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Relapse Prevention Study of Pimavanserin in Dementia-related Psychosis

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ClinicalTrials.gov Identifier: NCT03325556
Recruitment Status : Completed
First Posted : October 30, 2017
Results First Posted : June 21, 2021
Last Update Posted : June 21, 2021
Sponsor:
Information provided by (Responsible Party):
ACADIA Pharmaceuticals Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Dementia-related Psychosis
Interventions Drug: Placebo
Drug: Pimavanserin 34 mg
Drug: Pimavanserin 20 mg
Enrollment 392
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.
Arm/Group Title Pimavanserin Open-Label Period Pimavanserin Double-Blind Period Placebo Double-Blind Period
Hide Arm/Group Description 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. Pimavanserin 34 mg once daily or pimavanserin 20 mg once daily (the dose at which patients completed the Open-Label Period) for 26 weeks or until relapse Placebo once daily for 26 weeks or until relapse
Period Title: Open-label Period
Started 392 0 0
Completed 217 0 0
Not Completed 175 0 0
Reason Not Completed
Lack of Response in OL period             70             0             0
Adverse Event             27             0             0
Death             1             0             0
Lost to Follow-up             1             0             0
Non-compliance with study drug             5             0             0
Use of prohibited medication             1             0             0
Protocol Violation             4             0             0
Withdrawal by Subject             17             0             0
Not otherwise specified             8             0             0
Administrative discont. at study termination             41             0             0
Period Title: Double-blind Period
Started 0 105 112
Completed 0 44 35
Not Completed 0 61 77
Reason Not Completed
Relapse             0             15             34
Adverse Event             0             3             1
Noncompliance with study drug             0             0             1
Use of prohibited medication             0             1             0
Physician Decision             0             0             1
Withdrawal by Subject             0             6             4
Not otherwise specified             0             1             5
Administrative discont. at study termination             0             35             31
Arm/Group Title Pimavanserin Open-Label Period
Hide Arm/Group Description 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.
Overall Number of Baseline Participants 392
Hide Baseline Analysis Population Description
Patients who entered the respective study period and received at least one dose of study medication
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 392 participants
74.5  (8.28)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 392 participants
Female
229
  58.4%
Male
163
  41.6%
Race (NIH/OMB)   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 384 participants
American Indian or Alaska Native
0
   0.0%
Asian
0
   0.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
Black or African American
10
   2.6%
White
371
  96.6%
More than one race
0
   0.0%
Unknown or Not Reported
3
   0.8%
[1]
Measure Analysis Population Description: For 8 patients, Information on race was not available.
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 392 participants
118
Czechia Number Analyzed 392 participants
11
Ukraine Number Analyzed 392 participants
74
United Kingdom Number Analyzed 392 participants
8
Spain Number Analyzed 392 participants
9
Poland Number Analyzed 392 participants
42
Italy Number Analyzed 392 participants
13
Slovakia Number Analyzed 392 participants
35
Bulgaria Number Analyzed 392 participants
3
Chile Number Analyzed 392 participants
27
France Number Analyzed 392 participants
7
Serbia Number Analyzed 392 participants
44
Germany Number Analyzed 392 participants
1
Dementia severity  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 392 participants
Mild
65
  16.6%
Moderate
275
  70.2%
Severe
52
  13.3%
Scale for the Assessment of Positive Symptoms-Hallucinations+Delusions (SAPS-H+D) total score   [1] 
Mean (Standard Deviation)
Unit of measure:  Score on a scale
Number Analyzed 392 participants
24.4  (9.22)
[1]
Measure Description: The Scale for the Assessment of Positive Symptoms-Hallucinations and Delusions (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.
Clinical Global Impression-Severity (CGI-S)   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 392 participants
4.7  (0.69)
[1]
Measure Description: The Clinical Global Impression-Severity (CGI-S) is a clinician-rated, 7-point scale to rate the severity of the patient's hallucinations and delusions at the time of assessment. Scores range from 1 to 7, with a higher score marking a more severe state.
1.Primary Outcome
Title Time From Randomization to Relapse in the Double-blind (DB) Period
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
All patients randomized on or before the database cutoff date for the IA (i.e., when 40 adjudicated relapse events had accrued).
