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

• Sponsor: ACADIA Pharmaceuticals Inc. (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02992132
• Collaborator: (none)
• Enrollment: 111
• Locations: 56
• Arms: 3
• Duration (Months): 15.5
• Patients Per Site: 2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

To evaluate the efficacy of pimavanserin compared with placebo in treatment of agitation and aggression after 12 weeks of treatment

Condition or Disease	Intervention/Treatment	Phase
Agitation and Aggression in Alzheimer's Disease	Drug: Pimavanserin 34 mg; Drug: Pimavanserin 20 mg; Other: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 111 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Double-Blind, Placebo-Controlled Study to Examine the Safety and Efficacy of Pimavanserin for the Treatment of Agitation and Aggression in Alzheimer's Disease
• Study Start Date: Nov 1, 2016
• Actual Primary Completion Date: Jan 25, 2018
• Actual Study Completion Date: Feb 16, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pimavanserin 34 mg Drug- pimavanserin tartrate, 34 mg, taken as two 17 mg tablets, once daily by mouth	Drug: Pimavanserin 34 mg; Pimavanserin 34 mg, tablet, taken as two 17 mg tablets, once daily by mouth
Experimental: Pimavanserin 20 mg Drug- pimavanserin tartrate, 20 mg, taken as two 10 mg tablets, once daily by mouth	Drug: Pimavanserin 20 mg; Pimavanserin 20 mg, tablet, taken as two 10 mg tablets, once daily by mouth
Placebo Comparator: Placebo Placebo, taken as two tablets, once daily by mouth	Other: Placebo; Placebo, taken as two tablets, once daily by mouth

Outcome Measures

Primary Outcome Measures

1. Cohen-Mansfield Agitation Inventory (CMAI) [Baseline to 12 weeks]

   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

Secondary Outcome Measures

1. Zarit Burden Interview [Baseline to 12 weeks]

   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.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Male or female, 50 years of age or older

2. Can understand the nature of the trial and protocol requirements and provide signed informed consent

• from patient, if deemed competent to provide consent

• from an appropriate person (e.g. patient's Legally Authorized Representative (LAR) with the patient's assent) if patient is deemed not competent to provide informed consent.

1. Has a diagnosis of probable AD according to the National Institute on Aging-Alzheimer's Association (NIA-AA) guidelines

2. Meets criteria for agitation according to the International Psychogeriatric Association (IPA) guidelines

3. Lives at home or in an assisted living or care facility (but has the capacity to visit the clinic as an outpatient). Subjects must have been at their current location for at least 3 weeks prior to Screening and plan to remain at the same location for the duration of the trial.

4. Has a designated study partner/caregiver who is in contact with the patient at least 3 times a week on 3 separate days

5. Female patients must be of non-childbearing potential or must agree to use an acceptable method of contraception or abstinence , for at least 1 month prior to randomization, during the study, and 1 month following completion of the study

6. The patient and caregiver are willing and able to participate in all schedule evaluations and complete all required tests

Exclusion Criteria:

1. The agitation/aggression is attributable to concomitant medications, environmental conditions, substance abuse, or active medical or psychiatric condition

2. Patient is receiving skilled nursing care for any medical condition other than dementia

3. Treatment with an antipsychotic medication within 2 weeks of Baseline visit or 5 half lives, whichever is longer

4. Patient or study partner/caregiver has a medical condition (e.g., hearing, vision impairments) that would impair the ability to perform the study assessments.

