A Study of the Safety and Efficacy of Pimavanserin in Patients With Alzheimer's Disease Psychosis

• Sponsor: ACADIA Pharmaceuticals Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02035553
• Collaborator: (none)
• Enrollment: 181
• Location: 1
• Arms: 2
• Duration (Months): 35.8
• Patients Per Site Per Month: 5

Study Details

Study Description

Brief Summary

This study will evaluate the safety and efficacy of pimavanserin 40 mg compared to placebo in patients with Alzheimer's disease psychosis.

Condition or Disease	Intervention/Treatment	Phase
Alzheimer's Disease Psychosis	Drug: Pimavanserin tartrate; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 181 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Single Center, Double-Blind, Placebo-Controlled Study to Examine the Safety and Efficacy of Pimavanserin for the Treatment of Psychosis in Alzheimer's Disease
• Study Start Date: Nov 1, 2013
• Actual Primary Completion Date: Sep 28, 2016
• Actual Study Completion Date: Oct 27, 2016

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Placebo, two tablets, once daily by mouth	Drug: Placebo; Placebo, two tablets, once daily by mouth
Experimental: Pimavanserin 40 mg Pimavanserin tartrate, 40 mg (two 20 mg tablets), once daily by mouth (equivalent to 34 mg free base pimavanserin)	Drug: Pimavanserin tartrate; Pimavanserin tartrate, 40 mg (two 20 mg tablets), once daily by mouth (equivalent to 34 mg free base pimavanserin); Other Names: ACP-103

Outcome Measures

Primary Outcome Measures

1. Antipsychotic Efficacy [Day 43]

   Change from Baseline to Day 43 in the Neuropsychiatric Inventory-Nursing Home Version (NPI-NH) psychosis score (Delusions [Domain A]+Hallucinations [Domain B]) in the Full Analysis Set (FAS). The NPI-NH is a questionnaire that quantifies behavioral changes in dementia in nursing home patients and evaluates 12 behavioral domains. For each of the 12 behavioral domains the Frequency (scale:1=occasionally to 4=very frequently) is multiplied by the Severity (scale:1=Mild to 3=Severe) to obtain a domain score (frequency x severity), The NPI-NH Psychosis Subscale consists of the two domains of Delusions and Hallucinations, calculated by adding the Individual domain scores, to yield a possible total score of 0 to 24. Lower scores correspond to less severity. A negative change score from baseline indicates improvement.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patient must be 50 years of age or older with NINCDS-ADRDA defined possible or probable AD

• Patient must have psychotic symptoms that developed after the diagnosis of AD was established. These symptoms must include visual and/or auditory hallucinations, and/or delusions

• Patient must have been a nursing home resident for ≥ 4 weeks prior to randomization, not bedridden and expected to remain in the facility throughout the study

• Patient must have actively experienced and verbally communicated psychotic symptoms during the month prior to the Screening visit and weekly during the previous 2 weeks prior to Baseline

• If patient is on acetylcholinesterase inhibitor (AChEI) therapy and/or memantine, must be on stable doses for 3 months prior to the Baseline visit and during the study

• Patient is willing and able to provide informed consent. If the subject is unable to provide written consent due to the severity of dementia, consent must be given by a legally authorized representative

Exclusion Criteria:

• Patient has a history of significant psychotic disorders prior to or concomitantly with the diagnosis of Alzheimer's disease including, but not limited to, schizophrenia or bipolar disorder

• Patient is unable to communicate verbally

• Patient has current evidence of a serious and/or unstable cardiovascular, respiratory, gastrointestinal, renal, hematologic or other medical disorder, including cancer or malignancies, which would affect the patient's ability to participate in the study

• Patient has had a myocardial infarction in the last six months

• Patient has moderate to severe congestive heart failure

• Patient has any surgery planned during the screening, treatment, or follow-up periods that could interfere with participation in the study per the protocol assessments

Patients will be evaluated at screening to ensure that all criteria for study participation are met. These evaluations will include specific measures of psychosis severity, delirium, dementia, cardiovascular condition, and pregnancy status. Patients may be excluded from the study based on these assessments (and specifically if it is determined that their baseline health and psychiatric condition do not meet all protocol-specified entry criteria).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		London		United Kingdom

