Clinical trial NCT03325556
Conditions: Dementia-related Psychosis
Keywords: Dementia Dementia-related psychosis Dementia associated with Parkinson's disease Dementia with Lewy bodies Alzheimer's disease Behavioral variant frontotemporal dementia Progressive supranuclear palsy Corticobasal degeneration Vascular dementia Hallucinations Delusions Psychosis
Sponsor: ACADIA Pharmaceuticals Inc.
Start date: 2017-09-27; Completion date: 2019-10-30
Enrollment: 392 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy of pimavanserin compared to placebo in preventing relapse of psychotic symptoms in subjects with dementia-related psychosis who responded to 12 weeks of open label pimavanserin treatment.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Placebo intervention 2: Pimavanserin 34 mg intervention 3: Pimavanserin 20 mg
Intervention descriptions: intervention 1: Placebo, tablets, once daily by mouth intervention 2: Pimavanserin 34 mg total daily dose, tablets, once daily by mouth intervention 3: Pimavanserin 20 mg total daily dose, tablets, once daily by mouth

Protocol documents:
Prot_000.pdf: 
Official Title: A Double-blind, Placebo-controlled, Relapse Prevention Study of 
Pimavanserin for the Treatment of Hallucinations and Delusions Associated With 
Dementia-related Psychosis  
NCT Number: NCT03325556 
Document Date: 16 Aug 2018 


 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 1 of 100 
 
 
CLINICAL STUDY PROTOCOL 
 
A Double-blind, Placebo-controlled, Relapse Prevention Study of 
Pimavanserin for the Treatment of Hallucinations and Delusions Associated 
With Dementia-related Psychosis 
 
Protocol Number: ACP-103-045 
Amendment 1 
 
EudraCT Number: 2017-002227-13 
 
Original Protocol Date: 1 June 2017 
Protocol Version 1.1 Date: 5 July 2017 
Protocol Amendment 1 Date: 16 August 2018 
 
 
Confidentiality Statement 
This protocol is the confidential information of ACADIA Pharmaceuticals Inc. and is 
intended solely for the guidance of the clinical investigation. This protocol may not be 
disclosed to parties not associated with the clinical investigation or used for any purpose 
without the prior written consent of ACADIA Pharmaceuticals Inc. 




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DECLARATION OF INVESTIGATOR 
I confirm that I have read the above protocol. I understand it, and I will work according to the 
moral, ethical, and scientific principles governing clinical research as set out in the principles 
of GCP (International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use [ICH] Guidelines E6 and E2a]); as described in 21 CFR 
parts 50, 54, 56, 312, and 812; and according to applicable local requirements. 
Confidentiality Statement 
The confidential information in this document is provided to you as a Principal Investigator 
or Consultant for review by you, your staff, and the applicable institutional review 
board/ethics committee. Your acceptance of this document constitutes agreement that you 
will not disclose the information contained herein to others without written authorization 
from the Sponsor. 
Principal Investigator 
 
 
Signature 
 
Date 
 
 
 
Name (printed) 
 
 


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PROTOCOL SYNOPSIS 
Sponsor: ACADIA Pharmaceuticals Inc. 
Name of Investigational Product: Pimavanserin 
Indication: Treatment of hallucinations and delusions associated with dementia-related 
psychosis 
Protocol Title: A Double-blind, Placebo-controlled, Relapse Prevention Study of 
Pimavanserin for the Treatment of Hallucinations and Delusions Associated With Dementia-
related Psychosis 
Protocol Number: ACP-103-045 
EudraCT Number: 2017-002227-13 Phase: 3 
Primary Objective 
 To evaluate relapse prevention in 
subjects with dementia-related 
psychosis treated with pimavanserin 
compared to placebo 
Primary Endpoint 
 Time from randomization to relapse in the 
double-blind period 
Key Secondary Objective 
 To evaluate the time to discontinuation 
of the study for any reason in subjects 
with dementia-related psychosis 
treated with pimavanserin compared to 
placebo 
Key Secondary Endpoint 
 Time from randomization to discontinuation 
from the double-blind period for any reason 
Exploratory Objectives 
 To evaluate the benefit of 
pimavanserin compared to placebo in 
the following domains in subjects with 
dementia-related psychosis who have 
been stabilized on pimavanserin 
therapy: 
o symptoms of hallucinations and 
delusions 
o clinical global impressions 
o caregiver burden 
o daytime sleepiness 
o quality of life 
Exploratory Endpoints 
 Change from double-blind Baseline on the 
following: 
o Scale for the Assessment of Positive 
Symptoms-Hallucinations+Delusions 
(SAPS-H+D) score 
o SAPS Hallucinations domain score 
o SAPS Delusions domain score 
o Clinical Global Impression-Severity 
(CGI-S)-dementia-related psychosis 
o Zarit Burden Interview (ZBI) score 
o Karolinska Sleepiness Scale (KSS) score 
o EQ-5D-5L score 
o Clinical Global Impression-Improvement 
(CGI-I)-dementia-related psychosis  


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Safety Objective 
 To evaluate the safety and tolerability 
of pimavanserin compared to placebo 
in subjects with dementia-related 
psychosis who have been stabilized on 
pimavanserin therapy 
Safety Endpoints 
 Treatment-emergent adverse events (TEAEs) 
 Serious adverse events (SAEs) 
 Withdrawals due to adverse events (AEs) 
 Potentially clinically important changes in 
other safety assessments 
 Global Clinician Assessment of Suicidality 
(GCAS) score 
 Mini-Mental State Examination (MMSE) 
score 
 Extrapyramidal Symptom Rating Scale A 
(ESRS-A) score 
Pharmacokinetic Objectives 
 To characterize the pharmacokinetics 
(PK) of pimavanserin in subjects with 
dementia-related psychosis 
 To assess the pharmacokinetic/ 
pharmacodynamic (PK/PD) 
relationship using safety and efficacy 
endpoints in subjects with dementia-
related psychosis 
Pharmacokinetic Endpoints 
 Plasma concentration of pimavanserin and 
AC-279 
 Pimavanserin PK parameters using a 
population PK approach 
 PK/PD using appropriate PK/PD analysis 
methods 
Number of 
Study Sites 
Approximately 95 study sites will participate in this study. 
Number of 
Subjects Planned 
This study will enroll approximately 356 subjects in order to randomize 
approximately 178 subjects with dementia-related psychosis who meet 
response criteria. 
Criteria for 
Inclusion and 
Exclusion 
To be eligible for this study, subjects must meet all of the inclusion 
criteria and none of the exclusion criteria at Visit 1 (Screening), unless 
specified otherwise. 
Inclusion Criteria: 
1. Is a male or female ≥50 and ≤90 years of age 
2. Can understand the nature of the trial and protocol requirements 
and provide written informed consent 
If the subject is deemed not competent to provide informed 
consent, the following requirements for consent must be met: 
a. The subject’s legally acceptable representative (LAR) 
(or study partner/caregiver, if local regulations allow) 
must provide written informed consent 
b. The subject must provide written (if capable) informed 
assent 