5. Has had a myocardial infarction within the last six months

6. Has a history or symptoms of long QT syndrome

7. Has a history of a significant psychotic disorder before or during the diagnosis of probable Alzheimer's disease (including, but not limited to schizophrenia or bipolar disorder)

8. Patient is bedridden or has any significant medical condition that is unstable and would place the patient at undue risk from study drug or study procedures 9. Has a sensitivity to pimavanserin or its excipients

9. Has previously participated in a clinical study with pimavanserin

10. Has a Global Clinician Assessment of Suicidality (GCAS) score of 3 or 4 based on Investigator's assessment of behavior within the last 3 months at Screening or since last visit at Baseline

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Costa Mesa	California	United States	92626
2		Fresno	California	United States	93710
3		Fullerton	California	United States	92835
4		Los Angeles	California	United States	90073
5		Pasadena	California	United States	91105
6		San Diego	California	United States	92103
7		Danbury	Connecticut	United States	06810
8		Washington	District of Columbia	United States	20007
9		Boca Raton	Florida	United States	33486
10		Deerfield Beach	Florida	United States	33064
11		Miami	Florida	United States	33137
12		Naples	Florida	United States	34102
13		Atlanta	Georgia	United States	30322
14		Bangor	Maine	United States	04401
15		Quincy	Massachusetts	United States	02169
16		Clinton Township	Michigan	United States	48035
17		Flowood	Mississippi	United States	39232
18		Jackson	Mississippi	United States	39216
19		Eatontown	New Jersey	United States	07724
20		Marlton	New Jersey	United States	08053
21		Toms River	New Jersey	United States	08755
22		Albuquerque	New Mexico	United States	87131
23		Charlotte	North Carolina	United States	28270
24		Oklahoma City	Oklahoma	United States	73112
25		Medford	Oregon	United States	97504
26		Jenkintown	Pennsylvania	United States	19046
27		Norristown	Pennsylvania	United States	19401
28		Willow Grove	Pennsylvania	United States	19090
29		Charleston	South Carolina	United States	29401
30		Nashville	Tennessee	United States	37212
31		DeSoto	Texas	United States	75115
32		Salt Lake City	Utah	United States	84124
33		Spokane	Washington	United States	99202
34		Valdivia	Los Rios	Chile	5090000
35		Antofagasta		Chile	1270244
36		Santiago		Chile	7500710
37		Santiago		Chile	7560356
38		Toulouse	Cedex 9	France	31059
39		Paris		France	75010
40		Saint-Herblain		France	44800
41		Strasbourg		France	67200
42		Villeurbanne		France	69100
43		Algorta	Vizcaya	Spain	48993
44		Córdoba		Spain	14011
45		Elche		Spain	03203
46		Madrid		Spain	28044
47		Palma de Mallorca		Spain	07010
48		Pamplona		Spain	31014
49		Santa Coloma De Gramenet		Spain	08921
50		Terrassa		Spain	08221
51		Zaragoza		Spain	50012
52		Swindon	Wiltshire	United Kingdom	SN3 6BW
53		Bath		United Kingdom	BA1 3NG
54		Isleworth		United Kingdom	TW7 6AF
55		Manchester		United Kingdom	M21 9UN
56		Northampton		United Kingdom	NN5 6UD

Sponsors and Collaborators

• ACADIA Pharmaceuticals Inc.

Investigators

None specified.

Study Documents (Full-Text)

• Statistical Analysis Plan - Nov 22, 2017
• Study Protocol - Dec 28, 2017

More Information

Publications

None provided.

• Responsible Party: ACADIA Pharmaceuticals Inc.
• ClinicalTrials.gov Identifier: NCT02992132
• Other Study ID Numbers: ACP-103-032; 2016-001127-32
• First Posted: Dec 14, 2016
• Last Update Posted: Mar 28, 2019
• Last Verified: Mar 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Alzheimer Disease; Psychomotor Agitation; Aggression; Pimavanserin

Study Results

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 Detail	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