Sponsors and Collaborators

• ACADIA Pharmaceuticals Inc.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: ACADIA Pharmaceuticals Inc.
• ClinicalTrials.gov Identifier: NCT02035553
• Other Study ID Numbers: ACP-103-019
• First Posted: Jan 14, 2014
• Last Update Posted: Oct 25, 2017
• Last Verified: Sep 1, 2017

• Additional relevant MeSH terms: Alzheimer Disease; Psychotic Disorders; Mental Disorders; Pimavanserin

Study Results

Participant Flow

Arm/Group Title	Placebo	Pimavanserin 40 mg
Arm/Group Description	Placebo, two tablets, once daily by mouth	Pimavanserin tartrate, 40 mg (two 20 mg tablets), once daily by mouth (equivalent to 34 mg free base pimavanserin)
Period Title: Overall Study
STARTED	91	90
COMPLETED	73	67
NOT COMPLETED	18	23

Baseline Characteristics

Arm/Group Title	Placebo	Pimavanserin 40 mg	Total
Arm/Group Description	Placebo, two tablets, once daily by mouth	Pimavanserin tartrate, 40 mg (two 20 mg tablets), once daily by mouth (equivalent to 34 mg free base pimavanserin)	Total of all reporting groups
Overall Participants	91	90	181
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	86.1 (5.96)	85.7 (7.05)	85.9 (6.51)
Age, Customized (Count of Participants)
<=85	41 45.1%	41 45.6%	82 45.3%
>85	50 54.9%	49 54.4%	99 54.7%
Sex: Female, Male (Count of Participants)
Female	73 80.2%	73 81.1%	146 80.7%
Male	18 19.8%	17 18.9%	35 19.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	91 100%	90 100%	181 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
Asian	0 0%	3 3.3%	3 1.7%
Black or African American	1 1.1%	3 3.3%	4 2.2%
White	89 97.8%	84 93.3%	173 95.6%
Other	1 1.1%	0 0%	1 0.6%
Region of Enrollment (participants) [Number]
United Kingdom	91 100%	90 100%	181 100%

Outcome Measures

1. Primary Outcome

Title	Antipsychotic Efficacy
Description	Change from Baseline to Day 43 in the Neuropsychiatric Inventory-Nursing Home Version (NPI-NH) psychosis score (Delusions [Domain A]+Hallucinations [Domain B]) in the Full Analysis Set (FAS). The NPI-NH is a questionnaire that quantifies behavioral changes in dementia in nursing home patients and evaluates 12 behavioral domains. For each of the 12 behavioral domains the Frequency (scale:1=occasionally to 4=very frequently) is multiplied by the Severity (scale:1=Mild to 3=Severe) to obtain a domain score (frequency x severity), The NPI-NH Psychosis Subscale consists of the two domains of Delusions and Hallucinations, calculated by adding the Individual domain scores, to yield a possible total score of 0 to 24. Lower scores correspond to less severity. A negative change score from baseline indicates improvement.
Time Frame	Day 43

Outcome Measure Data

Analysis Population Description

All randomized subjects who received at least one dose of study treatment and have both a Baseline and at least one post-Baseline NPI-NH psychosis score evaluation.

Arm/Group Title	Placebo	Pimavanserin 40 mg
Arm/Group Description	Placebo, two tablets, once daily by mouth	Pimavanserin tartrate, 40 mg (two 20 mg tablets), once daily by mouth (equivalent to 34 mg free base pimavanserin)
Measure Participants	91	87
Least Squares Mean (95% Confidence Interval) [Score on the NPI-NH scale]	-1.93	-3.76

