the two domains of Delusions and Hallucinations, calculated by adding the Individual Item Scores, to yield a possible total score of 0 to 24. Lower score=less severity. A negative change score from baseline indicates improvement.

Time frame: Baseline (Day 0), Week 10

Secondary Outcomes

Change From Baseline in NPI Psychosis Subscale Score Through Week 8 in Acute Phase

Time frame: Baseline (Day 0), Weeks 1, 2, 3, 4, 6, and 8

Change From Baseline in NPI Total Score in Acute Phase

The NPI is a questionnaire that quantifies behavioral changes in dementia. For each of 12 behavioral domains there are 4 scores: Frequency (scale: 1=occasionally to 4=very frequently), Severity (scale:1=Mild to 3=Severe), Total (frequency x severity), Caregiver distress (scale: 0=not at all distressing to 5=extremely distressing).The NPI Total Score is calculated by adding the Individual Item Scores for all 12 domains, to yield a possible NPI Total Score of 0 to 144. Lower score=less severity. A negative change score from baseline indicates improvement.

Time frame: Baseline (Day 0), Weeks 1, 2, 3, 4, 6, 8, and 10

Data from ClinicalTrials.gov

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Participants Who Demonstrated a ≥ 50% Decrease From Baseline to Endpoint in the NPI Psychosis Subscale Score in Acute Phase

Time frame: Weeks 1, 2, 3, 4, 6, 8, and 10

Participants Who Demonstrated a ≥ 50% Decrease From Baseline in the Total NPI Score in Acute Phase

The NPI is a questionnaire that quantifies behavioral changes in dementia. For each of 12 behavioral domains there are 4 scores: Frequency (scale: 1=occasionally to 4=very frequently), Severity (scale:1=Mild to 3=Severe), Total (frequency x severity), Caregiver distress (scale: 0=not at all distressing to 5=extremely distressing).The NPI Total Score is calculated by adding the Individual Item Scores for all 12 domains, to yield a possible NPI Total Score of 0 to 144. Lower score=less severity. A negative change score from baseline indicates improvement.

Time frame: Weeks 1, 2, 3, 4, 6, 8, and 10

Change From Baseline in NPI Psychosis Subscale Caregiver Distress Score in Acute Phase

The NPI is a questionnaire that quantifies behavioral changes in dementia. For each of 12 behavioral domains there are 4 scores: Frequency (scale:1=occasionally to 4=very frequently), Severity (scale:1=Mild to 3=Severe), Total (frequency x severity), Caregiver distress (scale:0=not at all distressing to 5=extremely distressing). The NPI Psychosis Subscale Caregiver Distress Score is calculated by adding Individual Item Scores for the domains of Delusions and Hallucinations, to yield a possible total score of 0 to 10. Lower score=less severity. A negative change score from baseline=improvement.

Time frame: Baseline (Day 0), Weeks 1, 2, 3, 4, 6, 8, and 10

Change From Baseline in NPI Total Caregiver Distress Score in Acute Phase

The NPI is a questionnaire that quantifies behavioral changes in dementia. For each of 12 behavioral domains there are 4 scores: Frequency (scale: 1=occasionally to 4=very frequently), Severity (scale:1=Mild to 3=Severe), Total (frequency x severity), Caregiver distress (scale: 0=not at all distressing to 5=extremely distressing).The total NPI Caregiver Distress Score is calculated by adding the 12 Caregiver Distress Individual Item Scores, to yield a possible total score of 0 to 60. Lower score=less severity. A negative change score from baseline indicates improvement.

Time frame: Baseline (Day 0), Weeks 1, 2, 3, 4, 6, 8, and 10

Change From Baseline in Clinical Global Impression (CGI) Severity of Illness Score in Acute Phase

The CGI rating scale, which measures symptom severity, treatment response and the efficacy of treatments, is used in clinical studies on mental disorders. CGI Severity scale is a 7-point scale that requires the clinician to rate the severity of the illness at the time of assessment, relative to the clinician's past experience with participants who have the same diagnosis. The assessment is based on severity of mental illness at the time of rating, 0=not assessed, 1=normal, 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; or 7=extremely ill.