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3. Meets criteria for All-cause Dementia according to NIA-AA 
guidelines (Appendix A) 
4. Meets clinical criteria for one of the following disorders, with or 
without cerebrovascular disease (CVD): 
a. Dementia associated with Parkinson’s disease  
(Appendix B) 
b. Dementia with Lewy bodies (Appendix C) 
c. Possible or probable Alzheimer’s disease (Appendix A) 
d. Frontotemporal degeneration spectrum disorders, 
including possible or probable: 
 Behavioral variant frontotemporal dementia 
(Appendix D) 
 Progressive supranuclear palsy (Appendix E) 
 Corticobasal degeneration (Appendix F) 
e. Vascular dementia, including post-stroke dementia, 
multi-infarct dementia and/or subcortical ischemic 
vascular dementia (SIVD) (Appendix G) 
5. Has an MMSE score ≥6 and ≤24 
6. Has sufficient verbal and written ability to understand and 
answer questions and comply with procedures, with corrective 
measures such as hearing aids and reading glasses if necessary, 
and is willing and able to participate in all scheduled evaluations 
and complete all required tests 
7. Has had psychotic symptoms for at least 2 months 
8. Has all of the following scores at Visit 1 (Screening) and Visit 2 
(open-label Baseline): 
a. SAPS-H+D total score ≥10; AND 
b. CGI-S ≥4 (moderately ill); AND 
c. SAPS-H+D global item (H7 or D13) score ≥4 (marked) 
9. Has lived at the current place of residence for at least 3 weeks 
prior to Visit 1 (Screening) and there are no plans to move to a 
different location 
10. Has a designated study partner/caregiver who meets the 
following requirements: 
a. In the Investigator’s opinion, is in contact with the 
subject frequently enough to accurately report on the 
subject’s symptoms and whether or not the subject is 
taking the study drug 
b. Is fluent in the local language in which study 
assessments will be administered 
c. Agrees to participate in study assessments and provides 
written consent to participate in the study 


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11. Can come to the clinic for study visits with a study 
partner/caregiver 
12. Has an MRI or CT scan of the brain (completed within past 
3 years) taken during or subsequent to the onset of dementia. If 
not available, a non-contrast brain MRI or non-contrast head CT 
must be done during screening. 
13. If the subject is taking a cholinesterase inhibitor, memantine, or 
both: 
a. the dose of the medication(s) must be stable for at least 
12 weeks prior to Visit 2 (open-label Baseline) and there 
must be no current plan to change the dose; OR 
b. if the medication(s) was discontinued, the 
discontinuation must occur no fewer than 2 weeks prior 
to Visit 2 (open-label Baseline) 
14. If the subject is taking an antipsychotic medication at the time of 
screening, the antipsychotic must be discontinued 2 weeks or 
5 half-lives (whichever is longer) prior to Visit 2. Investigators 
should not withdraw a subject’s prohibited medication for the 
purpose of enrolling them into the study unless discontinuation 
of the medication is deemed to be clinically appropriate (e.g., 
symptoms are not well-controlled or the subject cannot tolerate 
the current medication). 
15. If the subject is female, she must not be pregnant or 
breastfeeding. She must also be of non-childbearing potential 
(defined as either surgically sterilized or at least 1 year 
postmenopausal) or must agree to use a clinically acceptable 
method of contraception or be abstinent for at least 1 month 
prior to Visit 2 (open-label Baseline), during the study, and 
1 month following completion of the study. Acceptable methods 
of birth control include the following: 
a. Condom, diaphragm, or cervical cap with spermicide 
b. Hormonal contraception, including oral, injectable, 
transdermal, or implantable methods 
c. Intrauterine device (IUD) 
Exclusion Criteria: 
1. Is in hospice or end-of-life care 
2. Is confined to bed (subjects who can attend clinic visits using a 
wheelchair or other ambulatory assistive device are permitted) 
3. Requires skilled nursing care (procedures that can only be 
administered by a registered nurse or doctor, such as but not 
limited to, intravenous administration of medication, procedures 
related to insertion or care of suprapubic catheters, and 
nasopharyngeal/tracheostomy aspiration) 


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4. Has psychotic symptoms that are primarily attributable to 
delirium, substance abuse, or a medical or psychiatric condition 
(e.g., schizophrenia, bipolar disorder, delusional disorder) other 
than dementia 
5. Has a current major depressive episode (within 3 months of 
Screening), according to the Diagnostic and Statistical Manual 
of Mental Disorders-Fifth Edition (DSM-5) criteria 
6. Has a Global Clinician Assessment of Suicidality (GCAS) score 
of 3 or 4 based on Investigator’s assessment of behavior within 
the 3 months prior to Visit 1 (Screening) or since-last-visit at 
Visit 2 (open-label Baseline) 
7. Has evidence of a non-neurologic medical comorbidity or 
medication use that could substantially impair cognition 
8. Has a history of ischemic stroke within the last 12 months or 
any evidence of hemorrhagic stroke 
9. Has a known history of cerebral amyloid angiopathy (CAA), 
epilepsy, CNS neoplasm, or unexplained syncope 
10. Has atrial fibrillation unless adequately anticoagulated 
11. Has any of the following: 
a. greater than New York Heart Association (NYHA) Class 
2 congestive heart failure (Appendix J) 
b. Grade 2 or greater angina pectoris (by Canadian 
Cardiovascular Society [CCS] Angina Grading Scale) 
(Appendix K) 
c. sustained ventricular tachycardia 
d. ventricular fibrillation 
e. torsade de pointes 
f. syncope due to an arrhythmia 
g. an implantable cardiac defibrillator 
12. Had a myocardial infarction within the 6 months prior to Visit 1 
(Screening) 
13. Has a known personal or family history or symptoms of long 
QT syndrome 
14. Has any of the following ECG results at Visit 1 (Screening) or 
Visit 2 (open-label Baseline): 
a. If the subject is not on citalopram, escitalopram, or 
venlafaxine: 
i. QTcF >450 ms, if QRS duration <120 ms 
ii. QTcF >470 ms, if QRS duration ≥120 ms 
b. If the subject is on citalopram, escitalopram, or 
venlafaxine: 
i. QTcF >425 ms, if QRS duration <120 ms 
ii. QTcF >450 ms, if QRS duration ≥120 ms 


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If the mean QTcF value from the set of ECGs done at Screening 
is prolonged due to an identifiable cause, and it is medically 
appropriate to address that cause, a repeat set of triplicate ECGs 
may be performed during Screening at the discretion of the 
Medical Monitor. 
15. Has a heart rate <50 beats per minute. If bradycardia is 
secondary to iatrogenic or treatable causes and these causes are 
addressed, a heart rate assessment can be repeated during the 
screening period. 
16. Has a significant unstable medical condition that could interfere 
with subject’s ability to complete the study or comply with 
study procedures 
17. Has severe renal impairment, severe or medically significant 
impairment of hepatic function, and/or a clinically significant 
laboratory abnormality that in the judgment of the Investigator 
or Medical Monitor will interfere with the conduct or 
interpretation of safety or efficacy evaluations in the study 
18. Has one of the following screening laboratory results: 
a. Platelets ≤75,000/mm3 
b. Hemoglobin ≤9.5 g/dL if male, or ≤8.5 g/dL if female 
c. Neutrophils, absolute ≤1000/mm3 
d. Aspartate aminotransferase (AST) >2×upper limit of 
normal 
e. Alanine aminotransferase (ALT) >2×upper limit of 
normal 
f. Creatinine ≥2 mg/dL 
g. Hemoglobin A1c (HbA1c) ≥8.5% 
h. Abnormal free thyroxine (T4) 
i. Vitamin B12 deficiency 
Laboratory testing may be repeated during Screening at the 
discretion of the Medical Monitor.  
19. Has a history of a positive test result for HIV or hepatitis C 
20. Has a clinically significant CNS abnormality that is most likely 
contributing to the dementia or findings on MRI or CT 
including: 
a. intracranial mass lesion (including but not limited to 
meningioma [>1 cm3 with evidence of peritumoral 
edema] or glioma) 
b. vascular malformation 
c. intracranial aneurysm >4 points by PHASES score 
(Appendix L) 
d. evidence of >4 hemosiderin deposits (definite 
microhemorrhage or superficial siderosis) 


