Antipsychotic Discontinuation in Alzheimer's Disease

Study Overview
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Brief Summary
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In patients with Alzheimer's disease (AD) who respond to antipsychotic treatment of psychosis and/or agitation/aggression, the relapse risk after discontinuation is not established. AD patients with psychosis and/or agitation/aggression receive 16 weeks of open risperidone treatment (Phase A). Responders are then randomized, double-blind, to one of three arms in Phase B: (1) continuation risperidone for 32 weeks, (2) risperidone for 16 weeks followed by placebo for 16 weeks, (3) placebo for 32 weeks. The primary outcome is time to relapse of psychosis/agitation.

Detailed Description
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This multicenter study (6 academic sites and 2 non-academic sites) involves treating AD patients (assisted living or nursing home patients, and outpatients) using an atypical antipsychotic, risperidone. In Phase A, 180 AD patients with psychosis and/or agitation/aggression receive open treatment with risperidone for 16 weeks. Responders are randomized, double-blind, to one of three arms in Phase B: (1) continuation risperidone for the next 32 weeks, (2) risperidone for the next 16 weeks followed by placebo for 16 weeks, or (3) placebo for the next 32 weeks. The primary hypothesis is that in the first 16 weeks of Phase B, relapse risk will be lower with continuation risperidone (Arms 1 + 2) compared to discontinuation on placebo (Arm 3). The secondary hypothesis is that in the second 16 weeks of Phase B, relapse risk will be lower with continuation risperidone (Arm 1) compared to discontinuation on placebo (Arm 2). For both randomized time periods, the proportions who relapse will be compared for interpretive support. This design provides useful data on the efficacy and side effects of longer term treatment with risperidone, and, in particular, critical information about the time to relapse and likelihood of relapse in patients switched from risperidone to placebo. This information is essential to guide the clinician toward optimal use of such medications in one of the most challenging types of patients: the AD patient with psychosis and/or agitation/aggression. The results of this study will also help to address Federal regulations urging early antipsychotic discontinuation in nursing homes.

Official Title
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Antipsychotic Discontinuation in Alzheimer's Disease

Conditions
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Alzheimer Disease, Psychotic Disorders, Agitation, Aggression

Intervention / Treatment
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* Drug: risperidone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Dementia, either sex, age 50-95 years Probable Alzheimer's disease Intellectual impairment present for at least 6 months Mini Mental State Exam (MMSE) score of 5-26 for outpatients and 2-26 for nursing home patients Availability of informant who has had direct contact with the patient for an average of at least once every week during the 3 months prior to study entry Meets Neuropsychiatric Inventory (NPI) criteria for either (1) psychosis, or (2) agitation/aggression Able to mobilize independently (if wheelchair-bound, the patient must be able to self-propel) Free of psychotropic medication (or able to tolerate washout) for at least 1 week prior to study entry. Low dose antidepressants and sedative/hypnotics allowed if they cannot be washed out and the dose remains stable for the study duration Expected to complete the study (including all efficacy evaluations) and be without major sensory impairment that would prevent participation in any aspect of the study Exclusion Criteria: Current primary Axis I psychiatric disorder other than AD Substance abuse or dependence currently, or within the past year Dementia due to head trauma History of allergy to risperidone or intolerance to risperidone Diffuse Lewy body disease History of seizure disorder, infectious encephalitis, Parkinson's disease, central nervous system (CNS) neoplasm, tardive dyskinesia, stroke, transient ischemic attack (TIA) or uncontrolled atrial fibrillation Use of monoamine oxidase inhibitors (MAOIs) and unable to undergo 3-week washout; patients also may not take MAOIs for 2 weeks after completing the study In treatment with (a) depot antipsychotic within 2 weeks of the screening visit Untreated or incompletely treated hypothyroidism Active, unstable medical condition that requires active medication adjustment or surgery Need for electroconvulsive treatment (ECT) Significant risk for harm to themselves or others as a result of randomization to placebo History of malignant neoplasm during the last 5 years

