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Clinical Trial Results:
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

Summary
EudraCT number	2010-020008-31
Trial protocol	GB
Global end of trial date	27 Oct 2016

Results information
Results version number	v1(current)
This version publication date	11 Nov 2017
First version publication date	11 Nov 2017
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

ACP-103-019

ISRCTN number

US NCT number

NCT02035553

WHO universal trial number (UTN)

Sponsor organisation name

ACADIA Pharmaceuticals Inc.

Sponsor organisation address

3611 Valley Centre Drive, Ste. 300, San Diego, CA, United States, 92130

Public contact

James Youakim, Vice President, Clinical Development & Clinical Research, ACADIA Pharmaceuticals Inc., +1 609-250-6900, jyouakim@acadia-pharm.com

Scientific contact

James Youakim, Vice President, Clinical Development & Clinical Research, ACADIA Pharmaceuticals Inc., +1 609-250-6900, jyouakim@acadia-pharm.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

27 Oct 2016

Is this the analysis of the primary completion data?

Yes

Primary completion date

27 Oct 2016

Global end of trial reached?

Yes

Global end of trial date

27 Oct 2016

Was the trial ended prematurely?

Main objective of the trial

To assess the efficacy of pimavanserin in subjects with Alzheimer’s disease psychosis (ADP) after 6 weeks of treatment

Protection of trial subjects

A Data Monitoring Ethics Committee (DMEC) reviewed the safety and clinical outcome data of subjects at regular intervals

Background therapy

None

Evidence for comparator

Actual start date of recruitment

16 Jan 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 181

Worldwide total number of subjects

181

EEA total number of subjects

181

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

111

Subject disposition

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Recruitment details

The study was performed in subjects with Alzheimer’s Disease (AD) who were to have had at least a one-month history of psychotic symptoms that developed after the diagnosis of AD was established, and active psychotic symptoms in the month prior to the Screening Visit. A total of 345 unique subjects were screened.

Screening details

Prior to randomisation, subjects entered a 3-week screening period with antipsychotic medication washout. During this period, subjects received brief psychosocial therapy following best practice guidelines, and safety assessments were performed.

Period 1 title

Treatment period (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Are arms mutually exclusive

Yes

Placebo

Arm description

Placebo, two tablets, once daily by mouth

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Two placebo tablets, once daily by mouth, during the treatment period (Week 1 to 12)

Pimavanserin tartrate 40 mg (equivalent to 34 mg pimavanserin)

Arm description

Pimavanserin tartrate 40 mg (two 20 mg tablets), once daily by mouth (equivalent to 34 mg pimavanserin)

Arm type

Experimental

Investigational medicinal product name

Pimavanserin

Investigational medicinal product code

ACP-103

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Plimavanserin tartrate 40 mg (two 20 mg tablets), equivalent to 34 mg pimavanserin (two 17 mg tablets), taken once daily by mouth during the treatment period (Week 1 to 12)

Number of subjects in period 1	Placebo	Pimavanserin tartrate 40 mg (equivalent to 34 mg pimavanserin)
Started	91	90
Completed	73	67
Not completed	18	23
Physician decision	3	2
Consent withdrawn by subject	4	7
Adverse event, non-fatal	10	6
Other	-	4
Death (see Serious Adverse Event Table)	-	1
Non-compliance with study drug	-	1
Lost to follow-up	-	1
Lack of efficacy	1	1

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Placebo, two tablets, once daily by mouth

Reporting group title

Pimavanserin tartrate 40 mg (equivalent to 34 mg pimavanserin)

Reporting group description

Pimavanserin tartrate 40 mg (two 20 mg tablets), once daily by mouth (equivalent to 34 mg pimavanserin)

Reporting group values	Placebo	Pimavanserin tartrate 40 mg (equivalent to 34 mg pimavanserin)	Total
Number of subjects	91	90	181
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	1	0	1
From 65-84 years	32	37	69
85 years and over	58	53	111
Age continuous
Units: years
arithmetic mean (standard deviation)	86.1 ( 5.96 )	85.7 ( 7.05 )	-
Gender categorical
Units: Subjects
Female	73	73	146
Male	18	17	35
Ethnicity
Units: Subjects
Hispanic or Latino	0	0	0
Not Hispanic or Latino	91	90	181
Unknown or Not Reported	0	0	0
Race
Units: Subjects
Asian	0	3	3
Black or African American	1	3	4
White	89	84	173
Other	1	0	1

End points

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Reporting group title

Placebo

Reporting group description

Placebo, two tablets, once daily by mouth

Reporting group title

Pimavanserin tartrate 40 mg (equivalent to 34 mg pimavanserin)

Reporting group description

Pimavanserin tartrate 40 mg (two 20 mg tablets), once daily by mouth (equivalent to 34 mg pimavanserin)

Primary: Change from baseline to Day 43 in the NPI-NH psychosis score (Delusions [Domain A]+Hallucinations [Domain B])

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End point title

Change from baseline to Day 43 in the NPI-NH psychosis score (Delusions [Domain A]+Hallucinations [Domain B])

End point 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. 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 score consists of the 2 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.