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21. Requires treatment with a medication or other substance that is 
prohibited by the protocol 
22. Has a body mass index (BMI) <18.5 kg/m2 or known 
unintentional weight loss ≥7% of body weight over past 6 
months 
23. The urine drug screen result at Visit 1 (Screening) indicates the 
presence of amphetamine/methamphetamine, barbiturates, 
cocaine, or phencyclidine (PCP). Subjects who test positive for 
amphetamines or barbituates may be retested during Screening 
if they agree to abstain from the medication for the length of 
their participation in the study and if abstinence from 
medication usage is achieved at least 7 days prior to Visit 2 
(open-label Baseline). The repeat Screening test must be 
negative for them to participate in the study. The presence of 
benzodiazepines, marijuana (THC), or opiates may not exclude 
the subject from the study. 
24. Has participated in or is participating in a clinical trial of any 
investigational drug, device, or intervention, within 30 days or 
5 half-lives, whichever is longer, of Visit 1 (Screening) OR has 
participated in a clinical trial for disease-modifying therapy 
within 6 months of Visit 1 
25. Has previously been enrolled in any prior clinical study with 
pimavanserin or is currently taking pimavanserin 
26. Has a significant sensitivity or allergic reaction to pimavanserin 
or its excipients 
27. Is an employee or is a family member of an employee of 
ACADIA Pharmaceuticals Inc. 
28. Is judged by the Investigator or the Medical Monitor to be 
inappropriate for the study for any reason 
Test Product, 
Dose, and 
Administration 
Pimavanserin 34 mg (provided as 2×17 mg tablets), 20 mg (provided as 
2×10 mg tablets), and matching placebo (2×placebo tablets [size- and 
color-matched to pimavanserin tablets]) 
Planned Duration 
of Treatment 
The duration of participation for individual study subjects will be up to 
47 weeks, consisting of a screening period of up to 5 weeks; an open-
label period of 12 weeks; a double-blind period of up to 26 weeks; and 
an approximately 4-week safety follow-up period.  
The study discontinuation date is defined as the day on which the 
Sponsor notifies sites that the study is ending (for example, in the event 
of a positive interim analysis or after 75 adjudicated relapses). The 
study completion date is defined as the day on which the last subject 
completes the last scheduled assessment (i.e., safety follow-up). 


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Study Design 
This is a Phase 3, prospective, double-blind, placebo-controlled, 
multicenter, relapse prevention study in subjects with dementia-related 
psychosis. 
This study will have 4 treatment periods (Figure S–1): 
 Screening period (3-35 days) 
 Open-label period (12 weeks) 
 Double-blind period (up to 26 weeks) 
 Safety follow-up period (approximately 4 weeks) 
The schedule of assessments is provided in Table S–1 and Table S–2. 
Screening Period (3-35 Days) 
During the screening period, subjects will be assessed for study 
eligibility and prohibited medications will be discontinued when 
medically appropriate. Subjects and partner/caregivers will also receive 
a standardized psychosocial therapy training. 
Investigators should not withdraw a subject’s prohibited medication for 
the purpose of enrolling them into the study. Medications should be 
discontinued only if it is deemed clinically appropriate to do so. 
Open-label Period (12 Weeks) 
During the open-label period, eligible subjects will begin receiving 
pimavanserin 34 mg once daily (QD) beginning at Week 0 (open-label 
Baseline); subsequent clinic visits will occur at Weeks 2, 4, 8, and 12. 
Dose adjustments are permitted at scheduled or unscheduled visits until 
Week 4. After Week 4, the subject’s dose will remain fixed at either 
34 mg or 20 mg once daily. 
To enter the double-blind period, eligible subjects must meet the 
following response criteria at Weeks 8 and 12: 
 Subject experiences a ≥30% reduction (improvement) from Week 0 
(open-label Baseline) on the SAPS-H+D Total Score AND 
 Subject has a CGI-I score of 1 (very much improved) or 2 (much 
improved), relative to Week 0 (open-label Baseline) 
A subject who does not meet response criteria at Week 8 and 12 will be 
withdrawn from study drug and enter the safety follow-up period of the 
study. 
Double-blind Period (up to 26 Weeks) 
Randomization will occur at the double-blind Baseline visit (Week 12). 
Subjects will be randomly assigned 1:1 to continue their pimavanserin 
dose (34 mg or 20 mg) or matching placebo. Randomization will be 
stratified by: 
1. Most likely dementia subtype or most prominent cause of 
dementia: 


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 Alzheimer's disease or frontotemporal dementia spectrum 
disorders 
 Vascular dementia 
 Parkinson’s disease dementia or dementia with Lewy 
bodies 
2. Region 
The protocol-defined relapse criteria for dementia-related psychosis are: 
 Subject experiences a ≥30% increase (worsening) from Week 12 
(double-blind Baseline) on the SAPS-H+D Total Score AND has a 
CGI-I score of 6 (much worse) or 7 (very much worse), relative to 
the double-blind Baseline; OR 
 Subject is treated with an antipsychotic (other than pimavanserin) 
for dementia-related delusions and/or hallucinations; OR 
 Subject stops study drug or withdraws from study for lack of 
efficacy (as reported by the subject or study partner/caregiver) or 
the Investigator discontinues study drug due to lack of efficacy; OR 
 Subject is hospitalized for worsening dementia-related psychosis 
Relapse criteria will be assessed weekly for the first 2 weeks after 
randomization (Weeks 13 and 14), every 2 weeks until Week 26, and 
every 4 weeks through Week 38. Relapse criteria may also be evaluated 
at unscheduled visits. Any subject who meets any of the relapse criteria 
after randomization will be withdrawn from study drug and enter the 
safety follow-up period of the study. 
All subjects who discontinue the study between randomization and 
Week 38 should complete an ET visit, if possible, and an independent 
adjudication committee (IAC) will review those cases that occurred 
before the study discontinuation date to determine if protocol-defined 
relapse criteria were met.  
Safety Follow-up Period (Approximately 4 Weeks) 
Approximately 4 weeks after the last dose of study drug, subjects will 
have a safety follow-up telephone call visit. 
The Sponsor will provide investigative sites with 3 months of after-
study assistance to transition subjects to standard of care therapy after 
their participation in the study. 
Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board will review safety 
information on a regular basis throughout the study. 
Pharmacokinetic 
Assessments 
During the open-label period, PK samples will be collected at Weeks 0, 
8, and 12. 
During the double-blind period, PK samples will be collected at Weeks 
13, 22, and 38/EOT. 


