Study to Examine the Safety and Efficacy of Pimavanserin for the Treatment of Agitation and Aggression in Alzheimer's Disease (SERENE)

• ClinicalTrials.gov Identifier: NCT02992132
• Recruitment Status: Terminated
• First Posted: December 14, 2016
• Results First Posted: March 28, 2019
• Last Update Posted: March 28, 2019
• Sponsor: ACADIA Pharmaceuticals Inc.
• 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: Agitation and Aggression in Alzheimer's Disease
• Interventions: Drug: Pimavanserin 34 mg; Drug: Pimavanserin 20 mg; Other: Placebo
• Enrollment: 111

Participant Flow

Recruitment Details	The study was planned to be conducted in approximately 432 subjects. For business reasons, and not related to safety, recruitment of subjects was stopped after 111 subjects were randomized. The last subject was randomized on 2 Nov 2017.
Pre-assignment Details	The screening visit was followed by a 2- to 4-week screening period, including wash-out of antipsychotic agents which were prohibited during the Treatment period (exception: protocol specified agents). Subjects had to be on stable doses of permitted medications for >=4 weeks before Baseline (>=12 weeks for cholinesterase inhibitors and memantine).

Arm/Group Title	Placebo	Pimavanserin 20 mg	Pimavanserin 34 mg
Arm/Group Description	Placebo, taken as two tablets, once daily by mouth Placebo: Placebo, taken as two tablets, once daily by mouth	Drug- pimavanserin tartrate, 20 mg, taken as two 10 mg tablets, once daily by mouth Pimavanserin 20 mg: Pimavanserin 20 mg, tablet, taken as two 10 mg tablets, once daily by mouth	Drug- pimavanserin tartrate, 34 mg, taken as two 17 mg tablets, once daily by mouth Pimavanserin 34 mg: Pimavanserin 34 mg, tablet, taken as two 17 mg tablets, once daily by mouth
Period Title: Overall Study
Started	40	35	36
Completed	27	27	29
Not Completed	13	8	7
Reason Not Completed
Adverse Event	4	1	3
Lack of Efficacy	2	0	0
Non-compliance with study drug	2	0	0
Progressive disease	1	0	0
Protocol Violation	2	2	0
Caregiver withdrew consent	2	3	2
Withdrawal by Subject	0	2	1
Physician Decision	0	0	1

Baseline Characteristics

Arm/Group Title		Placebo	Pimavanserin 20 mg	Pimavanserin 34 mg	Total
Arm/Group Description		Placebo, taken as two tablets, once daily by mouth Placebo: Placebo, taken as two tablets, once daily by mouth	Drug- pimavanserin tartrate, 20 mg, taken as two 10 mg tablets, once daily by mouth Pimavanserin 20 mg: Pimavanserin 20 mg, tablet, taken as two 10 mg tablets, once daily by mouth	Drug- pimavanserin tartrate, 34 mg, taken as two 17 mg tablets, once daily by mouth Pimavanserin 34 mg: Pimavanserin 34 mg, tablet, taken as two 17 mg tablets, once daily by mouth	Total of all reporting groups
Overall Number of Baseline Participants		40	35	36	111
Baseline Analysis Population Description		All patients randomized
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	40 participants	35 participants	36 participants	111 participants
		78.9 (7.58)	76.5 (8.74)	75.0 (7.90)	76.8 (8.15)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	40 participants	35 participants	36 participants	111 participants
	Female	25 62.5%	15 42.9%	18 50.0%	58 52.3%
	Male	15 37.5%	20 57.1%	18 50.0%	53 47.7%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	40 participants	35 participants	36 participants	111 participants
	Hispanic or Latino	20 50.0%	16 45.7%	17 47.2%	53 47.7%
	Not Hispanic or Latino	17 42.5%	15 42.9%	18 50.0%	50 45.0%
	Unknown or Not Reported	3 7.5%	4 11.4%	1 2.8%	8 7.2%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	40 participants	35 participants	36 participants	111 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Asian	0 0.0%	0 0.0%	2 5.6%	2 1.8%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Black or African American	1 2.5%	0 0.0%	0 0.0%	1 0.9%
	White	36 90.0%	31 88.6%	32 88.9%	99 89.2%
	More than one race	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	3 7.5%	4 11.4%	2 5.6%	9 8.1%

Outcome Measures

1. Primary Outcome

Title	Cohen-Mansfield Agitation Inventory (CMAI)
Description	The Cohen-Mansfield Agitation Inventory (CMAI) is a 29-item scale to assess agitation. Each item is rated on a 7-point scale of frequency, from least (1) to most frequent (7). Items are summed to calculate the CMAI total score. The CMAI total score has a range of 29-203 points; higher scores indicate more severe agitation
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis set, i.e. patients who had been randomized and treated and had both a baseline value and at least 1 post-baseline value for the CMAI total score.