End point type

Primary

End point timeframe

Day 43

End point values	Placebo	Pimavanserin tartrate 40 mg (equivalent to 34 mg pimavanserin)
Number of subjects analysed	91 ^[1]	87 ^[2]
Units: Score
least squares mean (confidence interval 95%)	-1.93 (-3.18 to -0.67)	-3.76 (-5.05 to -2.47)

Notes
[1] - Randomised subjects with >=1 dose of Treatment and baseline and >=1 post-baseline assessment
[2] - Randomised subjects with >=1 dose of Treatment and baseline and >=1 post-baseline assessment

Primary endpoint

Statistical analysis description

The primary efficacy endpoint was the mean change from Baseline to Day 43 in the NPI-NH psychosis score (delusions + hallucinations), analysed using a mixed-effects model for repeated measurements (MMRM).

Comparison groups

Placebo v Pimavanserin tartrate 40 mg (equivalent to 34 mg pimavanserin)

Number of subjects included in analysis

178

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0451

Method

Mixed models analysis

Parameter type

Difference in MMRM LSM

Point estimate

-1.84

Confidence interval

level

95%

sides

2-sided

lower limit

-3.64

upper limit

-0.04

Variability estimate

Standard error of the mean

Dispersion value

0.91

Adverse events

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Timeframe for reporting adverse events

12 weeks

Adverse event reporting additional description

From the time of signing informed consent, adverse events were to be reported through the 12-week treatment period and up to the follow-up phone call that was performed 4 weeks after the end of study treatment.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.0

Reporting group title

Placebo

Reporting group description

Placebo, two tablets, once daily by mouth

Reporting group title

Pimavanserin tartrate 40 mg (equivalent to 34 mg pimavanserin)

Reporting group description

Pimavanserin tartrate 40 mg (two 20 mg tablets), once daily by mouth (equivalent to 34 mg pimavanserin)