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Pimavanserin 40 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0451
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Diff in MMRM LSM
	Estimated Value	-1.84
	Confidence Interval	(2-Sided) 95%; -3.64 to -0.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	12 weeks
Adverse Event Reporting Description	From the time the informed consent was signed, adverse events were recorded in the subject's source documents and entered into the appropriate eCRF pages at the Screening visit, at visits on Study Days 1, 15, 29, 43, 64 and Day 85, and at the 4-week follow-up phone call.
Arm/Group Title	Placebo		Pimavanserin 40 mg
Arm/Group Description	Placebo, two tablets, once daily by mouth		Pimavanserin tartrate, 40 mg (two 20 mg tablets), once daily by mouth (equivalent to 34 mg free base pimavanserin)
All Cause Mortality
	Placebo		Pimavanserin 40 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/91 (4.4%)		4/90 (4.4%)
Serious Adverse Events
	Placebo		Pimavanserin 40 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/91 (11%)		15/90 (16.7%)
Cardiac disorders
Cardiopulmonary failure	1/91 (1.1%)	1	0/90 (0%)	0
Myocardial infarction	2/91 (2.2%)	2	0/90 (0%)	0
General disorders
General physical health deterioration	1/91 (1.1%)	1	0/90 (0%)	0
Infections and infestations
Pneumonia	2/91 (2.2%)	2	2/90 (2.2%)	3
Urinary tract infection	0/91 (0%)	0	2/90 (2.2%)	2
Bronchopneumonia	0/91 (0%)	0	1/90 (1.1%)	1
Lower respiratory tract infection	0/91 (0%)	0	1/90 (1.1%)	1
Injury, poisoning and procedural complications
Fall	0/91 (0%)	0	1/90 (1.1%)	1
Femoral neck fracture	0/91 (0%)	0	1/90 (1.1%)	1
Hip fracture	0/91 (0%)	0	1/90 (1.1%)	1
Laceration	0/91 (0%)	0	1/90 (1.1%)	1
Spinal fracture	1/91 (1.1%)	1	0/90 (0%)	0
Upper limb fracture	1/91 (1.1%)	1	0/90 (0%)	0
Wrist fracture	1/91 (1.1%)	1	0/90 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm of thorax	0/91 (0%)	0	1/90 (1.1%)	1
Nervous system disorders
Dementia	0/91 (0%)	0	1/90 (1.1%)	1
Depressed level of consciousness	0/91 (0%)	0	1/90 (1.1%)	1
Loss of consciousness	1/91 (1.1%)	1	1/90 (1.1%)	1
Transient ischaemic attack	0/91 (0%)	0	1/90 (1.1%)	1
Psychiatric disorders
Aggression	0/91 (0%)	0	1/90 (1.1%)	1
Renal and urinary disorders
Renal failure acute	0/91 (0%)	0	1/90 (1.1%)	1
Vascular disorders
Hypotension	1/91 (1.1%)	1	0/90 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Pimavanserin 40 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	70/91 (76.9%)		67/90 (74.4%)
Blood and lymphatic system disorders
Anaemia	8/91 (8.8%)	8	9/90 (10%)	9
General disorders
Oedema peripheral	2/91 (2.2%)	2	7/90 (7.8%)	7
Infections and infestations
Urinary tract infection	25/91 (27.5%)	36	18/90 (20%)	27
Lower respiratory tract infection	12/91 (13.2%)	13	13/90 (14.4%)	15
Cellulitis	3/91 (3.3%)	3	6/90 (6.7%)	7
Injury, poisoning and procedural complications
Fall	21/91 (23.1%)	35	20/90 (22.2%)	39
Contusion	14/91 (15.4%)	17	11/90 (12.2%)	16
Laceration	5/91 (5.5%)	6	3/90 (3.3%)	3
Investigations
Blood urea increased	8/91 (8.8%)	8	7/90 (7.8%)	7
Blood potassium increased	3/91 (3.3%)	3	5/90 (5.6%)	5
Blood lactate dehydrogenase increase	10/91 (11%)	10	4/90 (4.4%)	4
Blood alkaline phosphatase increased	8/91 (8.8%)	8	3/90 (3.3%)	3
Metabolism and nutrition disorders
Hyperglycaemia	11/91 (12.1%)	11	4/90 (4.4%)	4
Nervous system disorders
Somnolence	7/91 (7.7%)	7	3/90 (3.3%)	3
Psychiatric disorders
Agitation	13/91 (14.3%)	13	19/90 (21.1%)	19
Aggression	4/91 (4.4%)	4	9/90 (10%)	10
Anxiety	2/91 (2.2%)	2	5/90 (5.6%)	5
Behavioural and psychiatric symptoms of dementia	2/91 (2.2%)	2	5/90 (5.6%)	6
Skin and subcutaneous tissue disorders
Rash	7/91 (7.7%)	7	4/90 (4.4%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Investigator may publish the study results, relative to his/her 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.