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Pharmacokinetic samples will also be collected, if possible, at any ET 
visit or the visit immediately following any SAE or following an AE 
leading to discontinuation. 
For all PK samples (scheduled and unscheduled), the dates and times of 
administration of the last 3 doses of study drug should be recorded, as 
well as the date and time of the sample draw. For samples collected 
from subjects who experience any SAE or experience an AE leading to 
discontinuation, the date and time of the last dose of study drug prior to 
the SAE or AE should also be recorded. 
Optional 
Pharmacogenomic 
Assessments 
A blood sample will be collected at Visit 2 (open-label Baseline) or later 
from consenting subjects for potential future pharmacogenomics 
analyses (where local regulations permit). 
Data for genetic analyses will be anonymized, as is the customary 
approach according to Good Clinical Practice (GCP). 
Sample Size 
Calculations 
The sample size calculation was based on the following assumptions: a 
placebo relapse event rate of 60% over 26 weeks; a pimavanserin 
relapse event rate of 35% over 26 weeks; a dropout rate of 25% over 
26 weeks; an overall two-sided alpha level of 0.05; use of a one-sided 
(0.025) O’Brien-Fleming stopping boundary to adjust for a single 
interim analysis that will be performed when one half of the total 
planned number of post-randomization relapse events have occurred; 
and a power of 90%. The total number of post-randomization relapse 
events required at the final analysis is 75 and the calculated sample size 
is 89 in each of the two treatment groups (giving a total of 178). 
Study enrollment will be closed when approximately 178 subjects have 
been randomized in the double-blind period or when 75 adjudicated 
post-randomization relapse events have occurred. In the event that the 
randomization rate is lower than anticipated and/or the relapse event 
rate is lower than anticipated, the number enrolled and randomized may 
be increased up to a maximum of 400 randomized subjects in order to 
observe 75 post-randomization relapse events. 
An interim efficacy analysis of the primary efficacy endpoint will be 
performed after 38 adjudicated relapse events have occurred. The study 
may be terminated early if the interim analysis results meet prespecified 
stopping criteria For example, if there are exactly 38 relapse events at 
the interim analysis, the significance level will be 0.0054. If the study is 
not stopped early and the final analysis includes exactly 75 relapse 
events (including the 38 events from the interim analysis), the 
significance level for the final analysis will be 0.0479. The actual 
significance levels to be used at the interim and final analyses will be 
calculated based on the actual number of events observed. The interim 
efficacy analysis will be performed by an independent statistician. 
Investigators, subjects, and Sponsor personnel will remain blinded 
throughout the study. 


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Statistical 
Methods 
The primary efficacy analysis will be based on the Intent-to-treat (ITT) 
population, defined as all randomized subjects. The time from 
randomization to relapse in the double-blind period will be compared 
between treatment groups using a Cox regression model with effects for 
treatment group, dementia subtype, and region. The nominal p-value, 
hazard ratio, and 95% confidence interval will be reported. Subjects 
who discontinue early or complete the study without having 
experienced a relapse event will be censored at the time of last 
assessment for relapse. The key secondary endpoint of time from 
randomization to discontinuation from the double-blind period for any 
reason (other than termination of the study by the Sponsor) will be 
analyzed using the same methodology as for the primary endpoint. 
A hierarchical testing procedure will be used to control the overall 
type I error rate for the primary and key secondary endpoints. 
Exploratory Efficacy Analyses 
All exploratory efficacy endpoints will be summarized by treatment 
group using descriptive statistics. For all exploratory SAPS endpoints, 
CGI-S, ZBI, KSS, and EQ-5D-5L; the change from double-blind 
Baseline will be analyzed using mixed model repeated measures 
(MMRM). The independent variables in the model will include the 
following: treatment group (pimavanserin or placebo), visit, treatment 
by visit interaction, double-blind Baseline score, double-blind Baseline 
score by visit interaction, designated dementia subtype , and region. 
CGI-I will be analyzed using an MMRM model with the following 
independent variables: treatment group (pimavanserin or placebo), visit, 
treatment by visit interaction, double-blind Baseline CGI-S score, 
double-blind Baseline CGI-S score by visit interaction, designated 
dementia subtype , and region. 
The treatment comparisons will be based on the difference in least 
squares means and will be tested at a two-sided alpha level of 0.05. The 
double-blind Baseline score is defined as the last value prior to the first 
dose of double-blind study drug. 
In addition to the MMRM analyses described above, last-observation-
carried-forward analyses will also be performed. 
Descriptive summaries of efficacy endpoints, including the number and 
percent of subjects meeting response criteria, will be provided for the 
open-label period. 
Safety Analyses 
All safety results will be summarized using descriptive statistics. 
Separate summaries will be provided for the open-label and double-
blind periods. The double-blind summaries will be presented by 
treatment group. Adverse events will be classified into standard 
terminology using the Medical Dictionary for Regulatory Activities. 
Adverse events may also be categorized into categories of special 


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interest. Treatment-emergent AEs (TEAEs), TEAEs leading to 
discontinuation, TEAEs related to study drug, TEAEs by maximum 
severity, serious TEAEs, and serious TEAEs related to study drug will 
all be summarized. Other TEAEs of special interest may also be 
summarized. 
Descriptive statistics for ECG, vital signs, GCAS, MMSE, ESRS-A 
total score and all subscales, and clinical laboratory parameters, 
including change from Baseline when applicable, will be tabulated by 
treatment group and timepoint. Additionally, categorical analyses will 
be conducted on the incidence of subjects with prolonged QTc intervals 
and changes in QTc intervals in accordance with International Council 
for Harmonisation (ICH) guidelines. The incidence of clinically 
significant changes in selected laboratory parameters will also be 
summarized. 
Pharmacokinetic Analyses 
Plasma concentration data for pimavanserin and AC-279 will be listed 
and summarized using descriptive statistics. 
If data allow, population PK and PK/PD analyses will be performed to 
further characterize the PK profile and exposure response relationship 
of pimavanserin using measures of safety and efficacy parameters. The 
results of population PK and PK/PD modeling will be presented in a 
separate report. Investigators, subjects, and Sponsor personnel will 
remain blinded to plasma concentration data from the double-blind 
period until the unblinding of the clinical database at the end of the 
study. 
Date 
16 August 2018 
 


Study ACP-103-045 
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Figure S–1 
Schematic of Study Design for ACP-103-045 
 
 
 


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Table S–1 
Schedule of Assessments for ACP-103-045: Screening and Open-
label Period 
 
Screening 
Open-label Period 
Visit week 
-5 to 0 
0 
2 
4 
8 
12a 
Allowable visit window (# days) 
 
 
±3 
±3 
±3 
+7 
Visit Number 
1 
2 
3 
4 
5 
6 
Informed consent 
X 
 
 
 
 
 
Inclusion/exclusion criteria assessment 
X 
X 
 
 
 
 
Medical history and demographics 
X 
 
 
 
 
 
