Trial Outcomes & Findings for Relapse Prevention Study of Pimavanserin in Dementia-related Psychosis (NCT NCT03325556)

Last Updated: 2021-06-21

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

392 participants

Primary outcome timeframe

From randomization in the DB period through 26 weeks

Results posted on

2021-06-21

Participant Flow

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.

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.

Participant milestones

Participant milestones
Measure	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.	Pimavanserin Double-Blind Period 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 Double-Blind Period Placebo once daily for 26 weeks or until relapse
Open-label Period STARTED	392	0	0
Open-label Period COMPLETED	217	0	0
Open-label Period NOT COMPLETED	175	0	0
Double-blind Period STARTED	0	105	112
Double-blind Period COMPLETED	0	44	35
Double-blind Period NOT COMPLETED	0	61	77

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	Pimavanserin Double-Blind Period 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 Double-Blind Period Placebo once daily for 26 weeks or until relapse
Open-label Period Lack of Response in OL period	70	0	0
Open-label Period Adverse Event	27	0	0
Open-label Period Death	1	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 Use of prohibited medication	1	0	0
Open-label Period Protocol Violation	4	0	0
Open-label Period Withdrawal by Subject	17	0	0
Open-label Period Not otherwise specified	8	0	0
Open-label Period Administrative discont. at study termination	41	0	0
Double-blind Period Relapse	0	15	34
Double-blind Period Adverse Event	0	3	1
Double-blind Period Noncompliance with study drug	0	0	1
Double-blind Period Use of prohibited medication	0	1	0
Double-blind Period Physician Decision	0	0	1
Double-blind Period Withdrawal by Subject	0	6	4
Double-blind Period Not otherwise specified	0	1	5
Double-blind Period Administrative discont. at study termination	0	35	31

Baseline Characteristics

For 8 patients, Information on race was not available.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Pimavanserin Open-Label Period n=392 Participants 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.
Age, Continuous	74.5 years STANDARD_DEVIATION 8.28 • n=392 Participants
Sex: Female, Male Female	229 Participants n=392 Participants
Sex: Female, Male Male	163 Participants n=392 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=384 Participants • For 8 patients, Information on race was not available.
Race (NIH/OMB) Asian	0 Participants n=384 Participants • For 8 patients, Information on race was not available.
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=384 Participants • For 8 patients, Information on race was not available.
Race (NIH/OMB) Black or African American	10 Participants n=384 Participants • For 8 patients, Information on race was not available.
Race (NIH/OMB) White	371 Participants n=384 Participants • For 8 patients, Information on race was not available.
Race (NIH/OMB) More than one race	0 Participants n=384 Participants • For 8 patients, Information on race was not available.
Race (NIH/OMB) Unknown or Not Reported	3 Participants n=384 Participants • For 8 patients, Information on race was not available.
Region of Enrollment United States	118 participants n=392 Participants
Region of Enrollment Czechia	11 participants n=392 Participants
Region of Enrollment Ukraine	74 participants n=392 Participants
Region of Enrollment United Kingdom	8 participants n=392 Participants
Region of Enrollment Spain	9 participants n=392 Participants
Region of Enrollment Poland	42 participants n=392 Participants
Region of Enrollment Italy	13 participants n=392 Participants
Region of Enrollment Slovakia	35 participants n=392 Participants
Region of Enrollment Bulgaria	3 participants n=392 Participants
Region of Enrollment Chile	27 participants n=392 Participants
Region of Enrollment France	7 participants n=392 Participants
Region of Enrollment Serbia	44 participants n=392 Participants
Region of Enrollment Germany	1 participants n=392 Participants
Dementia severity Mild	65 Participants n=392 Participants
Dementia severity Moderate	275 Participants n=392 Participants
Dementia severity Severe	52 Participants n=392 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 • n=392 Participants
Clinical Global Impression-Severity (CGI-S)	4.7 units on a scale STANDARD_DEVIATION 0.69 • n=392 Participants

PRIMARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Pimavanserin Double-Blind Period n=95 Participants 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 Double-Blind Period n=99 Participants Placebo once daily for 26 weeks or until relapse
Time From Randomization to Relapse in the Double-blind (DB) Period	NA days 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%.	NA days 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%.

SECONDARY outcome

Timeframe: 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).

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.

Outcome measures

Outcome measures
Measure	Pimavanserin Double-Blind Period n=95 Participants 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 Double-Blind Period n=99 Participants Placebo once daily for 26 weeks or until relapse
Time From Randomization to Discontinuation From the DB Period for Any Reason	NA days 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%.	NA days 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%.