Time frame: Baseline (Day 0), Weeks 1, 2, 3, 4, 6, 8, and 10

CGI Improvement Score in Acute Phase

The CGI rating scale, which measures symptom severity, treatment response and the efficacy of treatments, is used in clinical studies on mental disorders. CGI Improvement scale is a 7 point scale that requires the clinician to assess how much the participant's illness has improved or worsened relative to a baseline state at the beginning of the intervention: 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; 7=very much worse.

Time frame: Weeks 1, 2, 3, 4, 6, 8, and 10

Change From Baseline in Brief Psychiatric Rating Scale (BPRS) Total Score in Acute Phase

The BPRS is designed to measure clinical change in participants and is used as a global measure of psychopathology. The BPRS includes 18 items with items devoted to hallucinatory behavior, suspiciousness, unusual thought content, etc. BPRS is an 18-item clinician rated scale with 11 general symptom items, 5 positive-symptom items, and 2 negative symptom items scored on a 7-point scale (1=not present and 7=extremely severe), with higher score indicating greater severity of symptom. Total possible score range=18 to 126. A negative change score signifies improvement.

Time frame: Baseline (Day 0), Weeks 1, 2, 3, 4, 6, 8, and 10

Change From Baseline in Mini Mental State Examination (MMSE) Total Score in Acute Phase

The MMSE is a screening test for cognitive dysfunction. The test consists of five sections (orientation, registration, attention-calculation, recall, and language). It is a 19 item scale, the total score can range from 0 to 30, with a higher score indicating better function. A positive change score indicates improvement from baseline.

Time frame: Baseline (Day 0), Week 10

Change From Baseline in NPI Individual Item Scores in Acute Phase: Delusions

The 12 individual items in NPI that quantify behavioral changes in dementia are delusions, hallucinations, agitation, depression, anxiety, apathy, disinhibition, irritability, euphoria, aberrant motor behavior, nighttime behaviors, and appetite. For each behavioral domain there are 4 scores (refer to outcome 1 for the scoring for frequency, severity, total, caregiver distress). Presence of symptoms (0=no, 1=yes) x ratings for frequency and severity yield a total possible score of 0 to 12 for each item. Lower score=less severity. A negative change score from baseline indicates improvement.

Time frame: Baseline (Day 0), Weeks 1, 2, 3, 4, 6, 8, and 10

Change From Baseline in NPI Individual Item Scores in Acute Phase: Hallucinations

Time frame: Baseline (Day 0), Weeks 1, 2, 3, 4, 6, 8, and 10

Change From Baseline in NPI Individual Item Scores in Acute Phase: Agitation/Aggression

Time frame: Baseline (Day 0), Weeks 1, 2, 3, 4, 6, 8, and 10

Change From Baseline in NPI Individual Item Scores in Acute Phase: Depression/Dysphoria

Time frame: Baseline (Day 0), Weeks 1, 2, 3, 4, 6, 8, and 10

Change From Baseline in NPI Individual Item Scores in Acute Phase: Anxiety

Time frame: Baseline (Day 0), Weeks 1, 2, 3, 4, 6, 8, and 10

Change From Baseline in NPI Individual Item Scores in Acute Phase: Apathy/Indifference

Time frame: Baseline (Day 0), Weeks 1, 2, 3, 4, 6, 8, and 10

Change From Baseline in NPI Individual Item Scores in Acute Phase: Elation/Euphoria

Time frame: Baseline (Day 0), Weeks 1, 2, 3, 4, 6, 8, and 10

Change From Baseline in NPI Individual Item Scores in Acute Phase: Disinhibition

Time frame: Baseline (Day 0), Weeks 1, 2, 3, 4, 6, 8, and 10

Change From Baseline in NPI Individual Item Scores in Acute Phase: Irritability/Lability

Time frame: Baseline (Day 0), Weeks 1, 2, 3, 4, 6, 8, and 10

Change From Baseline in NPI Individual Item Scores in Acute Phase: Aberrant Motor Behavior

Time frame: Baseline (Day 0), Weeks 1, 2, 3, 4, 6, 8, and 10

Change From Baseline in NPI Individual Item Scores in Acute Phase: Appetite/Eating Behaviors