Mini-Mental State Examination 
X 
X 
X 
X 
X 
X 
MRI or CTb 
X 
 
 
 
 
 
Psychosocial therapy training 
X 
 
 
 
 
 
Physical and neurological examinations 
X 
X 
 
 
 
X 
Vital signs and weight 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
12-lead electrocardiogramc 
X 
X 
X 
 
 
X 
Clinical laboratory tests 
X 
X 
 
 
 
X 
Pregnancy testd 
X 
X 
 
 
 
X 
SAPS-H+D 
X 
X 
X 
X 
X 
X 
Clinical Global Impression-Improvemente 
 
 
X 
X 
X 
X 
Clinical Global Impression-Severity 
X 
X 
X 
X 
X 
X 
Zarit Burden Interviewf 
 
X 
 
 
 
X 
Karolinska Sleepiness Scale 
 
X 
 
 
 
X 
EQ-5D-5L 
 
X 
 
 
 
X 
Assessment for response criteria 
 
 
 
 
X 
X 
Assessment for concomitant medications 
X 
X 
X 
X 
X 
X 
Global Clinician Assessment of Suicidality 
X 
X 
X 
X 
X 
X 
Extrapyramidal Symptom Rating Scale A 
 
X 
 
 
 
X 
Assessment for adverse events 
X 
X 
X 
X 
X 
X 
Pharmacokinetic sample collectiong 
 
X 
 
 
X 
X 
Pharmacogenomic sample collectionh 
 
X 
 
 
 
 
Drug dispensation 
 
X 
X 
X 
X 
Xi 
Drug return and accountability 
 
 
X 
X 
X 
X 
Randomization 
 
 
 
 
 
X 
Footnotes for Table S–1 on next page 
Abbreviations: CT=computed tomography; MRI=magnetic resonance imaging; SAPS-H+D=Scale for the 
Assessment of Positive Symptoms, Hallucinations and Delusions subscales 
Note: All efforts should be made to complete each visit in a single day. In the event of a split visit, the CGI-
S/CGI-I and the SAPS H+D must be completed on the same day. 
Note: When a subject is found to be appropriate for discontinuation from the trial, the visit during which this is 
determined should immediately be converted to an ET visit (as described in Table S–2) and all procedures 
and assessments listed in the schedule of events for the ET visit (Week 38/EOT; Visit 17/ET) should be 
completed (additional details provided in Section 4.4). Safety follow-up should be completed as scheduled. 


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For additional details on study procedures, see Section 6.  
a 
Visit 6 (Week 12) will serve as both the final visit of the open-label period and the Baseline visit of the 
double-blind period (Table S–2). 
b 
A non-contrast brain MRI or non-contrast head CT will be completed if the subject has not had a CT or 
MRI scan completed (a) within the past 3 years AND (b) during or subsequent to the onset of dementia. 
c 
The ECG will be completed in triplicate at Visit 1 (Screening). A single ECG will be completed at all other 
visits. 
d 
A pregnancy test (serum at Visit 1 and urine at all other visits) is only required for women of childbearing 
potential. If urine cannot be obtained in women of childbearing potential, a serum pregnancy test should be 
done. 
e 
The CGI-I should be scored relative to Visit 2, the subject’s open-label Baseline. 
f 
The ZBI should only be administered to study partners/caregivers who are family members. 
g 
Pharmacokinetic samples will also be collected, if possible, at any ET visit (Table S-2) or the visit 
immediately following any SAE or following an AE leading to discontinuation. 
h 
A separate informed consent (and assent, if applicable) must be given for the pharmacogenomic component 
of the study. This consent may be obtained at any time during the study. If informed consent is given in time 
for sample collection at Visit 2, a pre-dose sample should be collected at Visit 2. If informed consent for 
pharmacogenomics is not given in time for sample collection at Visit 2, a sample may be collected any time 
after informed consent for pharmacogenomics is given. 
i 
Blinded study drug will be dispensed after randomization at Visit 6 (Week 12). 


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Table S–2 
Schedule of Assessments for ACP-103-045: Double-blind Period 
Visit week 
13 
14 
16 
18 
20 
22 
24 
26 
30 
34 
38/EOT 
42 
Allowable visit window (# days) 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
+7 
+3 
Visit Number 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17/ET 
18 
Visit Type (Clinic [C] or Telephone [T]) 
C 
C 
C 
C 
T 
C 
T 
C 
C 
C 
C 
T 
Mini-Mental State Examination 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Physical and neurological examinations 
 
 
 
 
 
X 
 
 
 
 
X 
 
Vital signs and weight 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
12-lead electrocardiogram 
 
 
 
X 
 
 
 
X 
 
 
X 
 
Clinical laboratory tests 
 
 
 
X 
 
 
 
X 
 
 
X 
 
Pregnancy testa 
 
 
 
 
 
 
 
X 
 
 
X 
 
SAPS-H+D 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Clinical Global Impression-Improvementb 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Clinical Global Impression-Severity 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Zarit Burden Interviewc 
 
 
 
X 
 
 
 
X 
 
 
X 
 
Karolinska Sleepiness Scale 
 
 
 
X 
 
 
 
X 
 
 
X 
 
EQ-5D-5L 
 
 
 
X 
 
 
 
X 
 
 
X 
 
Assessment for protocol-defined relapse criteria 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Assessment for concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Global Clinician Assessment of Suicidality 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Extrapyramidal Symptom Rating Scale A 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Assessment for adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetic sample collectiond 
X 
 
 
 
 
X 
 
 
 
 
X 
 
Drug dispensation 
 
X 
X 
X 
 
X 
 
X 
X 
X 
 
 
Drug return and accountability 
Xe 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Footnotes and abbreviations for Table S–2 on next page 


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Abbreviations: EOT=end-of-treatment; ET=early termination; SAPS-H+D=Scale for the Assessment of Positive Symptoms, Hallucinations and Delusions 
subscales 
For additional details on study procedures, see Section 6. 
Note: All efforts should be made to complete each visit in a single day. In the event of a split visit, the CGI-S/CGI-I and the SAPS H+D must be completed on 
the same day. 
Note: When a subject is found to be appropriate for discontinuation from the trial, the visit during which this is determined should immediately be converted to 
an ET visit (as described in Table S–2) and all procedures and assessments listed in the schedule of events for the ET visit (Week 38/EOT; Visit 17/ET) 
should be completed (additional details provided in Section 4.4). Safety follow-up should be completed as scheduled. 
a 
A urine pregnancy test is only required for women of childbearing potential. If urine cannot be obtained in women of childbearing potential, a serum 
pregnancy test should be done. 
b 
The CGI-I should be scored relative to Visit 6 (Week 12), the subject’s double-blind Baseline. 
c 
The ZBI should only be administered to study partners/caregivers who are family members. 
d 
Pharmacokinetic samples will also be collected, if possible, at the visit immediately following any SAE or following an AE leading to discontinuation. 
e 
Only drug accountability will be completed at this visit. 