Adverse Events

Pimavanserin Open-Label Period

Serious events: 20 serious events

Other events: 24 other events

Deaths: 1 deaths

Pimavanserin Double-Blind Period

Serious events: 5 serious events

Other events: 16 other events

Deaths: 1 deaths

Placebo Double-Blind Period

Serious events: 4 serious events

Other events: 9 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Pimavanserin Open-Label Period n=392 participants at risk 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 Double-Blind Period n=105 participants at risk 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 Double-Blind Period n=112 participants at risk Placebo once daily for 26 weeks or until relapse
Infections and infestations Urinary tract infection	4.6% 18/392 • Number of events 19 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	5.7% 6/105 • Number of events 8 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	3.6% 4/112 • Number of events 5 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.
Nervous system disorders Headache	1.5% 6/392 • Number of events 6 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	9.5% 10/105 • Number of events 13 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	4.5% 5/112 • Number of events 8 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.

Additional Information

Sr. Dir. Medical Information and Medical Communications

Acadia Pharmaceuticals Inc.

Phone: 858-261-

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER

Measure	Pimavanserin Open-Label Period n=392 participants at risk 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 Double-Blind Period n=105 participants at risk 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 Double-Blind Period n=112 participants at risk Placebo once daily for 26 weeks or until relapse
Cardiac disorders Cardiac failure congestive	0.26% 1/392 • Number of events 1 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/105 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/112 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.
Cardiac disorders Myocardial infarction	0.26% 1/392 • Number of events 1 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/105 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/112 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.
Gastrointestinal disorders Abdominal pain lower	0.26% 1/392 • Number of events 1 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/105 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/112 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.
Gastrointestinal disorders Abdominal pain upper	0.26% 1/392 • Number of events 1 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/105 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/112 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.
Gastrointestinal disorders Diarrhoea	0.26% 1/392 • Number of events 1 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/105 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/112 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.
Gastrointestinal disorders Haematemesis	0.26% 1/392 • Number of events 1 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/105 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.89% 1/112 • Number of events 1 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.
Gastrointestinal disorders Intestinal obstruction	0.26% 1/392 • Number of events 1 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/105 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/112 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.
General disorders Oedema peripheral	0.26% 1/392 • Number of events 1 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/105 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/112 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.
Infections and infestations Urinary tract infection	0.51% 2/392 • Number of events 2 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.95% 1/105 • Number of events 1 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.89% 1/112 • Number of events 1 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.
Infections and infestations Abscess jaw	0.26% 1/392 • Number of events 1 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/105 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/112 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.
Infections and infestations Diverticulitis	0.26% 1/392 • Number of events 1 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/105 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/112 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.
Infections and infestations Erysipelas	0.26% 1/392 • Number of events 1 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/105 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/112 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.
Injury, poisoning and procedural complications Fall	0.51% 2/392 • Number of events 2 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/105 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/112 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.
Injury, poisoning and procedural complications Bone fissure	0.26% 1/392 • Number of events 1 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/105 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/112 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.
Metabolism and nutrition disorders Dehydration	0.51% 2/392 • Number of events 2 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/105 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/112 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.
Metabolism and nutrition disorders Malnutrition	0.26% 1/392 • Number of events 1 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/105 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/112 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.
Musculoskeletal and connective tissue disorders Back pain	0.26% 1/392 • Number of events 1 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/105 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/112 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.
Infections and infestations Pneumonia	0.00% 0/392 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/105 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.89% 1/112 • Number of events 1 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.
Infections and infestations Sepsis	0.00% 0/392 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.95% 1/105 • Number of events 1 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/112 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.
Infections and infestations Septic encephalopathy	0.00% 0/392 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.95% 1/105 • Number of events 1 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/112 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.
Metabolism and nutrition disorders Decreased appetite	0.00% 0/392 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/105 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.89% 1/112 • Number of events 1 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer metastatic	0.00% 0/392 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.95% 1/105 • Number of events 1 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/112 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.
Nervous system disorders Metabolic encephalopathy	0.00% 0/392 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.95% 1/105 • Number of events 1 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/112 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.
Nervous system disorders Transient ischaemic attack	0.00% 0/392 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.95% 1/105 • Number of events 1 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/112 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.
Psychiatric disorders Agression	0.26% 1/392 • Number of events 1 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.95% 1/105 • Number of events 1 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/112 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.
Nervous system disorders Dementia Alzheimer's type	0.26% 1/392 • Number of events 1 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/105 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/112 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.
Psychiatric disorders Agitation	0.26% 1/392 • Number of events 1 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/105 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/112 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.
Psychiatric disorders Mental status changes	0.26% 1/392 • Number of events 1 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/105 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/112 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.
Psychiatric disorders Neuropsychiatric symptoms	0.26% 1/392 • Number of events 1 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/105 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/112 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.
Psychiatric disorders Psychotic disorder	0.26% 1/392 • Number of events 1 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/105 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/112 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.
Renal and urinary disorders Acute kidney injury	0.26% 1/392 • Number of events 1 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/105 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/112 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.
Nervous system disorders Syncope	0.00% 0/392 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.00% 0/105 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.	0.89% 1/112 • Number of events 1 • Adverse Events (AEs) were to be documented through 30 days after the last dose in the study.