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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
Results First Received: February 11, 2013  
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
Conditions: Alzheimer Disease
Psychotic Disorders
Agitation
Aggression
Intervention: Drug: risperidone

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Patients were recruited from memory clinics including Alzheimer Research Centers, geriatric psychiatry clinics, VA clinics, physician referrals and advertising.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment

180 Patients with Alzheimer's disease (AD) & psychosis or agitation-aggression received open treatment with risperidone for 16 weeks in Phase A. Of 180 patients, 112 were responders and 110 were randomized in Phase B.

Phase B: 110 responders were randomized, double-blind, to one of three arms in Phase B.


Reporting Groups
  Description
Arm 1: Risperidone-Risperidone

Phase A involved open flexible dose risperidone treatment for 16 weeks. At 16 weeks, non-responders exited the study. Responders were randomized, double-blind, to one of three arms in Phase B: (1) continuation risperidone for 32 weeks (Arm 1), (2) risperidone for 16 weeks followed by placebo for 16 weeks (Arm 2), (3) placebo for 32 weeks (Arm 3).

Phase B Arm 1: Risperidone for 16 weeks followed by risperidone for 16 weeks; Risperidone open label flexible dose was administered at a dose of 0.25 to 3 mg daily for first 16 weeks; dose at 16 weeks then fixed for the randomized trial

Phase B Arm 2: Risperidone-Placebo

Phase A involved open flexible dose risperidone treatment for 16 weeks. At 16 weeks, non-responders exited the study. Responders were randomized, double-blind, to one of three arms in Phase B: (1) continuation risperidone for 32 weeks (Arm 1), (2) risperidone for 16 weeks followed by placebo for 16 weeks (Arm 2), (3) placebo for 32 weeks (Arm 3).

Phase B Arm 2: Risperidone for 16 weeks followed by placebo for 16 weeks;

Phase B Arm 3: Placebo-Placebo

Phase A involved open flexible dose risperidone treatment for 16 weeks. At 16 weeks, non-responders exited the study. Responders were randomized, double-blind, to one of three arms in Phase B: (1) continuation risperidone for 32 weeks (Arm 1), (2) risperidone for 16 weeks followed by placebo for 16 weeks (Arm 2), (3) placebo for 32 weeks (Arm 3).

Phase B Arm 3: Patients were randomized to placebo for 32 weeks.


Participant Flow for 2 periods

Period 1:   Phase B 1st 16 Weeks
    Arm 1: Risperidone-Risperidone     Phase B Arm 2: Risperidone-Placebo     Phase B Arm 3: Placebo-Placebo  
STARTED     32 [1]   38 [1]   40 [2]
COMPLETED     13     27     13  
NOT COMPLETED     19     11     27  
Lack of Efficacy                 14                 8                 24  
Adverse Event                 2                 0                 1  
Moved, Unclear reasons                 2                 3                 2  
Death                 1                 0                 0  
[1] Risperidone 16 weeks.
[2] Placebo 16 weeks.

Period 2:   Phase B 2nd 16 Weeks
    Arm 1: Risperidone-Risperidone     Phase B Arm 2: Risperidone-Placebo     Phase B Arm 3: Placebo-Placebo  
STARTED     13 [1]   27 [2]   13 [2]
COMPLETED     10     14     10  
NOT COMPLETED     3     13     3  
Lack of Efficacy                 1                 12                 2  
Adverse Event                 0                 0                 1  
Moved; unclear reason                 1                 0                 0  
Death                 1                 1                 0  
[1] Risperidone for 16 weeks.
[2] Placebo for 16 weeks.



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Phase B Arm 1: Risperidone-Risperidone Phase A involved open flexible dose risperidone treatment for 16 weeks. At 16 weeks, non-responders exited the study. Responders were randomized, double-blind, to one of three arms in Phase B: (1) continuation risperidone for 32 weeks (Arm 1), (2) risperidone for 16 weeks followed by placebo for 16 weeks (Arm 2), (3) placebo for 32 weeks (Arm 3). For patients receiving risperidone ≥ 2 mg daily at end-Phase A, assignment to placebo in Phase B required an initial one-week taper with sequential double-blind placebo substitution (e.g., one 2 mg tablet switched to one 1 mg tablet and then to one placebo tablet) to reduce antipsychotic physical withdrawal effects.
Phase B Arm 2: Risperidone -Placebo Phase A involved open flexible dose risperidone treatment for 16 weeks. At 16 weeks, non-responders exited the study. Responders were randomized, double-blind, to one of three arms in Phase B: (1) continuation risperidone for 32 weeks (Arm 1), (2) risperidone for 16 weeks followed by placebo for 16 weeks (Arm 2), (3) placebo for 32 weeks (Arm 3). For patients receiving risperidone ≥ 2 mg daily at end-Phase A, assignment to placebo in Phase B required an initial one-week taper with sequential double-blind placebo substitution (e.g., one 2 mg tablet switched to one 1 mg tablet and then to one placebo tablet) to reduce antipsychotic physical withdrawal effects.
Phase B Arm 3: Placebo-Placebo Phase A involved open flexible dose risperidone treatment for 16 weeks. At 16 weeks, non-responders exited the study. Responders were randomized, double-blind, to one of three arms in Phase B: (1) continuation risperidone for 32 weeks (Arm 1), (2) risperidone for 16 weeks followed by placebo for 16 weeks (Arm 2), (3) placebo for 32 weeks (Arm 3). For patients receiving risperidone ≥ 2 mg daily at end-Phase A, assignment to placebo in Phase B required an initial one-week taper with sequential double-blind placebo substitution (e.g., one 2 mg tablet switched to one 1 mg tablet and then to one placebo tablet) to reduce antipsychotic physical withdrawal effects.
Total Total of all reporting groups

