Antipsychotic Discontinuation in Alzheimer's Disease (ADAD)

March 14, 2013 updated by: New York State Psychiatric Institute
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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

180

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Alabama
      • Tuscaloosa, Alabama, United States, 35404
        • Tuscaloosa VA Medical Center, Department of Psychiatry
    • California
      • Los Angeles, California, United States, 90073
        • WLA VA Medical Center/UCLA, Psychiatry
    • Connecticut
      • Norwalk, Connecticut, United States, 06851
        • Research Center for Clinical Studies, Inc.
    • Iowa
      • Iowa City, Iowa, United States, 52242
        • University of Iowa College of Medicine
    • New York
      • New York, New York, United States, 10029
        • Mount Sinai School of Medicine, Alzheimer's Disease Research Center
      • New York, New York, United States, 10032
        • New York State Psychiatric Institute, Columbia University
    • South Carolina
      • North Charleston, South Carolina, United States, 29406
        • Medical University of South Carolina

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

48 years to 93 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: 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 Names:
  • Risperdal
Other: 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 Names:
  • Risperdal
Other: 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 Names:
  • Risperdal

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Relapse by Study Week 32
Time Frame: 0-16 weeks in Phase B (16-32 weeks in study)

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.
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
Time Frame: 16-32 weeks in Phase B (32-48 weeks in study)
Same definition and criteria as the primary outcome
16-32 weeks in Phase B (32-48 weeks in study)
Mini Mental State Exam (MMSE)
Time Frame: Phase B, weeks 1-16 (study weeks 16-32)
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)
Time Frame: Phase B, weeks 1-16 (study weeks 16-32)
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)
Time Frame: Phase B, weeks 1-16 (study weeks 16-32)
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
Time Frame: Phase B, weeks 1-16 (study weeks 16-32)
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)
Time Frame: Phase B, weeks 1-16 (study weeks 16-32)
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
Time Frame: Phase B, weeks 1-16 (study weeks 16-32)
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)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

New York State Psychiatric Institute

Collaborators

Columbia University
National Institute on Aging (NIA)

Investigators

  • Principal Investigator: Davangere P. Devanand, MD, NYSPI/Columbia University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

August 1, 2004

Primary Completion (Actual)

April 1, 2011

Study Completion (Actual)

April 1, 2011

Study Registration Dates

First Submitted

December 28, 2006

First Submitted That Met QC Criteria

December 28, 2006

First Posted (Estimate)

January 1, 2007

Study Record Updates

Last Update Posted (Estimate)

April 24, 2013

Last Update Submitted That Met QC Criteria

March 14, 2013

Last Verified

March 1, 2013

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • #5598R
  • 5R01AG021488 (U.S. NIH Grant/Contract)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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