Now Available: Final Rule for FDAAA 801 and NIH Policy on Clinical Trial Reporting

Antipsychotic Discontinuation in Alzheimer's Disease (ADAD)

This study has been completed.
Sponsor:
Collaborators:
National Institute on Aging (NIA)
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
  Hide Participant Flow

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
  Hide Baseline Characteristics

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 
Overall Participants Analyzed 
[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) ]

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
  Hide Other Adverse Events

Time Frame Adverse event data were collected for the duration of the trial, in both the open treatment Phase A (study week 1-16) and in the post-randomization Phase B (study weeks 16-48)
Additional Description No text entered.

Frequency Threshold
Threshold above which other adverse events are reported   1  

Reporting Groups
  Description
Wk0-16 Phase B Arm 1 (Risp-Risp) & Arm 2 (Risp-Pla) 32 patients randomized to Phase B Arm 1 received continuation risperidone for another 32 weeks; 38 patients randomized to Phase B Arm 2 received risperidone for 16 weeks followed by placebo for 16 weeks. Therefore there were a total of 70 patients in this group.
Wk 0-16 Phase B Arm 3: Placebo -Placebo 40 patients randomized to Phase B Arm 3 received placebo for 32 weeks.
Wk 17-32 Phase B Arm 1: Risperdone-Risperdone 13 patients completed Wk 0-16 of Phase 2 Arm 1 and entered Wk 17-32 where they received risperidone for another 16 weeks.
Wk 17-32 Phase B Arm 2: Risperdone-Placebo 27 patients completed Wk 0-16 of Phase B Arm 2 and entered Week 17-32 of Phase B Arm 2 where they receive placebo for 16 weeks.
Wek 17-32 Phase B Arm 3: Placebo -Placebo 13 patients completed Week 0-16 of Phase B Arm 3 and entered Week 17-32 were they were given placebo for another 16 weeks.

Other Adverse Events
    Wk0-16 Phase B Arm 1 (Risp-Risp) & Arm 2 (Risp-Pla)   Wk 0-16 Phase B Arm 3: Placebo -Placebo   Wk 17-32 Phase B Arm 1: Risperdone-Risperdone   Wk 17-32 Phase B Arm 2: Risperdone-Placebo   Wek 17-32 Phase B Arm 3: Placebo -Placebo
Total, other (not including serious) adverse events           
# participants affected / at risk   36/70 (51.43%)   24/40 (60.00%)   9/13 (69.23%)   13/27 (48.15%)   7/13 (53.85%) 
Gastrointestinal disorders           
nausea or vomiting † [2]           
# participants affected / at risk   2/70 (2.86%)   2/40 (5.00%)   2/13 (15.38%)   0/27 (0.00%)   1/13 (7.69%) 
# events   2   2   2   0   1 
Nervous system disorders           
Extrapyramidal signs † [3]           
# participants affected / at risk   13/70 (18.57%)   4/40 (10.00%)   4/13 (30.77%)   4/27 (14.81%)   2/13 (15.38%) 
# events   13   4   4   4   2 
akathisia or restlessness † [4]           
# participants affected / at risk   4/70 (5.71%)   6/40 (15.00%)   1/13 (7.69%)   3/27 (11.11%)   1/13 (7.69%) 
# events   4   6   1   3   1 
sedation † [5]           
# participants affected / at risk   7/70 (10.00%)   5/40 (12.50%)   1/13 (7.69%)   1/27 (3.70%)   1/13 (7.69%) 
# events   7   5   1   1   1 
insomnia † [6]           
# participants affected / at risk   3/70 (4.29%)   1/40 (2.50%)   0/13 (0.00%)   1/27 (3.70%)   0/13 (0.00%) 
# events   3   1   0   1   0 
confusion † [7]           
# participants affected / at risk   4/70 (5.71%)   4/40 (10.00%)   1/13 (7.69%)   3/27 (11.11%)   1/13 (7.69%) 
# events   4   4   1   3   1 
Agitation-Aggression † [8]           
# participants affected / at risk   1/70 (1.43%)   1/40 (2.50%)   0/13 (0.00%)   1/27 (3.70%)   1/13 (7.69%) 
# events   1   1   0   1   1 
fall † [9]           
# participants affected / at risk   2/70 (2.86%)   1/40 (2.50%)   0/13 (0.00%)   0/27 (0.00%)   0/13 (0.00%) 
# events   2   1   0   0   0 
Events were collected by systematic assessment
[2] Nausea or vomiting was either a report of clinically significant new adverse event or a worsening of a symptom from baseline to a moderate or severe level, as assessed by means of the Treatment Emergent Symptom scale (TESS).
[3] Extrapyramidal signs was considered to be adverse events if there was an average increase from baseline of more than 1 point on the Simpson-Angus scale.
[4] Akathisia or restlessness was considered to be adverse events if there was an average increase from baseline of more than 1 point on the Simpson-Angus scale.
[5] Sedation was either a report of clinically significant new adverse event or a worsening of a symptom from baseline to a moderate or severe level, as assessed by means of the Treatment Emergent Symptom scale (TESS).
[6] Insomnia was either a report of clinically significant new adverse event or a worsening of a symptom from baseline to a moderate or severe level, as assessed by means of the Treatment Emergent Symptom scale (TESS).
[7] Confusion was either a report of clinically significant new adverse event or a worsening of a symptom from baseline to a moderate or severe level, as assessed by means of the Treatment Emergent Symptom scale (TESS).
[8] Agitation-aggression was either a report of clinically significant new adverse event or a worsening of a symptom from baseline to a moderate or severe level, as assessed by means of the Treatment Emergent Symptom scale (TESS).
[9] Fall was either a report of clinically significant new adverse event or a worsening of a symptom from baseline to a moderate or severe level, as assessed by means of the Treatment Emergent Symptom scale (TESS).



  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