Time frame: Baseline (Day 0), Weeks 1, 2, 3, 4, 6, 8, and 10

Change From Baseline in NPI Individual Item Scores in Acute Phase: Sleep

Time frame: Baseline (Day 0), Weeks 1, 2, 3, 4, 6, 8, and 10

Change From Baseline in Simpson-Angus Scale (SAS) Total Score in Acute Phase

The SAS is a 10-item instrument used to evaluate the presence and severity of parkinsonian symptomatology. It is the most commonly used rating scale for Parkinsonism in clinical trials over the past 25 years. The ten items focus on rigidity rather than bradykinesia, and do not assess subjective rigidity or slowness. Items are rated for severity on a 0-4 scale, with definitions given for each anchor point. The total SAS Score has a possible range from 10 to 50.(lower score=less severe). Negative change scores indicate improvement.

Time frame: Baseline (Day 0), Weeks 2, 4, and 10

Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Total Score in Acute Phase

The Abnormal Involuntary Movement Scale (AIMS) is a rating scale that was designed to measure involuntary movements (tardive dyskinesia). The AIMS test has a total of twelve items rating involuntary movements of various areas of the patient's body. These items are rated on a five-point scale of severity from 0-4. The scale is rated from 0 (none), 1 (minimal), 2 (mild), 3 (moderate), 4 (severe). AIMS Total Score is from 0 to 28. A negative change score signifies improvement.

Time frame: Baseline (Day 0), Weeks 2, 4, 8, and 10

Change From Baseline in Barnes Global Clinical Assessment of Akathisia in Acute Phase

The Barnes Akathisia Rating Scale is a 4-item scale to assess presence and severity of drug-induced akathisia, including both objective items and subjective items, together with a global clinical assessment of akathisia. Global assessment is made on a scale of 0 to 5 with comprehensive definitions provided for each anchor point on scale: 0=absent; 1=questionable; 2=mild akathisia; 3=moderate akathisia; 4=marked akathisia; 5=severe akathisia. Score has a possible range from 0 (absent) to 5 (severe akathisia). Negative change scores indicate improvement in akathisia.

Time frame: Baseline (Day 0), Weeks 1, 2, 3, 4, 6, 8, and 10

Participants With Extrapyramidal Symptoms (EPS) Related Adverse Events in Acute Phase

Extrapyramidal symptoms (EPS) are various movement disorders such as acute dystonic reactions, pseudoparkinsonism, or akathisia

Time frame: Week 1 to week 10

Participants Who Died, Experienced Serious Adverse Events (SAEs), Adverse Events (AEs) or Discontinuations Due to AEs in Acute Phase

AE is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition. SAE is any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a cancer, is a congenital anomaly/birth defect, results in the development of drug dependency or drug abuse, is an important medical event.

Time frame: Week 1 to week 10

Participants With Potentially Clinically Significant Laboratory Abnormalities in Acute Phase

Criteria for identifying potentially clinically significant laboratory values were based on guidelines suggested by the FDA Division of Neuropharmacological Drug Products. Normal ranges are local lab data and vary according to the site. M=male, F=female. Criteria for hematocrit also includes a 3 point shift from baseline.

Time frame: Week 1 to Week 10

Participants With Potentially Clinically Significant (PCS) Vital Sign Abnormalities in Acute Phase

Systolic BP: increase defined as ≥180 and a ≥20-mmHg increase from baseline (BL); decrease defined as ≤90 and a ≥20mmHg decrease from BL. Diastolic BP: increase defined as ≥105 and a ≥15mmHg decrease from BL, decrease defined as ≤50 and a ≥15mmHg decrease from BL. Heart rate: increase defined as ≥120 and ≥15bpm increase from BL, decrease defined as ≤50 and ≥15bpm decrease from BL; Weight: increase defined as ≥7% from BL, decrease defined as ≤7% decrease BL. Criteria for identifying PCS measurements are based on guidelines suggested by the FDA Division of Neuropharmacological Drug Products

Time frame: Week 1 to week 10

Participants With Potentially Clinically Significant Electrocardiogram Abnormalities in Acute Phase

