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

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.
Time Frame 0-16 weeks in Phase B (16-32 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.
Analysis was performed as per intention to treat (ITT) principles.

Reporting Groups
  Description
Phase B Arm 1: Risperidone-Risperidone 32 patients randomized to Phase B Arm 1 received continuation risperidone for another 32 weeks.
Phase B Arm 2: Risperidone -Placebo

38 patients randomized to Phase B Arm 2 received risperidone therapy for 16 weeks followed by placebo for 16 weeks.

In Phase B, relapse required ≥ 30% increase or 5-point increase in NPI core scores from end-Phase A and a score of 6 (much worse) or 7 (very much worse) on the CGI-C.

Phase B Arm 3: Placebo-Placebo

40 patients randomized to Phase B Arm 3 received placebo for 32 weeks. 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.

In Phase B, relapse required ≥ 30% increase or 5-point increase in NPI core scores from end-Phase A and a score of 6 (much worse) or 7 (very much worse) on the CGI-C.


Measured Values
    Phase B Arm 1: Risperidone-Risperidone     Phase B Arm 2: Risperidone -Placebo     Phase B Arm 3: Placebo-Placebo  
Number of Participants Analyzed  
[units: participants]
  32     38     40  
Relapse by Study Week 32  
[units: participants]
  15     8     24  


Statistical Analysis 1 for Relapse by Study Week 32
Groups [1] All groups
Method [2] Stratified Cox analysis
P Value [3] 0.02
Hazard Ratio (HR) [4] 1.94
95% Confidence Interval ( 1.09 to 3.45 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The primary hypothesis of a difference in survival functions between the initial Phase B placebo (Arm 3) and risperidone continuation (Arms 1+2) conditions was tested in the primary analysis using the stratified Cox analysis. For descriptive purposes, the overall rate of relapse was assessed as the number of follow-up or for secondary interpretative support, as a simple proportion of patients entering a 16-week period.
[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.



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

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