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 Participants	40	35	36	111
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	78.9 (7.58)	76.5 (8.74)	75.0 (7.90)	76.8 (8.15)
Sex: Female, Male (Count of Participants)
Female	25 62.5%	15 42.9%	18 50%	58 52.3%
Male	15 37.5%	20 57.1%	18 50%	53 47.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	20 50%	16 45.7%	17 47.2%	53 47.7%
Not Hispanic or Latino	17 42.5%	15 42.9%	18 50%	50 45%
Unknown or Not Reported	3 7.5%	4 11.4%	1 2.8%	8 7.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	2 5.6%	2 1.8%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	1 2.5%	0 0%	0 0%	1 0.9%
White	36 90%	31 88.6%	32 88.9%	99 89.2%
More than one race	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
Measure Participants	37	34	35
Baseline	70.3 (4.5)	56.9 (2.2)	68.0 (3.3)
Week 12	54.3 (4.3)	52.5 (4.3)	53.7 (3.0)
Week 12 change from baseline	-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
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
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

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
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
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

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
Measure Participants	34	33	32
Baseline	41.5 (2.6)	40.8 (2.4)	41.7 (2.5)
Week 12	37.0 (3.2)	36.8 (3.7)	35.7 (3.5)
Week 12 change from baseline	-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)
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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/40 (0%)		0/35 (0%)		0/36 (0%)
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 (7.5%)		4/35 (11.4%)		3/36 (8.3%)
Gastrointestinal disorders
Diverticulum	0/40 (0%)	0	1/35 (2.9%)	1	0/36 (0%)	0
Lower gastrointestinal haemorrhage	0/40 (0%)	0	1/35 (2.9%)	1	0/36 (0%)	0
Upper gastrointestinal haemorrhage	1/40 (2.5%)	1	0/35 (0%)	0	0/36 (0%)	0
Infections and infestations
Sepsis	0/40 (0%)	0	1/35 (2.9%)	1	0/36 (0%)	0
Injury, poisoning and procedural complications
Femoral neck fracture	0/40 (0%)	0	1/35 (2.9%)	1	0/36 (0%)	0
Pelvic fracture	0/40 (0%)	0	0/35 (0%)	0	1/36 (2.8%)	1
Investigations
Weight decreased	1/40 (2.5%)	1	0/35 (0%)	0	0/36 (0%)	0
Metabolism and nutrition disorders
Hyponatraemia	0/40 (0%)	0	1/35 (2.9%)	1	0/36 (0%)	0
Nervous system disorders
Encephalopathy	0/40 (0%)	0	1/35 (2.9%)	1	0/36 (0%)	0
Psychiatric disorders
Agitation	0/40 (0%)	0	1/35 (2.9%)	1	2/36 (5.6%)	2
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	1/40 (2.5%)	1	0/35 (0%)	0	0/36 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Pimavanserin 20 mg		Pimavanserin 34 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/40 (27.5%)		15/35 (42.9%)		15/36 (41.7%)
Blood and lymphatic system disorders
Anaemia	1/40 (2.5%)	1	2/35 (5.7%)	2	0/36 (0%)	0
Gastrointestinal disorders
Diarrhoea	3/40 (7.5%)	3	2/35 (5.7%)	2	2/36 (5.6%)	2
Constipation	1/40 (2.5%)	1	2/35 (5.7%)	2	2/36 (5.6%)	2
Gastrointestinal haemorrhage	0/40 (0%)	0	2/35 (5.7%)	2	0/36 (0%)	0
Infections and infestations
Nasopharyngitis	1/40 (2.5%)	1	0/35 (0%)	0	2/36 (5.6%)	2
Urinary tract infection	0/40 (0%)	0	2/35 (5.7%)	2	1/36 (2.8%)	1
Injury, poisoning and procedural complications
Fall	1/40 (2.5%)	1	3/35 (8.6%)	3	3/36 (8.3%)	3
Contusion	1/40 (2.5%)	1	1/35 (2.9%)	2	2/36 (5.6%)	2
Metabolism and nutrition disorders
Decreased appetite	0/40 (0%)	0	2/35 (5.7%)	2	2/36 (5.6%)	2
Psychiatric disorders
Agitation	5/40 (12.5%)	5	5/35 (14.3%)	5	1/36 (2.8%)	1
Insomnia	0/40 (0%)	0	4/35 (11.4%)	5	3/36 (8.3%)	3

Limitations/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.

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.