Aggression, Agitation, Alzheimer Disease, Psychotic Disorders
Conditions
Keywords
Risperidone treatment, psychosis, agitation, aggression,, discontinuation, placebo
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.
Interventions
DRUGrisperidone
Risperidone open label flexible dose 0.25 to 3 mg daily for first 16 weeks; dose at 16 weeks then fixed for randomized trial
Sponsors
National Institute on Aging (NIA)
Columbia University
New York State Psychiatric Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to 95 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Relapse by Study Week 32 | 0-16 weeks in Phase B (16-32 weeks in study) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mini Mental State Exam (MMSE) | Phase B, weeks 1-16 (study weeks 16-32) | The MMSE assesses cognition. Scores range from 0-30, with higher scores indicating better cognition. For each subject, the change in MMSE between week 16 and baseline (randomization) was calculated by subtraction, so that a positive value indicates an increase in MMSE over time. |
| Treatment Emergent Symptoms Scale (TESS) | Phase B, weeks 1-16 (study weeks 16-32) | The Treatment Emergent Symptom Scale (TESS) assesses 26 somatic symptoms. Total scores range from 0-26, with a score of 0 or 1 for each item. Higher scores indicate more somatic symptoms. For each subject, the change in TESS between week 16 and baseline (randomization) was calculated by subtraction, so that a positive value indicates an increase in TESS over time. |
| Extrapyramidal Signs (EPS) | Phase B, weeks 1-16 (study weeks 16-32) | Extrapyramidal signs, also known as Parkinsonian signs, refer to signs of tremor, rigidity, and bradykinesia (slowed movement) that are seen in Parkinson's disease. Assessment of extrapyramidal signs (EPS) were made with the use of the Simpson-Angus scale (which ranges from 1-40) with higher scores indicating more extrapyramidal signs. For each subject, the change in EPS between week 16 and baseline (randomization) was calculated by subtraction, so that a positive value indicates an increase in EPS over time. |
| Relapse by Study Week 48 | 16-32 weeks in Phase B (32-48 weeks in study) | Same definition and criteria as the primary outcome |
| Physical Self-Maintenance Scale (PSMS) | Phase B, weeks 1-16 (study weeks 16-32) | Physical Self-Maintenance Scale, which ranges from 1 to 30, with higher scores indicating WORSE functioning. For each subject, the change in PSMS between week 16 and randomization was calculated by subtraction, so that a positive value indicates an increase in PSMS (worse functioning) over time. |
| Weight | Phase B, weeks 1-16 (study weeks 16-32) | For each subject, the change in weight in pounds between week 16 and randomization was calculated by subtraction, so that a positive value indicates an increase in weight over time. |
| AIMS | Phase B, weeks 1-16 (study weeks 16-32) | The Abnormal Involuntary Movement Scale (AIMS) assesses signs of tardive dyskinesia, a movement disorder that can occur with prolonged use of antipsychotic medication. The AIMS score ranges from 0 to 35, with higher scores indicating more severe symptoms. For each subject, the change in AIMS score between week 16 and randomization was calculated by subtraction, so that a positive value indicates an increase in AIMS over time. |
Countries
United States
Participant flow
Recruitment details
Patients were recruited from memory clinics including Alzheimer Research Centers, geriatric psychiatry clinics, VA clinics, physician referrals and advertising.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 32 |
| 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. | 38 |
| 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. | 40 |
| Total | 110 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Phase B 1st 16 Weeks | Adverse Event | 2 | 0 | 1 |
| Phase B 1st 16 Weeks | Death | 1 | 0 | 0 |
| Phase B 1st 16 Weeks | Lack of Efficacy | 14 | 8 | 24 |
| Phase B 1st 16 Weeks | Moved, Unclear reasons | 2 | 3 | 2 |
| Phase B 2nd 16 Weeks | Adverse Event | 0 | 0 | 1 |
| Phase B 2nd 16 Weeks | Death | 1 | 1 | 0 |
| Phase B 2nd 16 Weeks | Lack of Efficacy | 1 | 12 | 2 |
