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Antipsychotic Discontinuation in Alzheimer's Disease (ADAD)

This study has been completed.
Sponsor:
Collaborators:
Columbia University
Information provided by (Responsible Party):
New York State Psychiatric Institute
ClinicalTrials.gov Identifier:
NCT00417482
First received: December 28, 2006
Last updated: March 14, 2013
Last verified: March 2013
  Purpose

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.


Condition Intervention Phase
Alzheimer Disease
Psychotic Disorders
Agitation
Aggression
Drug: risperidone
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Antipsychotic Discontinuation in Alzheimer's Disease

Resource links provided by NLM:


Further study details as provided by New York State Psychiatric Institute:

Primary Outcome Measures:
  • Relapse by Study Week 32 [ Time Frame: 0-16 weeks in Phase B (16-32 weeks in study) ] [ Designated as safety issue: No ]

    A relapse occurred in Phase B (post-randomization) if both of the following criteria were met:

    1. 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
    2. A score of 6 (much worse) or 7 (very much worse) on the Clinical Global Impression-Change (CGI-C) at any visit.


Secondary Outcome Measures:
  • Relapse by Study Week 48 [ Time Frame: 16-32 weeks in Phase B (32-48 weeks in study) ] [ Designated as safety issue: No ]
    Same definition and criteria as the primary outcome

  • Mini Mental State Exam (MMSE) [ Time Frame: Phase B, weeks 1-16 (study weeks 16-32) ] [ Designated as safety issue: Yes ]
    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.

  • Treatment Emergent Symptoms Scale (TESS) [ Time Frame: Phase B, weeks 1-16 (study weeks 16-32) ] [ Designated as safety issue: Yes ]
    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.

  • Extrapyramidal Signs (EPS) [ Time Frame: Phase B, weeks 1-16 (study weeks 16-32) ] [ Designated as safety issue: Yes ]
    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.

  • AIMS [ Time Frame: Phase B, weeks 1-16 (study weeks 16-32) ] [ Designated as safety issue: Yes ]
    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.

  • Physical Self-Maintenance Scale (PSMS) [ Time Frame: Phase B, weeks 1-16 (study weeks 16-32) ] [ Designated as safety issue: Yes ]
    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.

  • Weight [ Time Frame: Phase B, weeks 1-16 (study weeks 16-32) ] [ Designated as safety issue: Yes ]
    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.


Enrollment: 180
Study Start Date: August 2004
Study Completion Date: April 2011
Primary Completion Date: April 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Risperidone-risperidone
Risperidone for 16 weeks followed by risperidone for 16 weeks
Drug: risperidone
Risperidone open label flexible dose 0.25 to 3 mg daily for first 16 weeks; dose at 16 weeks then fixed for randomized trial
Other Name: Risperdal
Risperidone-Placebo
Risperidone for 16 weeks followed by placebo for 16 weeks
Drug: risperidone
Risperidone open label flexible dose 0.25 to 3 mg daily for first 16 weeks; dose at 16 weeks then fixed for randomized trial
Other Name: Risperdal
Placebo-Placebo
Placebo for 16 weeks followed by placebo for 16 weeks
Drug: risperidone
Risperidone open label flexible dose 0.25 to 3 mg daily for first 16 weeks; dose at 16 weeks then fixed for randomized trial
Other Name: Risperdal

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   50 Years to 95 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00417482

Locations
United States, Alabama
Tuscaloosa VA Medical Center, Department of Psychiatry
Tuscaloosa, Alabama, United States, 35404
United States, California
WLA VA Medical Center/UCLA, Psychiatry
Los Angeles, California, United States, 90073
United States, Connecticut
Research Center for Clinical Studies, Inc.
Norwalk, Connecticut, United States, 06851
United States, Iowa
University of Iowa College of Medicine
Iowa City, Iowa, United States, 52242
United States, New York
Mount Sinai School of Medicine, Alzheimer's Disease Research Center
New York, New York, United States, 10029
New York State Psychiatric Institute, Columbia University
New York, New York, United States, 10032
United States, South Carolina
Medical University of South Carolina
North Charleston, South Carolina, United States, 29406
Sponsors and Collaborators
New York State Psychiatric Institute
Columbia University
Investigators
Principal Investigator: Davangere P. Devanand, MD NYSPI/Columbia University
  More Information

Additional Information:
Publications:
Responsible Party: New York State Psychiatric Institute
ClinicalTrials.gov Identifier: NCT00417482     History of Changes
Other Study ID Numbers: #5598R, 5R01AG021488
Study First Received: December 28, 2006
Results First Received: February 11, 2013
Last Updated: March 14, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by New York State Psychiatric Institute:
Risperidone treatment, psychosis, agitation, aggression,
discontinuation, placebo

Additional relevant MeSH terms:
Aggression
Alzheimer Disease
Mental Disorders
Psychotic Disorders
Behavioral Symptoms
Brain Diseases
Central Nervous System Diseases
Delirium, Dementia, Amnestic, Cognitive Disorders
Dementia
Nervous System Diseases
Neurodegenerative Diseases
Schizophrenia and Disorders with Psychotic Features
Tauopathies
Antipsychotic Agents
Risperidone
Central Nervous System Agents
Central Nervous System Depressants
Dopamine Agents
Dopamine Antagonists
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Pharmacologic Actions
Physiological Effects of Drugs
Psychotropic Drugs
Serotonin Agents
Serotonin Antagonists
Therapeutic Uses
Tranquilizing Agents

ClinicalTrials.gov processed this record on November 20, 2014