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

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.


Arm/Group Title	Pimavanserin Open-Label Period	Pimavanserin Double-Blind Period	Placebo Double-Blind Period
Arm/Group Description	Pimavanserin 34 mg once daily, with...	Pimavanserin 34 mg once daily or pi...	Placebo once daily for 26 weeks or ...
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

Baseline Characteristics

Arm/Group Title		Pimavanserin Open-Label Period
Arm/Group Description		Pimavanserin 34 mg once daily, with...
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
Baseline Analysis Population Description		...
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
United States		118
Czechia	Number Analyzed	392 participants
Czechia		11
Ukraine	Number Analyzed	392 participants
Ukraine		74
United Kingdom	Number Analyzed	392 participants
United Kingdom		8
Spain	Number Analyzed	392 participants
Spain		9
Poland	Number Analyzed	392 participants
Poland		42
Italy	Number Analyzed	392 participants
Italy		13
Slovakia	Number Analyzed	392 participants
Slovakia		35
Bulgaria	Number Analyzed	392 participants
Bulgaria		3
Chile	Number Analyzed	392 participants
Chile		27
France	Number Analyzed	392 participants
France		7
Serbia	Number Analyzed	392 participants
Serbia		44
Germany	Number Analyzed	392 participants
Germany		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.

Outcome Measures

1.Primary Outcome


Title	Time From Randomization to Relapse in the Double-blind (DB) Period
Description	The time from randomization to relapse in the DB period was compared b...
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

Outcome Measure Data

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
Arm/Group Description:	Pimavanserin 34 mg once daily or pi...	Placebo once daily for 26 weeks or ...
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%.

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
Description	The endpoint of time from randomization to discontinuation from the DB...
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

Outcome Measure Data

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
Arm/Group Description:	Pimavanserin 34 mg once daily or pi...	Placebo once daily for 26 weeks or ...
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%.

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.

Adverse Events

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
Arm/Group Description	Pimavanserin 34 mg once daily, with...		Pimavanserin 34 mg once daily or pi...		Placebo once daily for 26 weeks or ...
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%)
Serious Adverse Events 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
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

Limitations and Caveats

[Not Specified]

More Information

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

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Cummings JL, Ismail Z, Dickerson BC, Ballard C, Grossberg G, McEvoy B, Foff E, Atri A. Development and assessment of a brief screening tool for psychosis in dementia. Alzheimers Dement (Amst). 2021 Dec 7;13(1):e12254. doi: 10.1002/dad2.12254. eCollection 2021. Erratum in: Alzheimers Dement (Amst). 2022 Feb 09;14(1):e12290.

Tariot PN, Cummings JL, Soto-Martin ME, Ballard C, Erten-Lyons D, Sultzer DL, Devanand DP, Weintraub D, McEvoy B, Youakim JM, Stankovic S, Foff EP. Trial of Pimavanserin in Dementia-Related Psychosis. N Engl J Med. 2021 Jul 22;385(4):309-319. doi: 10.1056/NEJMoa2034634.

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

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