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Table of Contents
SPONSOR SIGNATURE PAGE ............................................................................................... 2 
DECLARATION OF INVESTIGATOR .................................................................................... 3 
PROTOCOL SYNOPSIS ........................................................................................................... 4 
Table of Contents ..................................................................................................................... 21 
List of Tables ............................................................................................................................ 25 
List of Figures .......................................................................................................................... 25 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................. 26 
1 INTRODUCTION ............................................................................................................. 28 
1.1 
Background Information ................................................................................................ 28 
1.2 
Investigational Product .................................................................................................. 30 
1.3 
Previous Clinical Experience ......................................................................................... 30 
1.3.1 
Parkinson’s Disease Psychosis Program ................................................................... 30 
1.3.2 
Alzheimer’s Disease Psychosis ................................................................................. 31 
1.4 
Study Rationale.............................................................................................................. 33 
2 STUDY OBJECTIVES AND ENDPOINTS ..................................................................... 35 
2.1 
Primary Objective .......................................................................................................... 35 
2.1.1 
Primary Endpoint ....................................................................................................... 35 
2.2 
Key Secondary Objective .............................................................................................. 35 
2.2.1 
Key Secondary Endpoint ........................................................................................... 35 
2.3 
Exploratory Objectives .................................................................................................. 35 
2.3.1 
Exploratory Endpoints ............................................................................................... 35 
2.4 
Safety Objective ............................................................................................................ 36 
2.4.1 
Safety Endpoints ........................................................................................................ 36 
2.5 
Pharmacokinetic Objectives .......................................................................................... 36 
2.5.1 
Pharmacokinetic Endpoints ....................................................................................... 36 
3 STUDY DESCRIPTION ................................................................................................... 36 
3.1 
Overview of Study Design ............................................................................................ 36 
3.2 
Screening Period (3-35 Days)........................................................................................ 37 
3.3 
Open-label Period (12 Weeks) ....................................................................................... 37 
3.4 
Double-blind Period (up to 26 Weeks) .......................................................................... 38 
3.5 
Safety Follow-up Period (Approximately 4 Weeks)...................................................... 38 
4 SUBJECT ELIGIBILITY AND WITHDRAWAL CRITERIA ......................................... 39 


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4.1 
Subject Selection and Withdrawal ................................................................................. 39 
4.2 
Inclusion Criteria ........................................................................................................... 39 
4.3 
Exclusion Criteria .......................................................................................................... 41 
4.4 
Subject Withdrawal or Termination ............................................................................... 44 
4.5 
Prior and Concomitant Therapy..................................................................................... 46 
4.5.1 
Permitted, Restricted, and Prohibited Medications ................................................... 46 
5 INVESTIGATIONAL PRODUCT .................................................................................... 47 
5.1 
Investigational Product Description .............................................................................. 47 
5.1.1 
Formulation, Appearance, Packaging, and Labeling ................................................. 47 
5.1.2 
Product Storage and Stability .................................................................................... 48 
5.1.3 
Dosing and Administration ........................................................................................ 48 
5.1.4 
Dose Adjustments/Modifications/Delays .................................................................. 48 
5.1.5 
Method of Assigning Subjects to Treatment Groups ................................................. 48 
5.1.6 
Blinding ..................................................................................................................... 48 
5.1.7 
Study Drug Compliance ............................................................................................ 49 
5.1.8 
Overdose .................................................................................................................... 49 
5.2 
Investigational Product Accountability Procedures ....................................................... 49 
6 STUDY PROCEDURES ................................................................................................... 50 
6.1 
Screening Assessments .................................................................................................. 50 
6.1.1 
Mini-Mental State Examination ................................................................................ 50 
6.1.2 
Medical History and Demographics .......................................................................... 50 
6.1.3 
Brain Imaging ............................................................................................................ 50 
6.1.4 
Psychosocial Therapy – Non-pharmacologic Intervention Prior to 
Randomization ........................................................................................................... 50 
6.2 
Efficacy Assessments..................................................................................................... 51 
6.2.1 
Scale for the Assessment of Positive Symptoms – Hallucinations and Delusions .... 51 
6.2.2 
Clinical Global Impression – Severity and Clinical Global Impression –
Improvement Scales ................................................................................................... 51 
6.2.3 
Zarit Burden Interview .............................................................................................. 51 
6.2.4 
Karolinska Sleepiness Scale ...................................................................................... 52 
6.2.5 
EQ-5D-5L .................................................................................................................. 52 
6.3 
Safety Assessments ........................................................................................................ 52 
6.3.1 
Physical and Neurological Examinations .................................................................. 52 
6.3.2 
Vital Signs .................................................................................................................. 52 
6.3.3 
Height, Weight and Body Mass Index ....................................................................... 52 
6.3.4 
Electrocardiograms .................................................................................................... 53 


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6.3.5 
Global Clinician Assessment of Suicidality .............................................................. 53 
6.3.6 
Extrapyramidal Symptom Rating Scale ..................................................................... 53 
6.3.7 
Laboratory Evaluations .............................................................................................. 54 
6.3.8 
Safety Follow-up ....................................................................................................... 56 
6.4 
Pharmacokinetic Assessments ....................................................................................... 56 
6.4.1 
Pharmacogenomic Assessment .................................................................................. 57 
6.4.2 
Specimen Preparation, Handling, Storage, and Shipment ......................................... 57 
6.5 
Unscheduled Visits ........................................................................................................ 57 
7 ADVERSE EVENTS ......................................................................................................... 57 
7.1 
Specification of Safety Parameters ................................................................................ 57 
7.1.1 
Definition of Adverse Event ...................................................................................... 57 
7.1.2 
Definition of Serious Adverse Event ......................................................................... 58 
7.2 
Classification of an Adverse Event ................................................................................ 60 
7.2.1 
Severity of Event ....................................................................................................... 60 
7.2.2 
Relationship to Study Drug ....................................................................................... 60 
7.2.2.1 
Duration ................................................................................................................. 60 
7.2.2.2 
Frequency ............................................................................................................... 60 
7.2.2.3 
Action Taken with Study Drug .............................................................................. 61 
7.2.2.4 
Therapy .................................................................................................................. 61 
7.2.2.5 
Outcome ................................................................................................................. 61 
7.2.2.6 
Seriousness ............................................................................................................. 61 
7.2.3 
Definition of Unexpectedness .................................................................................... 61 
7.3 
Time Period and Frequency for Event Assessment and Follow-up ............................... 61 
7.4 
Reporting Procedures .................................................................................................... 62 
7.4.1 
Adverse Event Reporting ........................................................................................... 62 
7.4.2 
Serious Adverse Event Reporting .............................................................................. 62 
7.4.3 
Reporting of Pregnancy ............................................................................................. 63 
7.4.4 
Reporting of Overdose ............................................................................................... 63 
8 CLINICAL MONITORING .............................................................................................. 63 
9 STATISTICAL METHODS AND DATA ANALYSIS ...................................................... 64 
9.1 
Statistical and Analytical Plans...................................................................................... 64 
9.2 
Statistical Hypotheses .................................................................................................... 64 
9.3 
Sample Size Determination ........................................................................................... 64 
9.4 
Subject Populations for Analysis ................................................................................... 65 
9.5 
Description of Statistical Methods ................................................................................ 65 
9.5.1 
Primary Efficacy Analyses ......................................................................................... 65 


