Clinical trial NCT00417482: Antipsychotic Discontinuation in Alzheimer's Disease
Official title: Antipsychotic Discontinuation in Alzheimer's Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Alzheimer Disease
Psychotic Disorders
Agitation
Aggression
Keywords: Risperidone treatment, psychosis, agitation, aggression,
discontinuation, placebo
Lead sponsor: New York State Psychiatric Institute
Sponsor class: OTHER
Collaborators: name: National Institute on Aging (NIA)
name: Columbia University
First posted: 2007-01-01
Enrollment: 180
Sex: ALL
Minimum age (years): 50
Maximum age (years): 95
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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 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

Primary outcomes:
measure: Relapse by Study Week 32
timeFrame: 0-16 weeks in Phase B (16-32 weeks in study)
Secondary outcomes:
measure: Relapse by Study Week 48
timeFrame: 16-32 weeks in Phase B (32-48 weeks in study)
measure: Mini Mental State Exam (MMSE)
timeFrame: Phase B, weeks 1-16 (study weeks 16-32)
measure: Treatment Emergent Symptoms Scale (TESS)
timeFrame: Phase B, weeks 1-16 (study weeks 16-32)
measure: Extrapyramidal Signs (EPS)
timeFrame: Phase B, weeks 1-16 (study weeks 16-32)
measure: AIMS
timeFrame: Phase B, weeks 1-16 (study weeks 16-32)
measure: Physical Self-Maintenance Scale (PSMS)
timeFrame: Phase B, weeks 1-16 (study weeks 16-32)
measure: Weight
timeFrame: Phase B, weeks 1-16 (study weeks 16-32)
Other outcomes:
Locations:
city: Tuscaloosa
country: United States
facility: Tuscaloosa VA Medical Center, Department of Psychiatry
state: Alabama
city: Los Angeles
country: United States
facility: WLA VA Medical Center/UCLA, Psychiatry
state: California
city: Norwalk
country: United States
facility: Research Center for Clinical Studies, Inc.
state: Connecticut
city: Iowa City
country: United States
facility: University of Iowa College of Medicine
state: Iowa
city: New York
country: United States
facility: Mount Sinai School of Medicine, Alzheimer's Disease Research Center
state: New York
city: New York
country: United States
facility: New York State Psychiatric Institute, Columbia University
state: New York
city: North Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
Study officials:
affiliation: NYSPI/Columbia University
name: Davangere P. Devanand, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Devanand DP, Mintzer J, Schultz SK, Andrews HF, Sultzer DL, de la Pena D, Gupta S, Colon S, Schimming C, Pelton GH, Levin B. Relapse risk after discontinuation of risperidone in Alzheimer's disease. N Engl J Med. 2012 Oct 18;367(16):1497-507. doi: 10.1056/NEJMoa1114058.
citation: Patel AN, Lee S, Andrews HF, Pelton GH, Schultz SK, Sultzer DL, Mintzer J, de la Pena D, Gupta S, Colon S, Schimming C, Levin B, Devanand DP. Prediction of Relapse After Discontinuation of Antipsychotic Treatment in Alzheimer's Disease: The Role of Hallucinations. Am J Psychiatry. 2017 Apr 1;174(4):362-369. doi: 10.1176/appi.ajp.2016.16020226. Epub 2016 Nov 18.