| Phase B 2nd 16 Weeks | Moved; unclear reason | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Phase B Arm 2: Risperidone -Placebo | Phase B Arm 3: Placebo-Placebo | Phase B Arm 1: Risperidone-Risperidone | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 35 Participants | 38 Participants | 30 Participants | 103 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 2 Participants | 2 Participants | 7 Participants |
| Age Continuous | 79.1 years STANDARD_DEVIATION 8 | 80.3 years STANDARD_DEVIATION 7.7 | 80.7 years STANDARD_DEVIATION 7.9 | 80.0 years STANDARD_DEVIATION 7.8 |
| Region of Enrollment United States | 38 participants | 40 participants | 32 participants | 110 participants |
| Sex: Female, Male Female | 20 Participants | 24 Participants | 22 Participants | 66 Participants |
| Sex: Female, Male Male | 18 Participants | 16 Participants | 10 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 36 / 70 | 24 / 40 | 9 / 13 | 13 / 27 | 7 / 13 |
| serious Total, serious adverse events | 5 / 70 | 8 / 40 | 2 / 13 | 0 / 27 | 0 / 13 |
Outcome results
Primary
Relapse by Study Week 32
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)
Population: Analysis was performed as per intention to treat (ITT) principles.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase B Arm 1: Risperidone-Risperidone | Relapse by Study Week 32 | 15 participants |
| Phase B Arm 2: Risperidone -Placebo | Relapse by Study Week 32 | 8 participants |
| Phase B Arm 3: Placebo-Placebo | Relapse by Study Week 32 | 24 participants |
Comparison: 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.p-value: 0.0295% CI: [1.09, 3.45]Stratified Cox analysis
Secondary
AIMS
The Abnormal Involuntary Movement Scale (AIMS) assesses signs of tardive dyskinesia, a movement disorder that can occur with prolonged use of antipsychotic medication. The AIMS score ranges from 0 to 35, with higher scores indicating more severe symptoms. For each subject, the change in AIMS score between week 16 and randomization was calculated by subtraction, so that a positive value indicates an increase in AIMS over time.
Time frame: Phase B, weeks 1-16 (study weeks 16-32)
Population: All randomized subjects were included in this analysis (N=110).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase B Arm 1: Risperidone-Risperidone | AIMS | 0.03 units on a scale | Standard Deviation 0.48 |
| Phase B Arm 2: Risperidone -Placebo | AIMS | 0.24 units on a scale | Standard Deviation 1.01 |
Comparison: The null hypothesis is that the difference between placebo and risperidone groups in terms of mean change in AIMS, between randomization and week 16, is zero.p-value: 0.1395% CI: [-0.5, 0.07]t-test, 2 sided
Secondary
Extrapyramidal Signs (EPS)
Extrapyramidal signs, also known as Parkinsonian signs, refer to signs of tremor, rigidity, and bradykinesia (slowed movement) that are seen in Parkinson's disease. Assessment of extrapyramidal signs (EPS) were made with the use of the Simpson-Angus scale (which ranges from 1-40) with higher scores indicating more extrapyramidal signs. For each subject, the change in EPS between week 16 and baseline (randomization) was calculated by subtraction, so that a positive value indicates an increase in EPS over time.
Time frame: Phase B, weeks 1-16 (study weeks 16-32)
Population: All randomized subjects were included in the analysis (N=110).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase B Arm 1: Risperidone-Risperidone | Extrapyramidal Signs (EPS) | -0.20 units on a scale | Standard Deviation 1.91 |
| Phase B Arm 2: Risperidone -Placebo | Extrapyramidal Signs (EPS) | 0.34 units on a scale | Standard Deviation 2.68 |
Comparison: The null hypothesis is that the difference between placebo and risperidone groups in terms of mean change in EPS, between randomization and week 16, is zero.p-value: 0.2695% CI: [-1.5, 0.41]t-test, 2 sided
Secondary
Mini Mental State Exam (MMSE)
The MMSE assesses cognition. Scores range from 0-30, with higher scores indicating better cognition. For each subject, the change in MMSE between week 16 and baseline (randomization) was calculated by subtraction, so that a positive value indicates an increase in MMSE over time.