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9.5.2 
Key Secondary Analyses ........................................................................................... 66 
9.5.3 
Exploratory Efficacy Analyses .................................................................................. 66 
9.5.4 
Safety Analyses .......................................................................................................... 67 
9.5.5 
Pharmacokinetic Analyses ......................................................................................... 67 
9.5.6 
Data and Safety Monitoring Board ............................................................................ 67 
9.5.7 
Independent Adjudication Committee ....................................................................... 67 
9.5.8 
Planned Interim Analyses .......................................................................................... 68 
9.5.9 
Additional Subgroup Analyses .................................................................................. 68 
9.5.10 
Multiple Comparisons/Multiplicity ........................................................................... 69 
9.6 
Enrollment, Randomization, and Masking Procedures ................................................. 69 
9.6.1 
Breaking the Study Blind/Subject Code .................................................................... 69 
10 STUDY MANAGEMENT AND DATA COLLECTION .................................................. 70 
10.1 Data Collection and Management Responsibilities ....................................................... 70 
10.2 Source Documents ......................................................................................................... 70 
10.3 Case Report Forms ........................................................................................................ 70 
10.4 Confidentiality ............................................................................................................... 71 
10.5 Study Records Retention ............................................................................................... 71 
10.6 Protocol Exceptions and Deviations .............................................................................. 71 
10.7 Protocol Amendments.................................................................................................... 72 
11 STUDY MONITORING, AUDITING, AND INSPECTING............................................ 72 
11.1 Quality Control and Quality Assurance ......................................................................... 72 
12 ETHICAL CONSIDERATIONS ....................................................................................... 72 
12.1 Ethical Standard ............................................................................................................. 72 
12.2 Institutional Review Board/Ethics Committee .............................................................. 73 
12.3 Informed Consent Process ............................................................................................. 73 
12.3.1 
Consent and Other Informational Documents Provided to Subjects ......................... 74 
12.3.2 
Consent Procedures and Documentation ................................................................... 74 
13 PUBLICATION PLAN ...................................................................................................... 74 
14 CONFLICT OF INTEREST POLICY ............................................................................... 74 
14.1 Finance, Insurance, and Indemnity ................................................................................ 74 
15 LITERATURE REFERENCES ......................................................................................... 75 
16 APPENDICES ................................................................................................................... 79 
Appendix A 
NIA-AA Guidelines for All-cause Dementia and Alzheimer’s Disease.......... 79 
Appendix B 
Movement Disorder Society’s Task Force Clinical Diagnostic Criteria for 
Dementia Associated with Parkinson’s Disease ............................................. 82 


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Appendix C 
Dementia with Lewy Bodies Consortium Clinical Diagnostic Criteria .......... 84 
Appendix D 
International Consensus Criteria for Behavioral Variant Frontotemporal 
Dementia ......................................................................................................... 86 
Appendix E 
Neuroprotection and Natural History in Parkinson Plus Syndromes 
Diagnostic Criteria for Progressive Supranuclear Palsy ................................. 88 
Appendix F 
Corticobasal Degeneration Diagnostic Criteria ............................................... 89 
Appendix G 
VASCOG Criteria for Vascular Dementia ....................................................... 90 
Appendix H 
Prohibited and Restricted Medications ........................................................... 92 
Appendix I 
Prohibited and Restricted Concomitant Medications: Inhibitors and 
Inducers of Cytochrome P450 Enzyme 3A4 ................................................... 96 
Appendix J 
New York Heart Association Classification of Heart Failure .......................... 98 
Appendix K 
Canadian Cardiovascular Society Angina Grading Scale ............................... 99 
Appendix L 
Predictors Composing the PHASES Aneurysm Rupture Risk Score ............ 100 
 
List of Tables 
Table S–1 
Schedule of Assessments for ACP-103-045: Screening and Open-label 
Period ............................................................................................................... 17 
Table S–2 
Schedule of Assessments for ACP-103-045: Double-blind Period.................. 19 
Table 1–1 
Prevalence of Delusions and Hallucinations in Dementia, Alzheimer's 
Disease, Parkinson's Disease, and Lewy Body Dementia ............................... 29 
Table 1–2 
NPI-NH Psychosis Score Percent Responder Analysis – Full Analysis Set 
– Week 6 (Day 43) ........................................................................................... 32 
Table 6–1 
Safety Laboratory Evaluations ......................................................................... 56 
 
List of Figures 
Figure S–1 
Schematic of Study Design for ACP-103-045 ................................................. 16 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Term 
Definition 
AC-279 
N-desmethyl-pimavanserin, major metabolite of pimavanserin 
AD 
Alzheimer’s disease 
AE 
adverse event 
bvFTD 
behavioral variant FTD 
CGI-I 
Clinical Global Impression-Improvement 
CGI-S 
Clinical Global Impression-Severity 
CNS 
central nervous system 
CT 
computed tomography 
DLB 
dementia with Lewy bodies 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition  
DSMB 
Data and Safety Monitoring Board 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOT 
end-of-treatment 
ESRS-A 
Extrapyramidal Symptom Rating Scale A 
ET 
early termination 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FTD 
frontotemporal dementia 
GCAS 
Global Clinician Assessment of Suicidality 
GCP 
Good Clinical Practice 
IAC 
independent adjudication committee 
ICH 
International Council for Harmonisation  
IRB 
institutional review board 
IRT 
interactive response technology 
ITT 
Intent-to-treat 
KSS 
Karolinska Sleepiness Scale 
LAR 
legally acceptable representative 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model repeated measures 
MMSE 
Mini-Mental State Examination 
MRI 
magnetic resonance imaging 
NIA-AA 
National Institute on Aging-Alzheimer’s Association 
NINDS 
National Institute of Neurological Disorders and Stroke 


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Term 
Definition 
NPI-NH 
Neuropsychiatric Inventory-Nursing Home Version 
PDD 
Parkinson’s disease dementia 
PDP 
Parkinson’s disease psychosis 
PK 
pharmacokinetic(s) 
PK/PD 
pharmacokinetic/pharmacodynamic 
PP 
Per-protocol 
QD 
once daily 
SAE 
serious adverse event 
SAPS 
Scale for the Assessment of Positive Symptoms 
SAPS-H+D 
SAPS Hallucinations and Delusions subscales 
SAS® 
Statistical Analysis System 
SUSAR 
suspected unexpected serious adverse reactions 
TEAE 
treatment emergent adverse event 
VaD 
vascular dementia 
VASCOG 
International Society for Vascular Behavioral and Cognitive 
Disorders 
ZBI 
Zarit Burden Interview 