Arm/Group Title Pimavanserin Double-Blind Period Placebo Double-Blind Period
Hide Arm/Group Description:
Pimavanserin 34 mg once daily or pimavanserin 20 mg once daily (the dose at which patients completed the Open-Label Period) for 26 weeks or until relapse
Placebo once daily for 26 weeks or until relapse
Overall Number of Participants Analyzed 95 99
Median (Full Range)
Unit of Measure: days
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
The median time to relapse could not be estimated as the Kaplan-Meier probability estimate of relapse over the 26-week DB period did not exceed 50%.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pimavanserin Double-Blind Period, Placebo Double-Blind Period
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0023
Comments 1-sided p-value reported. The protocol-defined O'Brien Flemming stopping boundary for the planned IA was a 1-sided p-value equal to 0.0033
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.353
Confidence Interval (2-Sided) 95%
0.172 to 0.727
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.3676
Estimation Comments Model included covariates for Treatment group, dementia subtype, and region, and robust sandwich-type variance estimator.
2.Secondary Outcome
Title Time From Randomization to Discontinuation From the DB Period for Any Reason
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
All patients randomized on or before the database cutoff date for the IA (i.e., when 40 adjudicated relapse events had accrued).
Arm/Group Title Pimavanserin Double-Blind Period Placebo Double-Blind Period
Hide Arm/Group Description:
Pimavanserin 34 mg once daily or pimavanserin 20 mg once daily (the dose at which patients completed the Open-Label Period) for 26 weeks or until relapse
Placebo once daily for 26 weeks or until relapse
Overall Number of Participants Analyzed 95 99
Median (Full Range)
Unit of Measure: days
NA [1] 
(NA to NA)
NA [1] 
(NA to NA)
[1]
The median time to discontinuation could not be estimated as the Kaplan-Meier probability estimate over the 26-week DB period did not exceed 50%.
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pimavanserin Double-Blind Period, Placebo Double-Blind Period
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0024
Comments 1-sided p-value
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.452
Confidence Interval (2-Sided) 95%
0.261 to 0.785
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.2812
Estimation Comments Model included covariates for Treatment group, dementia subtype, and region, and robust sandwich-type variance estimator.
Time Frame Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Pimavanserin Open-Label Period Pimavanserin Double-Blind Period Placebo Double-Blind Period
Hide Arm/Group Description 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 Pimavanserin 34 mg once daily or pimavanserin 20 mg once daily (the dose at which patients completed the Open-Label Period) for 26 weeks or until relapse Placebo once daily for 26 weeks or until relapse
All-Cause Mortality
Pimavanserin Open-Label Period Pimavanserin Double-Blind Period Placebo Double-Blind Period
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1/392 (0.26%)      1/105 (0.95%)      0/112 (0.00%)    
Hide Serious Adverse Events
Pimavanserin Open-Label Period Pimavanserin Double-Blind Period Placebo Double-Blind Period
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   20/392 (5.10%)      5/105 (4.76%)      4/112 (3.57%)    
Cardiac disorders       
Cardiac failure congestive * 1  1/392 (0.26%)  1 0/105 (0.00%)  0 0/112 (0.00%)  0
Myocardial infarction * 1  1/392 (0.26%)  1 0/105 (0.00%)  0 0/112 (0.00%)  0
Gastrointestinal disorders       
Abdominal pain lower * 1  1/392 (0.26%)  1 0/105 (0.00%)  0 0/112 (0.00%)  0
Abdominal pain upper * 1  1/392 (0.26%)  1 0/105 (0.00%)  0 0/112 (0.00%)  0
Diarrhoea * 1  1/392 (0.26%)  1 0/105 (0.00%)  0 0/112 (0.00%)  0
Haematemesis * 1  1/392 (0.26%)  1 0/105 (0.00%)  0 1/112 (0.89%)  1