Time frame: Phase B, weeks 1-16 (study weeks 16-32)
Population: MMSE data were missing for 2 subjects in the placebo group and 1 subject in the risperidone group, so the number of subjects in this analysis were 38 (placebo) and 69 (risperidone), for a total of 107.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase B Arm 1: Risperidone-Risperidone | Mini Mental State Exam (MMSE) | -0.13 units on a scale | Standard Deviation 1.49 |
| Phase B Arm 2: Risperidone -Placebo | Mini Mental State Exam (MMSE) | -0.77 units on a scale | Standard Deviation 2.23 |
Comparison: The null hypothesis is that there is no difference between the risperidone and placebo groups over the 16 week period post randomization, with respect to change in MMSE.p-value: 0.0895% CI: [-0.08, 1.35]t-test, 2 sided
Secondary
Physical Self-Maintenance Scale (PSMS)
Physical Self-Maintenance Scale, which ranges from 1 to 30, with higher scores indicating WORSE functioning. For each subject, the change in PSMS between week 16 and randomization was calculated by subtraction, so that a positive value indicates an increase in PSMS (worse functioning) over time.
Time frame: Phase B, weeks 1-16 (study weeks 16-32)
Population: All randomized subjects were included in this analysis, with the exception of one placebo subject for whom PSMS data was not available at one time point
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase B Arm 1: Risperidone-Risperidone | Physical Self-Maintenance Scale (PSMS) | 0.18 units on a scale | Standard Deviation 1.73 |
| Phase B Arm 2: Risperidone -Placebo | Physical Self-Maintenance Scale (PSMS) | 0.80 units on a scale | Standard Deviation 2.72 |
Comparison: The null hypothesis is that the difference between placebo and risperidone groups in terms of mean change in PSMS, between randomization and week 16, is zero.p-value: 0.14995% CI: [-1.47, 0.23]t-test, 2 sided
Secondary
Relapse by Study Week 48
Same definition and criteria as the primary outcome
Time frame: 16-32 weeks in Phase B (32-48 weeks in study)
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase B Arm 1: Risperidone-Risperidone | Relapse by Study Week 48 | 2 participants |
| Phase B Arm 2: Risperidone -Placebo | Relapse by Study Week 48 | 13 participants |
Comparison: 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.p-value: 0.0295% CI: [1.08, 21.98]stratified cox analyses
Secondary
Treatment Emergent Symptoms Scale (TESS)
The Treatment Emergent Symptom Scale (TESS) assesses 26 somatic symptoms. Total scores range from 0-26, with a score of 0 or 1 for each item. Higher scores indicate more somatic symptoms. For each subject, the change in TESS between week 16 and baseline (randomization) was calculated by subtraction, so that a positive value indicates an increase in TESS over time.
Time frame: Phase B, weeks 1-16 (study weeks 16-32)
Population: All randomized subjects were included in this analysis (N=110)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase B Arm 1: Risperidone-Risperidone | Treatment Emergent Symptoms Scale (TESS) | 0.18 units on a scale | Standard Deviation 2.4 |
| Phase B Arm 2: Risperidone -Placebo | Treatment Emergent Symptoms Scale (TESS) | 0.21 units on a scale | Standard Deviation 2.5 |
Comparison: The null hypothesis is that there is no difference between the risperidone and placebo groups over the 16 week period post randomization, with respect to change in TESS.p-value: 0.9495% CI: [-1.01, 0.93]t-test, 2 sided
Secondary
Weight
For each subject, the change in weight in pounds between week 16 and randomization was calculated by subtraction, so that a positive value indicates an increase in weight over time.
Time frame: Phase B, weeks 1-16 (study weeks 16-32)
Population: Available data from all randomized subject (N=110) was used in this analysis. Weight measurements were unavailable at one or more time points for 3 subjects in the placebo group and for 6 subjects in the risperidone group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase B Arm 1: Risperidone-Risperidone | Weight | 0.32 pounds | Standard Deviation 7.18 |
| Phase B Arm 2: Risperidone -Placebo | Weight | 0.73 pounds | Standard Deviation 8.71 |
Comparison: The null hypothesis is that the difference between placebo and risperidone groups in terms of mean change in weight, between randomization and week 16, is zero.p-value: 0.8195% CI: [-3.77, 2.95]t-test, 2 sided