Baseline Measures
    Phase B Arm 1: Risperidone-Risperidone     Phase B Arm 2: Risperidone -Placebo     Phase B Arm 3: Placebo-Placebo     Total  
Number of Participants  
[units: participants]
  32     38     40     110  
Age  
[units: participants]
       
<=18 years     0     0     0     0  
Between 18 and 65 years     2     3     2     7  
>=65 years     30     35     38     103  
Age  
[units: years]
Mean ± Standard Deviation
  80.7  ± 7.9     79.1  ± 8.0     80.3  ± 7.7     80.0  ± 7.8  
Gender  
[units: participants]
       
Female     22     20     24     66  
Male     10     18     16     44  
Region of Enrollment  
[units: participants]
       
United States     32     38     40     110  



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Relapse by Study Week 32   [ Time Frame: 0-16 weeks in Phase B (16-32 weeks in study) ]

2.  Secondary:   Relapse by Study Week 48   [ Time Frame: 16-32 weeks in Phase B (32-48 weeks in study) ]
  Hide Outcome Measure 2

Measure Type Secondary
Measure Title Relapse by Study Week 48
Measure Description Same definition and criteria as the primary outcome
Time Frame 16-32 weeks in Phase B (32-48 weeks in study)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Randomized subjects in each Arm who had not relapsed or terminated the study by the end of the first 16 weeks of Phase B were analyzed in the second 16 weeks of Phase B using intent to treat (ITT) principles.

Reporting Groups
  Description
Arm 1: Risperidone - Risperidone Subjects in Arm 1 who did not relapse or terminate from the study in the first 16 weeks of Phase B continued to receive risperidone in the second 16 weeks of Phase B.
Arm 2: Risperidone - Placebo Subjects in Arm 2 who did not relapse or terminate from the study in the first 16 weeks of Phase B received placebo in the second 16 weeks of Phase B.

Measured Values
    Arm 1: Risperidone - Risperidone     Arm 2: Risperidone - Placebo  
Number of Participants Analyzed  
[units: participants]
  13     27  
Relapse by Study Week 48  
[units: participants]
  2     13  


Statistical Analysis 1 for Relapse by Study Week 48
Groups [1] All groups
Method [2] stratified cox analyses
P Value [3] 0.02
Hazard Ratio (HR) [4] 4.88
95% Confidence Interval ( 1.08 to 21.98 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Similar analyses were used to test the secondary hypothesis in the relapse risk in weeks 17 to 32 of Phase B between the patients who continued to receive risperidone (Arm 1) & the patients who discontinued risperidone at week 16 & were switched to placebo (Arm 2). Patients who died & those in whom a relapse was considered to be imminent before they were dropped out in Phase B were classified as having relapse.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.



3.  Secondary:   Mini Mental State Exam (MMSE)   [ Time Frame: Phase B, weeks 1-16 (study weeks 16-32) ]

4.  Secondary:   Treatment Emergent Symptoms Scale (TESS)   [ Time Frame: Phase B, weeks 1-16 (study weeks 16-32) ]

5.  Secondary:   Extrapyramidal Signs (EPS)   [ Time Frame: Phase B, weeks 1-16 (study weeks 16-32) ]

6.  Secondary:   AIMS   [ Time Frame: Phase B, weeks 1-16 (study weeks 16-32) ]

7.  Secondary:   Physical Self-Maintenance Scale (PSMS)   [ Time Frame: Phase B, weeks 1-16 (study weeks 16-32) ]

8.  Secondary:   Weight   [ Time Frame: Phase B, weeks 1-16 (study weeks 16-32) ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
Comparisons of adverse events in Phase B were limited by the small sample & the truncated observation period for relapsed subjects. Identification of predictors of relapse after discontinuation of treatment was limited by the small sample.


  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.


Results Point of Contact:  
Name/Title: Davangere P. Devanand, MD
Organization: New York State Psychiatric Institute
phone: 212-543-5612
e-mail: dpd3@columbia.edu


Publications of Results:

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