Bradycardia:Heart rate ≤50 bpm and ≥15 bpm decrease from baseline; Supraventricular premature beat: ≥2 per 10 seconds and any increase from baseline; 1st degree A-V Block: PR ≥0.20 seconds and increase of ≥0.05 second from baseline; Intraventricular conduction block:QRS ≥0.12 second and increase of ≥0.02 second from baseline; QTcB= ≥450 msec and ≥10% increase from baseline; QTcN =≥450 msec and ≥10% increase from baseline. All other events were not present at baseline but observed during the study. Inc=increase

Time frame: Week 1 to Week 10

Change in Neuropsychiatric Inventory (NPI) Psychosis Subscale Score From Baseline During Extension Phase

Time frame: Baseline (Day 0), Weeks 18,26,40,52,68,84,100,116,132,140

Clinical Global Impression (CGI) Improvement Score During Extension Phase

Time frame: Weeks 12, 14, 18, 22, 26, 30, 34, 40, 46, 52, 68, 84, 100, 116, 132, 140

Change in Abnormal Involuntary Movement Scale (AIMS) Total Score During Extension Phase

AIMS is a rating scale that was designed to measure involuntary movements (tardive dyskinesia). The AIMS test has a total of twelve items rating involuntary movements of various areas of the patient's body. These items are rated on a five-point scale of severity from 0-4. The scale is rated from 0 (none), 1 (minimal), 2 (mild), 3 (moderate), 4 (severe). AIMS Total Score is from 0 to 28. A negative change score signifies improvement.

Time frame: End of Acute Phase (Week 10), Weeks 14, 18, 22, 26, 30, 34, 40, 46, 52, 68, 84, 100, 116, 140

Change in Simpson-Angus Scale (SAS) Total Score During Extension Phase

The SAS is a 10-item instrument used to evaluate the presence and severity of parkinsonian symptomatology. It is the most commonly used rating scale for Parkinsonism in clinical trials over the past 25 years. The ten items focus on rigidity rather than bradykinesia, and do not assess subjective rigidity or slowness. Items are rated for severity on a 0-4 scale, with definitions given for each anchor point. The total SAS Score has a possible range from 10 to 50 (lower score=less severe). Negative change scores indicate improvement.

Time frame: End of Acute Phase (Week 10), Weeks 18,26, 40, 52

Change in Barnes Global Clinical Assessment of Akathisia Score During Extension Phase

Time frame: End of Acute Phase (Week 10), Weeks 18,26, 40, 52

Participants With Extrapyramidal Symptoms (EPS) Related Adverse Events During Extension Phase

Extrapyramidal symptoms (EPS) are various movement disorders such as acute dystonic reactions, pseudoparkinsonism, or akathisia

Time frame: Week 11 to Week 140

Participants Who Died, Experienced Serious Adverse Events (SAEs), Adverse Events (AEs) or Discontinuations Due to AE During Extension Phase

Time frame: Week 11 to Week 140

Participants With a Potentially Clinically Significant Vital Sign Abnormality During Extension Phase

Systolic BP: increase defined as ≥180 and a ≥20-mmHg increase from baseline (BL); decrease defined as ≤90 and a ≤20mmHg decrease from BL. Diastolic BP: increase defined as ≥105 and a ≥15mmHg decrease from BL, decrease defined as ≤50 and a ≤15mmHg decrease from BL. Heart rate: increase defined as ≥120 and ≥15bpm increase from bBL, decrease defined as ≤50 and ≤15bpm decrease from BL; Weight: increase defined as ≥7% from baseline, decrease defined as ≤7% decrease BL. Criteria for identifying PCS measurements based on guidelines suggested by the FDA Division of Neuropharmacological Drug Products

Time frame: Week 11 to Week 140

Participants With a Potentially Clinically Significant Electrocardiogram Abnormalities During Extension Phase

Time frame: Week 11 to Week 140

Participants With Potentially Clinically Significant Laboratory Abnormalities During Extension Phase

Criteria for identifying potentially clinically significant laboratory values were based on guidelines suggested by the FDA Division of Neuropharmacological Drug Products.

Time frame: Week 11 to Week 140

Participants Who Died, Experienced Serious Adverse Events (SAEs), Adverse Events (AEs) or Discontinuations Due to AE During Treatment Beyond 140 Weeks

Time frame: Week 140 to Week 328