Dementia-related Psychosis
Conditions
Keywords
Dementia, Dementia-related psychosis, Dementia associated with Parkinson's disease, Dementia with Lewy bodies, Alzheimer's disease, Behavioral variant frontotemporal dementia, Progressive supranuclear palsy, Corticobasal degeneration, Vascular dementia, Hallucinations, Delusions, Psychosis
Brief summary
The purpose of this study is to evaluate the efficacy of pimavanserin compared to placebo in preventing relapse of psychotic symptoms in subjects with dementia-related psychosis who responded to 12 weeks of open label pimavanserin treatment.
Interventions
DRUGPlacebo
Placebo, tablets, once daily by mouth
Pimavanserin 34 mg total daily dose, tablets, once daily by mouth
Pimavanserin 20 mg total daily dose, tablets, once daily by mouth
Sponsors
ACADIA Pharmaceuticals Inc.
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 90 Years
Healthy volunteers
No
Inclusion criteria
1. Meets criteria for All-cause Dementia according to NIA-AA guidelines 2. Meets clinical criteria for one of the following disorders: Dementia associated with Parkinson's disease, Dementia with Lewy bodies, Possible or probable Alzheimer's disease, Frontotemporal degeneration spectrum disorders, Vascular dementia 3. Has an MMSE score ≥6 and ≤24 4. Has had psychotic symptoms for at least 2 months 5. Must be on a stable does of cholinesterase inhibitor or memantine, if applicable 6. If the subject is female, she must not be pregnant or breastfeeding. She must also be of non-childbearing potential or must agree to use a clinically acceptable method of contraception for the duration of the study
Exclusion criteria
1. Has psychotic symptoms that are primarily attributable to a condition other than dementia 2. Has had a recent major depressive episode 3. Has experienced suicidal ideation or behavior within 3 months prior to study enrollment 4. Has evidence of a non-neurologic medical comorbidity or medication use that could substantially impair cognition 5. Has a history of ischemic stroke within the last 12 months or any evidence of hemorrhagic stroke 6. Has a known history of cerebral amyloid angiopathy (CAA), epilepsy, CNS neoplasm, or unexplained syncope 7. Has any of the following: greater than New York Heart Association (NYHA) Class 2 congestive heart failure, Grade 2 or greater angina pectoris, sustained ventricular tachycardia, ventricular fibrillation, torsade de pointes, syncope due to an arrhythmia, an implantable cardiac defibrillator 8. Had a myocardial infarction within the last 6 months 9. Has a known personal or family history or symptoms of long QT syndrome 10. Has a significant unstable medical condition that could interfere with subject's ability to complete the study or comply with study procedures 11. Requires treatment with a medication or other substance that is prohibited by the protocol Additional inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time From Randomization to Relapse in the Double-blind (DB) Period | From randomization in the DB period through 26 weeks | The time from randomization to relapse in the DB period was compared between treatment groups using a Cox regression model. The treatment effect was measured by the hazard ratio (HR). Relapse was defined as (1) ≥30% increase in SAPS-H+D total score from DB baseline (BL) and CGI-I score ≥6 relative to DB BL, (2) treatment with antipsychotic for dementia-related delusions/hallucinations, (3) treatment/study discontinuation due to lack of efficacy, and/or (4) hospitalization for worsening dementia-related psychosis. SAPS-H+D is a 20-item scale; the total score is the sum of the 20 item scores (range 0-100); higher scores denote more severe symptoms. CGI-I is a clinician-rated 7-point scale to rate improvement in hallucinations/delusions relative to BL (range 1-7); higher scores denote less improvement or worsening. A pre-specified IA was conducted after accrual of 40 adjudicated relapse events. The prespecified stopping criterion was met; the study was stopped for efficacy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time From Randomization to Discontinuation From the DB Period for Any Reason | From randomization in the DB period through 26 weeks | The endpoint of time from randomization to discontinuation from the DB period for any reason (other than termination of the study by the sponsor) was compared between treatment groups using a Cox regression model. The treatment effect was measured by the HR. |
Countries
Bulgaria, Chile, Czechia, France, Germany, Italy, Poland, Serbia, Slovakia, Spain, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
The study was performed in subjects with all-cause dementia according to NIA-AA guidelines, including dementia associated with Parkinson's disease, dementia with Lewy Bodies, possible or probable Alzheimer's disease, frontotemporal degeneration spectrum disorder, and/or vascular dementia, and were to have had at least a 2-month history of psychotic symptoms.
Pre-assignment details
During the screening period, subjects were assessed for study eligibility and prohibited medications were discontinued when medically appropriate. Subjects and partner/caregivers also received a standardized psychosocial therapy training.
