Antipsychotic Discontinuation in Alzheimer's Disease (ADAD)

Study Type:	Interventional
Study Design:	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, 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
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

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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: 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; 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)

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
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
Statistical Test Type [2]	Superiority or Other
Statistical Method [3]	Stratified Cox analysis
P Value [4]	0.02
Hazard Ratio (HR) [5]	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]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	No text entered.
[3]	Other relevant method information, such as adjustments or degrees of freedom:
	No text entered.
[4]	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.
[5]	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) ]

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3. Secondary:

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

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4. Secondary:

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

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5. Secondary:

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

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6. Secondary:

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

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7. Secondary:

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

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8. Secondary:

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

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  Serious Adverse Events

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  Other Adverse Events

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  Limitations and Caveats

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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.

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