Arm/Group Title		Placebo	Pimavanserin 20 mg	Pimavanserin 34 mg
Arm/Group Description:		Placebo, taken as two tablets, once daily by mouth Placebo: Placebo, taken as two tablets, once daily by mouth	Drug- pimavanserin tartrate, 20 mg, taken as two 10 mg tablets, once daily by mouth Pimavanserin 20 mg: Pimavanserin 20 mg, tablet, taken as two 10 mg tablets, once daily by mouth	Drug- pimavanserin tartrate, 34 mg, taken as two 17 mg tablets, once daily by mouth Pimavanserin 34 mg: Pimavanserin 34 mg, tablet, taken as two 17 mg tablets, once daily by mouth
Overall Number of Participants Analyzed		37	34	35
Mean (Standard Error); Unit of Measure: score on a scale
Baseline	Number Analyzed	37 participants	34 participants	35 participants
		70.3 (4.5)	56.9 (2.2)	68.0 (3.3)
Week 12	Number Analyzed	29 participants	28 participants	29 participants
		54.3 (4.3)	52.5 (4.3)	53.7 (3.0)
Week 12 change from baseline	Number Analyzed	29 participants	28 participants	29 participants
		-16.8 (5.0)	-3.7 (3.7)	-12.3 (2.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Pimavanserin 20 mg
	Comments	Mixed-effect model repeated measures (MMRM), with the dependent variable being the change from Baseline in CMAI total score.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in LSM
	Estimated Value	5.1
	Confidence Interval	(2-Sided) 95%; -4.8 to 15.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.0
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Pimavanserin 34 mg
	Comments	Mixed-effect model repeated measures (MMRM), with the dependent variable being the change from Baseline in CMAI total score.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Difference in LSM
	Estimated Value	1.0
	Confidence Interval	(2-Sided) 95%; -8.5 to 10.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.8
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Zarit Burden Interview
Description	The Zarit Burden Interview (ZBI) assess the stresses experienced by caregivers of patients with dementia. It assesses 22 questions about the impact of the patient's disabilities on the caregiver's life, each rated from least (0) to most (4) frequent. Items are summed to calculate the ZBI total score. The ZBI total score ranges from 0 to 88; higher scores denoting more stresses experienced by caregivers.
Time Frame	Baseline to 12 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis set, i.e. patients who had been randomized and treated and had both a baseline value and at least 1 post-baseline value for the CMAI total score.

Arm/Group Title		Placebo	Pimavanserin 20 mg	Pimavanserin 34 mg
Arm/Group Description:		Placebo, taken as two tablets, once daily by mouth Placebo: Placebo, taken as two tablets, once daily by mouth	Drug- pimavanserin tartrate, 20 mg, taken as two 10 mg tablets, once daily by mouth Pimavanserin 20 mg: Pimavanserin 20 mg, tablet, taken as two 10 mg tablets, once daily by mouth	Drug- pimavanserin tartrate, 34 mg, taken as two 17 mg tablets, once daily by mouth Pimavanserin 34 mg: Pimavanserin 34 mg, tablet, taken as two 17 mg tablets, once daily by mouth
Overall Number of Participants Analyzed		34	33	32
Mean (Standard Error); Unit of Measure: score on a scale
Baseline	Number Analyzed	34 participants	33 participants	32 participants
		41.5 (2.6)	40.8 (2.4)	41.7 (2.5)
Week 12	Number Analyzed	28 participants	27 participants	27 participants
		37.0 (3.2)	36.8 (3.7)	35.7 (3.5)
Week 12 change from baseline	Number Analyzed	28 participants	27 participants	27 participants
		-6.5 (2.3)	-4.9 (2.3)	-5.5 (2.5)