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 95 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 |
| --- | --- |
| Other: Risperidone-risperidone<br>Risperidone for 16 weeks followed by risperidone for 16 weeks | Drug: risperidone<br>* Risperidone open label flexible dose 0.25 to 3 mg daily for first 16 weeks; dose at 16 weeks then fixed for randomized trial<br>* Other names: Risperdal;|
| Other: Risperidone-Placebo<br>Risperidone for 16 weeks followed by placebo for 16 weeks | Drug: risperidone<br>* Risperidone open label flexible dose 0.25 to 3 mg daily for first 16 weeks; dose at 16 weeks then fixed for randomized trial<br>* Other names: Risperdal;|
| Other: Placebo-Placebo<br>Placebo for 16 weeks followed by placebo for 16 weeks | Drug: risperidone<br>* Risperidone open label flexible dose 0.25 to 3 mg daily for first 16 weeks; dose at 16 weeks then fixed for randomized trial<br>* Other names: Risperdal;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relapse by Study Week 32 | A relapse occurred in Phase B (post-randomization) if both of the following criteria were met: Increase in the Neuropsychiatric Inventory (NPI) core score of 30% or more OR a 5-point increase from the baseline NPI score at the end of Phase A A score of 6 (much worse) or 7 (very much worse) on the Clinical Global Impression-Change (CGI-C) at any visit. | 0-16 weeks in Phase B (16-32 weeks in study) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relapse by Study Week 48 | Same definition and criteria as the primary outcome | 16-32 weeks in Phase B (32-48 weeks in study) | 
| Mini Mental State Exam (MMSE) | The MMSE assesses cognition. Scores range from 0-30, with higher scores indicating better cognition. For each subject, the change in MMSE between week 16 and baseline (randomization) was calculated by subtraction, so that a positive value indicates an increase in MMSE over time. | Phase B, weeks 1-16 (study weeks 16-32) | 
| Treatment Emergent Symptoms Scale (TESS) | The Treatment Emergent Symptom Scale (TESS) assesses 26 somatic symptoms. Total scores range from 0-26, with a score of 0 or 1 for each item. Higher scores indicate more somatic symptoms. For each subject, the change in TESS between week 16 and baseline (randomization) was calculated by subtraction, so that a positive value indicates an increase in TESS over time. | Phase B, weeks 1-16 (study weeks 16-32) | 
| Extrapyramidal Signs (EPS) | Extrapyramidal signs, also known as Parkinsonian signs, refer to signs of tremor, rigidity, and bradykinesia (slowed movement) that are seen in Parkinson's disease. Assessment of extrapyramidal signs (EPS) were made with the use of the Simpson-Angus scale (which ranges from 1-40) with higher scores indicating more extrapyramidal signs. For each subject, the change in EPS between week 16 and baseline (randomization) was calculated by subtraction, so that a positive value indicates an increase in EPS over time. | Phase B, weeks 1-16 (study weeks 16-32) | 
| AIMS | The Abnormal Involuntary Movement Scale (AIMS) assesses signs of tardive dyskinesia, a movement disorder that can occur with prolonged use of antipsychotic medication. The AIMS score ranges from 0 to 35, with higher scores indicating more severe symptoms. For each subject, the change in AIMS score between week 16 and randomization was calculated by subtraction, so that a positive value indicates an increase in AIMS over time. | Phase B, weeks 1-16 (study weeks 16-32) | 
| Physical Self-Maintenance Scale (PSMS) | Physical Self-Maintenance Scale, which ranges from 1 to 30, with higher scores indicating WORSE functioning. For each subject, the change in PSMS between week 16 and randomization was calculated by subtraction, so that a positive value indicates an increase in PSMS (worse functioning) over time. | Phase B, weeks 1-16 (study weeks 16-32) | 
| Weight | For each subject, the change in weight in pounds between week 16 and randomization was calculated by subtraction, so that a positive value indicates an increase in weight over time. | Phase B, weeks 1-16 (study weeks 16-32) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Risperidone treatment, psychosis, agitation, aggression,, discontinuation, placebo