Intestinal obstruction * 1  1/392 (0.26%)  1 0/105 (0.00%)  0 0/112 (0.00%)  0
General disorders       
Oedema peripheral * 1  1/392 (0.26%)  1 0/105 (0.00%)  0 0/112 (0.00%)  0
Infections and infestations       
Urinary tract infection * 1  2/392 (0.51%)  2 1/105 (0.95%)  1 1/112 (0.89%)  1
Abscess jaw * 1  1/392 (0.26%)  1 0/105 (0.00%)  0 0/112 (0.00%)  0
Diverticulitis * 1  1/392 (0.26%)  1 0/105 (0.00%)  0 0/112 (0.00%)  0
Erysipelas * 1  1/392 (0.26%)  1 0/105 (0.00%)  0 0/112 (0.00%)  0
Pneumonia * 1  0/392 (0.00%)  0 0/105 (0.00%)  0 1/112 (0.89%)  1
Sepsis * 1  0/392 (0.00%)  0 1/105 (0.95%)  1 0/112 (0.00%)  0
Septic encephalopathy * 1  0/392 (0.00%)  0 1/105 (0.95%)  1 0/112 (0.00%)  0
Injury, poisoning and procedural complications       
Fall * 1  2/392 (0.51%)  2 0/105 (0.00%)  0 0/112 (0.00%)  0
Bone fissure * 1  1/392 (0.26%)  1 0/105 (0.00%)  0 0/112 (0.00%)  0
Metabolism and nutrition disorders       
Dehydration * 1  2/392 (0.51%)  2 0/105 (0.00%)  0 0/112 (0.00%)  0
Malnutrition * 1  1/392 (0.26%)  1 0/105 (0.00%)  0 0/112 (0.00%)  0
Decreased appetite * 1  0/392 (0.00%)  0 0/105 (0.00%)  0 1/112 (0.89%)  1
Musculoskeletal and connective tissue disorders       
Back pain * 1  1/392 (0.26%)  1 0/105 (0.00%)  0 0/112 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Prostate cancer metastatic * 1  0/392 (0.00%)  0 1/105 (0.95%)  1 0/112 (0.00%)  0
Nervous system disorders       
Metabolic encephalopathy * 1  0/392 (0.00%)  0 1/105 (0.95%)  1 0/112 (0.00%)  0
Transient ischaemic attack * 1  0/392 (0.00%)  0 1/105 (0.95%)  1 0/112 (0.00%)  0
Dementia Alzheimer's type * 1  1/392 (0.26%)  1 0/105 (0.00%)  0 0/112 (0.00%)  0
Syncope * 1  0/392 (0.00%)  0 0/105 (0.00%)  0 1/112 (0.89%)  1
Psychiatric disorders       
Agression * 1  1/392 (0.26%)  1 1/105 (0.95%)  1 0/112 (0.00%)  0
Agitation * 1  1/392 (0.26%)  1 0/105 (0.00%)  0 0/112 (0.00%)  0
Mental status changes * 1  1/392 (0.26%)  1 0/105 (0.00%)  0 0/112 (0.00%)  0
Neuropsychiatric symptoms * 1  1/392 (0.26%)  1 0/105 (0.00%)  0 0/112 (0.00%)  0
Psychotic disorder * 1  1/392 (0.26%)  1 0/105 (0.00%)  0 0/112 (0.00%)  0
Renal and urinary disorders       
Acute kidney injury * 1  1/392 (0.26%)  1 0/105 (0.00%)  0 0/112 (0.00%)  0
1
Term from vocabulary, MedDRA 22.0
*
Indicates events were collected by non-systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Pimavanserin Open-Label Period Pimavanserin Double-Blind Period Placebo Double-Blind Period
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   24/392 (6.12%)      16/105 (15.24%)      9/112 (8.04%)    
Infections and infestations       
Urinary tract infection * 1  18/392 (4.59%)  19 6/105 (5.71%)  8 4/112 (3.57%)  5
Nervous system disorders       
Headache * 1  6/392 (1.53%)  6 10/105 (9.52%)  13 5/112 (4.46%)  8
1
Term from vocabulary, MedDRA 22.0
*
Indicates events were collected by non-systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Investigator may publish the study results, relative to their own patients, only after review, comment and approval by the sponsor. No publication of confidential information shall be made without the sponsor's prior written consent. At least 60 days prior to submitting a manuscript or prior to any public presentation, a copy of the manuscript or presentation will be provided to the Sponsor for review and comment. The sponsor has 60 days to review and comment.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Sr. Dir. Medical Information and Medical Communications
Organization: Acadia Pharmaceuticals Inc.
Phone: 858-261- ext 2897
EMail: medicalinformation@acadia-pharm.com
Layout table for additonal information
Responsible Party: ACADIA Pharmaceuticals Inc.
ClinicalTrials.gov Identifier: NCT03325556    
Other Study ID Numbers: ACP-103-045
2017-002227-13 ( EudraCT Number )
First Submitted: October 18, 2017
First Posted: October 30, 2017
Results First Submitted: April 30, 2021
Results First Posted: June 21, 2021
Last Update Posted: June 21, 2021