Adverse Events

Time Frame	From the time of informed consent through the completion of procedures at the Week 12 visit (for subjects continuing into an Open-Label Extension study) or through to 30 days after the last dose of study drug (for all other subjects)
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Placebo		Pimavanserin 20 mg		Pimavanserin 34 mg
Arm/Group Description	Placebo, taken as two tablets, once daily by mouth Placebo: Placebo, taken as two tablets, once daily by mouth		Drug- pimavanserin tartrate, 20 mg, taken as two 10 mg tablets, once daily by mouth Pimavanserin 20 mg: Pimavanserin 20 mg, tablet, taken as two 10 mg tablets, once daily by mouth		Drug- pimavanserin tartrate, 34 mg, taken as two 17 mg tablets, once daily by mouth Pimavanserin 34 mg: Pimavanserin 34 mg, tablet, taken as two 17 mg tablets, once daily by mouth
All-Cause Mortality
	Placebo		Pimavanserin 20 mg		Pimavanserin 34 mg
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	0/40 (0.00%)		0/35 (0.00%)		0/36 (0.00%)
Serious Adverse Events
	Placebo		Pimavanserin 20 mg		Pimavanserin 34 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/40 (7.50%)		4/35 (11.43%)		3/36 (8.33%)
Gastrointestinal disorders
Diverticulum * 1	0/40 (0.00%)	0	1/35 (2.86%)	1	0/36 (0.00%)	0
Lower gastrointestinal haemorrhage * 1	0/40 (0.00%)	0	1/35 (2.86%)	1	0/36 (0.00%)	0
Upper gastrointestinal haemorrhage * 1	1/40 (2.50%)	1	0/35 (0.00%)	0	0/36 (0.00%)	0
Infections and infestations
Sepsis * 1	0/40 (0.00%)	0	1/35 (2.86%)	1	0/36 (0.00%)	0
Injury, poisoning and procedural complications
Femoral neck fracture * 1	0/40 (0.00%)	0	1/35 (2.86%)	1	0/36 (0.00%)	0
Pelvic fracture * 1	0/40 (0.00%)	0	0/35 (0.00%)	0	1/36 (2.78%)	1
Investigations
Weight decreased * 1	1/40 (2.50%)	1	0/35 (0.00%)	0	0/36 (0.00%)	0
Metabolism and nutrition disorders
Hyponatraemia * 1	0/40 (0.00%)	0	1/35 (2.86%)	1	0/36 (0.00%)	0
Nervous system disorders
Encephalopathy * 1	0/40 (0.00%)	0	1/35 (2.86%)	1	0/36 (0.00%)	0
Psychiatric disorders
Agitation * 1	0/40 (0.00%)	0	1/35 (2.86%)	1	2/36 (5.56%)	2
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism * 1	1/40 (2.50%)	1	0/35 (0.00%)	0	0/36 (0.00%)	0
1 Term from vocabulary, MedDRA (19.0); * Indicates events were collected by non-systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Placebo		Pimavanserin 20 mg		Pimavanserin 34 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/40 (27.50%)		15/35 (42.86%)		15/36 (41.67%)
Blood and lymphatic system disorders
Anaemia * 1	1/40 (2.50%)	1	2/35 (5.71%)	2	0/36 (0.00%)	0
Gastrointestinal disorders
Diarrhoea * 1	3/40 (7.50%)	3	2/35 (5.71%)	2	2/36 (5.56%)	2
Constipation * 1	1/40 (2.50%)	1	2/35 (5.71%)	2	2/36 (5.56%)	2
Gastrointestinal haemorrhage * 1	0/40 (0.00%)	0	2/35 (5.71%)	2	0/36 (0.00%)	0
Infections and infestations
Nasopharyngitis * 1	1/40 (2.50%)	1	0/35 (0.00%)	0	2/36 (5.56%)	2
Urinary tract infection * 1	0/40 (0.00%)	0	2/35 (5.71%)	2	1/36 (2.78%)	1
Injury, poisoning and procedural complications
Fall * 1	1/40 (2.50%)	1	3/35 (8.57%)	3	3/36 (8.33%)	3
Contusion * 1	1/40 (2.50%)	1	1/35 (2.86%)	2	2/36 (5.56%)	2
Metabolism and nutrition disorders
Decreased appetite * 1	0/40 (0.00%)	0	2/35 (5.71%)	2	2/36 (5.56%)	2
Psychiatric disorders
Agitation * 1	5/40 (12.50%)	5	5/35 (14.29%)	5	1/36 (2.78%)	1
Insomnia * 1	0/40 (0.00%)	0	4/35 (11.43%)	5	3/36 (8.33%)	3
1 Term from vocabulary, MedDRA (19.0); * Indicates events were collected by non-systematic assessment

Limitations and Caveats

The original study (n=432) was powered to detect a treatment effect on CMAI, however recruitment was discontinued early for business reasons and amended accordingly The final study (n=111) was no longer adequately powered to detect a treatment effect

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 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.

Results Point of Contact

• Name/Title: Sr. Dir. Medical Information and Medical Communications
• Organization: ACADIA Pharmaceuticals Inc.
• Phone: 858-261-2897
• EMail: medicalinformation@acadia-pharm.com

• Responsible Party: ACADIA Pharmaceuticals Inc.
• ClinicalTrials.gov Identifier: NCT02992132
• Other Study ID Numbers: ACP-103-032; 2016-001127-32 ( EudraCT Number )
• First Submitted: December 12, 2016
• First Posted: December 14, 2016
• Results First Submitted: January 25, 2019
• Results First Posted: March 28, 2019
• Last Update Posted: March 28, 2019