Serious adverse events	Placebo	Pimavanserin tartrate 40 mg (equivalent to 34 mg pimavanserin)
Total subjects affected by serious adverse events
subjects affected / exposed	10 / 91 (10.99%)	15 / 90 (16.67%)
number of deaths (all causes)	4	4
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm of thorax
subjects affected / exposed	0 / 91 (0.00%)	1 / 90 (1.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 91 (0.00%)	1 / 90 (1.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	0 / 91 (0.00%)	1 / 90 (1.11%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	0 / 91 (0.00%)	1 / 90 (1.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Laceration
subjects affected / exposed	0 / 91 (0.00%)	1 / 90 (1.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal fracture
subjects affected / exposed	1 / 91 (1.10%)	0 / 90 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Upper limb fracture
subjects affected / exposed	1 / 91 (1.10%)	0 / 90 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Wrist fracture
subjects affected / exposed	1 / 91 (1.10%)	0 / 90 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Hypotension
subjects affected / exposed	1 / 91 (1.10%)	0 / 90 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Cardiopulmonary failure
subjects affected / exposed	1 / 91 (1.10%)	0 / 90 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Myocardial infarction
subjects affected / exposed	2 / 91 (2.20%)	0 / 90 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Dementia
subjects affected / exposed	0 / 91 (0.00%)	1 / 90 (1.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Depressed level of consciousness
subjects affected / exposed	0 / 91 (0.00%)	1 / 90 (1.11%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Loss of consciousness
subjects affected / exposed	1 / 91 (1.10%)	1 / 90 (1.11%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 91 (0.00%)	1 / 90 (1.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
General physical health deterioration
subjects affected / exposed	1 / 91 (1.10%)	0 / 90 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Psychiatric disorders
Aggression
subjects affected / exposed	0 / 91 (0.00%)	1 / 90 (1.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Renal failure acute
subjects affected / exposed	0 / 91 (0.00%)	1 / 90 (1.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Bronchopneumonia
subjects affected / exposed	0 / 91 (0.00%)	1 / 90 (1.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Lower respiratory tract infection
subjects affected / exposed	0 / 91 (0.00%)	1 / 90 (1.11%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	2 / 91 (2.20%)	2 / 90 (2.22%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 2	0 / 1
Urinary tract infection
subjects affected / exposed	0 / 91 (0.00%)	2 / 90 (2.22%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Placebo	Pimavanserin tartrate 40 mg (equivalent to 34 mg pimavanserin)
Total subjects affected by non serious adverse events
subjects affected / exposed	70 / 91 (76.92%)	67 / 90 (74.44%)
Investigations
Blood alkaline phosphatase increased
subjects affected / exposed	8 / 91 (8.79%)	3 / 90 (3.33%)
occurrences all number	8	3
Blood lactate dehydrogenase increased
subjects affected / exposed	10 / 91 (10.99%)	4 / 90 (4.44%)
occurrences all number	10	4
Blood potassium increased
subjects affected / exposed	3 / 91 (3.30%)	5 / 90 (5.56%)
occurrences all number	3	5
Blood urea increased
subjects affected / exposed	8 / 91 (8.79%)	7 / 90 (7.78%)
occurrences all number	8	7
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	14 / 91 (15.38%)	11 / 90 (12.22%)
occurrences all number	17	16
Fall
subjects affected / exposed	21 / 91 (23.08%)	20 / 90 (22.22%)
occurrences all number	35	39
Laceration
subjects affected / exposed	5 / 91 (5.49%)	3 / 90 (3.33%)
occurrences all number	6	3
Nervous system disorders
Somnolence
subjects affected / exposed	7 / 91 (7.69%)	3 / 90 (3.33%)
occurrences all number	7	3
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	8 / 91 (8.79%)	9 / 90 (10.00%)
occurrences all number	8	9
General disorders and administration site conditions
Oedema peripheral
subjects affected / exposed	2 / 91 (2.20%)	7 / 90 (7.78%)
occurrences all number	2	7
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	7 / 91 (7.69%)	4 / 90 (4.44%)
occurrences all number	7	4
Psychiatric disorders
Aggression
subjects affected / exposed	4 / 91 (4.40%)	9 / 90 (10.00%)
occurrences all number	4	10
Agitation
subjects affected / exposed	13 / 91 (14.29%)	19 / 90 (21.11%)
occurrences all number	13	19
Anxiety
subjects affected / exposed	2 / 91 (2.20%)	5 / 90 (5.56%)
occurrences all number	2	5
Behavioural and psychiatric symptoms of dementia
subjects affected / exposed	2 / 91 (2.20%)	5 / 90 (5.56%)
occurrences all number	2	6
Infections and infestations
Cellulitis
subjects affected / exposed	3 / 91 (3.30%)	6 / 90 (6.67%)
occurrences all number	3	7
Lower respiratory tract infection
subjects affected / exposed	12 / 91 (13.19%)	13 / 90 (14.44%)
occurrences all number	13	15
Urinary tract infection
subjects affected / exposed	25 / 91 (27.47%)	18 / 90 (20.00%)
occurrences all number	36	27
Metabolism and nutrition disorders
Hyperglycaemia
subjects affected / exposed	11 / 91 (12.09%)	4 / 90 (4.44%)
occurrences all number	11	4

More information

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Were there any global substantial amendments to the protocol? Yes

26 Jul 2013

Key amendment changes: -Study design was changed from multi-centre to single-centre -Consent process clarifications made for staff/caregivers -Entry criteria were revised to clarify symptoms of ADP and broaden allowed MMSE score range -Modifications to clinical laboratory and ECG test schedule and/or methods -Sample size assumptions adjusted and statistical analysis methods were modified -Stratification criteria added for cognition and severity of psychosis -DMEC included in study

24 Jan 2014

Key amendment changes: -Various procedural clarifications -Modifications to several rating instruments were made to enhance the practical application of the assessments -The analysis plan was updated to accommodate the stratified study design and to specify evaluation of cognition

16 Nov 2015

Key amendment changes: -The description of the primary efficacy endpoint updated to change from baseline to D43 for NPI-NH psychosis score (Delusions + Hallucinations domains A and B); and other efficacy endpoints were revised and/or categorized as being either secondary or exploratory. -Various procedural clarifications -Clarifications to exclusion criteria and prohibited and concomitant medications

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from baseline to Day 43 in the NPI-NH psychosis score (Delusions [Domain A]+Hallucinations [Domain B])

Primary: Change from baseline to Day 43 in the NPI-NH psychosis score (Delusions [Domain A]+Hallucinations [Domain B])

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

Clinical Trial Results: 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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from baseline to Day 43 in the NPI-NH psychosis score (Delusions [Domain A]+Hallucinations [Domain B])

Primary: Change from baseline to Day 43 in the NPI-NH psychosis score (Delusions [Domain A]+Hallucinations [Domain B])

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
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