Participants by arm
| Arm | Count |
|---|---|
| Pimavanserin Open-Label Period Pimavanserin 34 mg once daily, with the possibility to adjust to pimavanserin 20 mg once daily between Weeks 1 and 4 based on tolerability. After Week 4, the dose of study drug remained fixed at either 34 or 20 mg once daily. | 392 |
| Total | 392 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Double-blind Period | Administrative discont. at study termination | 0 | 35 | 31 |
| Double-blind Period | Adverse Event | 0 | 3 | 1 |
| Double-blind Period | Noncompliance with study drug | 0 | 0 | 1 |
| Double-blind Period | Not otherwise specified | 0 | 1 | 5 |
| Double-blind Period | Physician Decision | 0 | 0 | 1 |
| Double-blind Period | Relapse | 0 | 15 | 34 |
| Double-blind Period | Use of prohibited medication | 0 | 1 | 0 |
| Double-blind Period | Withdrawal by Subject | 0 | 6 | 4 |
| Open-label Period | Administrative discont. at study termination | 41 | 0 | 0 |
| Open-label Period | Adverse Event | 27 | 0 | 0 |
| Open-label Period | Death | 1 | 0 | 0 |
| Open-label Period | Lack of Response in OL period | 70 | 0 | 0 |
| Open-label Period | Lost to Follow-up | 1 | 0 | 0 |
| Open-label Period | Non-compliance with study drug | 5 | 0 | 0 |
| Open-label Period | Not otherwise specified | 8 | 0 | 0 |
| Open-label Period | Protocol Violation | 4 | 0 | 0 |
| Open-label Period | Use of prohibited medication | 1 | 0 | 0 |
| Open-label Period | Withdrawal by Subject | 17 | 0 | 0 |
Baseline characteristics
| Characteristic | Pimavanserin Open-Label Period |
|---|---|
| Age, Continuous | 74.5 years STANDARD_DEVIATION 8.28 |
| Clinical Global Impression-Severity (CGI-S) | 4.7 units on a scale STANDARD_DEVIATION 0.69 |
| Dementia severity Mild | 65 Participants |
| Dementia severity Moderate | 275 Participants |
| Dementia severity Severe | 52 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 371 Participants |
| Region of Enrollment Bulgaria | 3 participants |
| Region of Enrollment Chile | 27 participants |
| Region of Enrollment Czechia | 11 participants |
| Region of Enrollment France | 7 participants |
| Region of Enrollment Germany | 1 participants |
| Region of Enrollment Italy | 13 participants |
| Region of Enrollment Poland | 42 participants |
| Region of Enrollment Serbia | 44 participants |
| Region of Enrollment Slovakia | 35 participants |
| Region of Enrollment Spain | 9 participants |
| Region of Enrollment Ukraine | 74 participants |
| Region of Enrollment United Kingdom | 8 participants |
| Region of Enrollment United States | 118 participants |
| Scale for the Assessment of Positive Symptoms-Hallucinations+Delusions (SAPS-H+D) total score | 24.4 Score on a scale STANDARD_DEVIATION 9.22 |
| Sex: Female, Male Female | 229 Participants |
| Sex: Female, Male Male | 163 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 392 | 1 / 105 | 0 / 112 |
| other Total, other adverse events | 24 / 392 | 16 / 105 | 9 / 112 |
| serious Total, serious adverse events | 20 / 392 | 5 / 105 | 4 / 112 |
Outcome results
Primary
Time From Randomization to Relapse in the Double-blind (DB) Period
The time from randomization to relapse in the DB period was compared between treatment groups using a Cox regression model. The treatment effect was measured by the hazard ratio (HR). Relapse was defined as (1) ≥30% increase in SAPS-H+D total score from DB baseline (BL) and CGI-I score ≥6 relative to DB BL, (2) treatment with antipsychotic for dementia-related delusions/hallucinations, (3) treatment/study discontinuation due to lack of efficacy, and/or (4) hospitalization for worsening dementia-related psychosis. SAPS-H+D is a 20-item scale; the total score is the sum of the 20 item scores (range 0-100); higher scores denote more severe symptoms. CGI-I is a clinician-rated 7-point scale to rate improvement in hallucinations/delusions relative to BL (range 1-7); higher scores denote less improvement or worsening. A pre-specified IA was conducted after accrual of 40 adjudicated relapse events. The prespecified stopping criterion was met; the study was stopped for efficacy.
Time frame: From randomization in the DB period through 26 weeks
Population: All patients randomized on or before the database cutoff date for the IA (i.e., when 40 adjudicated relapse events had accrued).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pimavanserin Double-Blind Period | Time From Randomization to Relapse in the Double-blind (DB) Period | NA days |
| Placebo Double-Blind Period | Time From Randomization to Relapse in the Double-blind (DB) Period | NA days |
p-value: 0.002395% CI: [0.172, 0.727]Regression, Cox
Secondary
Time From Randomization to Discontinuation From the DB Period for Any Reason
The endpoint of time from randomization to discontinuation from the DB period for any reason (other than termination of the study by the sponsor) was compared between treatment groups using a Cox regression model. The treatment effect was measured by the HR.
Time frame: From randomization in the DB period through 26 weeks
Population: All patients randomized on or before the database cutoff date for the IA (i.e., when 40 adjudicated relapse events had accrued).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pimavanserin Double-Blind Period | Time From Randomization to Discontinuation From the DB Period for Any Reason | NA days |
| Placebo Double-Blind Period | Time From Randomization to Discontinuation From the DB Period for Any Reason | NA days |
p-value: 0.002495% CI: [0.261, 0.785]Regression, Cox