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1 INTRODUCTION 
This document is a research protocol and the described study will be conducted in 
compliance with the protocol and International Council for Harmonisation (ICH) Good 
Clinical Practice Guideline (GCP). All key personnel (all individuals responsible for the 
design and conduct of this study) have completed or will complete human subjects protection 
training. 
1.1 
Background Information 
Dementia is a syndrome with core symptoms, most notably a decline in cognitive function, 
but with a variety of other manifestations that are rarely confined to one subtype. Alzheimer’s 
disease (AD) is the most common and well-known cause of dementia. Most studies of 
dementia-related psychosis focus on AD. However the various subtypes of dementia have 
more features in common than they have distinguishing them. The current study allows 
enrollment of subjects with psychosis associated with the most common subtypes of 
dementia: AD, vascular dementia (VaD), Parkinson’s disease dementia (PDD), dementia with 
Lewy bodies (DLB), and the frontotemporal dementia (FTD)-spectrum disorders (including 
behavioral variant FTD [bvFTD], progressive supranuclear palsy [PSP], and corticobasal 
degeneration [CBD]). These subtypes of dementia overlap greatly in 1) their clinical 
presentation and nosology and in 2) their pathological findings on autopsy 
(Brenowitz et al. 2017). 
Psychosis is common in dementia. It is typical of DLB, very common in AD (Table 1–1) and 
occurs, although to a lesser degree, in VaD and the FTD-spectrum disorders. It is also a 
frequent complication of PDD. The psychosis in most dementias is typically dominated by 
visual hallucinations, with delusions often consisting of the reactions or rationalizations that 
follow. However delusions do occur as distinct phenomena, often taking the form of 
misinterpretations of real or imaginary objects, delusions of infidelity or abandonment, or 
beliefs such as thinking that spouses or relatives are duplicates of the original person. Among 
AD patients, delusions are more common than hallucinations (Fischer et al. 2016; 
Ballard et al. 1995) while hallucinations are more common in patients with DLB and PDD. 
Patients with psychosis who had a clinical diagnosis of AD are often found on autopsy to 
have Lewy bodies or vascular lesions in addition to amyloidopathy (Fischer et al. 2016; 
Kim et al. 2017). Thus, the premortem diagnosis of dementia subtype may be less important 
when treating psychosis in dementia than the confirmation that the psychotic symptoms are 
associated with dementia and not with another psychiatric or medical illness such as 
schizophrenia or delirium. 


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Table 1–1 
Prevalence of Delusions and Hallucinations in Dementia, Alzheimer's 
Disease, Parkinson's Disease, and Lewy Body Dementia 
Dementia—prevalence 
Delusions 
60% 
Hallucinations 
20% 
Alzheimer's Disease—prevalence 
Delusions 
36% 
Hallucinations 
18% 
Parkinson's Disease—prevalence 
Hallucinations 
42% 
 
Visual hallucinations 
15.8%-50% 
Delusions 
21% 
Dementia with Lewy Bodies—prevalence 
Hallucinations 
13%-92% 
Paranoid delusions 
25%-28.6% 
Source: Adapted from Jellinger 2012 
 
Dementia-related psychosis differs substantially from schizophrenia, mania with psychotic 
features, major depressive disorder with psychotic features, and other major mental illnesses. 
Jeste and Finkel (2000) laid out the ways in which the psychosis of AD is a different 
syndrome than the psychosis of schizophrenia in elderly patients. The same comparison can 
be made between dementia-related psychosis in general and psychosis in schizophrenia. 
Because of these differences, the assessment of psychosis in dementia is focused on a narrow 
set of symptoms (e.g., hallucinations and delusions) distinct from schizophrenia 
(Jeste and Finkel 2000; Cohen-Mansfield and Golander 2011). There is evidence that 
psychotic features in AD, DLB, and PDD are associated with polymorphisms in the 
serotonergic pathway genes, in particular the 5HTTLPR polymorphism in SLA6A4, which 
codes for the serotonin transporter (Sweet et al. 2001; Quaranta et al. 2009; 
DeMichele-Sweet and Sweet 2010; Creese et al. 2014). 
Treatment of dementia-related psychosis represents an area of high unmet need. Clinical 
experience and clinical trial data with atypical antipsychotics have consistently shown 
treatment effects across the spectrum of all neurodegenerative dementias (Devanand et al. 
2012 supplementary material; DeDeyn et al. 1999; Devanand et al. 1998; Katz et al. 1999; 
Street et al. 2000). However, the CATIE-AD study concluded that the adverse effects of 
risperidone, olanzapine, and quetiapine offset their advantages in efficacy. Although the 
atypical antipsychotic drugs were more effective than placebo, adverse effects limited their 
overall effectiveness. The authors stated that use of these agents may be restricted to patients 
who have few or no side effects and for whom benefits can be discerned (Schneider et al. 2006). 


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1.2 
Investigational Product 
Pimavanserin is an atypical antipsychotic that is present in the investigational product as 
pimavanserin tartrate salt with the chemical name, urea, N-[(4-fluorophenyl)methyl]-N-(1-
methyl-4-piperidinyl)-N’-[[4-(2-methylpropoxy)phenyl]methyl]-,(2R,3R)-2,3-
dihydroxybutanedioate (2:1). In April 2016, pimavanserin was approved in the United States 
(US) for the treatment of hallucinations and delusions associated with Parkinson’s disease 
psychosis (PDP). 
Pimavanserin is a novel small molecule designed to specifically block serotoninergic 
neurotransmission mediated by the 5-hydroxytryptamine (5-HT [serotonin]) 2A (5-HT2A) 
receptor. At higher doses pimavanserin may block 5HT2C receptors (Vanover et al. 2006). 
Pimavanserin shows no appreciable activity at dopaminergic, adrenergic, histaminergic, or 
muscarinic receptors. Activity at these receptors has been implicated in a range of dose-
limiting side effects associated with existing antipsychotic drugs including cognitive dulling 
(Saeedi et al. 2006; Mehta et al. 2004; Peretti et al. 1997) and an increased risk of mortality in 
elderly patients with dementia (Wang et al. 2005). On the basis of its novel receptor binding 
profile, pimavanserin may be effective in treating hallucinations and delusions associated 
with dementia-related psychosis and may have added benefits with regard to overall 
tolerability relative to other antipsychotic agents. 
In this study, subjects will be asked to take pimavanserin tablets once daily as an oral 
formulation. 
1.3 
Previous Clinical Experience 
Pimavanserin is an atypical antipsychotic that is approved for the treatment of hallucinations 
and delusions associated with PDP. Studies have also been conducted in Alzheimer’s disease 
psychosis (ADP) and schizophrenia. The PDP program and Phase 2 ADP study are reviewed 
below. A more complete discussion of these studies, as well as the schizophrenia program, is 
available in the pimavanserin Investigator’s brochure. 
1.3.1 
Parkinson’s Disease Psychosis Program 
The scope of the development program for pimavanserin is the largest ever conducted in 
PDP. At the time of approval, 616 mostly older, late-stage PDP subjects had been evaluated in 
16 countries over a span of >10 years. Clinically meaningful efficacy was established in 
Study ACP-103-020, a 6-week, placebo-controlled Phase 3 study (Cummings et al. 2014). 
This efficacy was supported by data from additional short-term Phase 2b/3 studies. In 
ACP-103-020, pimavanserin 34 mg consistently demonstrated statistically significant 
efficacy across multiple and independent endpoints, subject subgroups, and sensitivity 
analyses. Improvements in sleep and daytime wakefulness were also observed. These clinical 


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benefits were achieved without worsening of Parkinson’s disease motor symptoms and 
without a number of other safety concerns associated with atypical antipsychotics. 
Pimavanserin is considered to be generally safe and well tolerated. Across all clinical studies 
of pimavanserin, the most frequently reported treatment-emergent adverse events (TEAEs) 
were in the central nervous system (CNS), gastrointestinal, and psychiatric systems. Most 
events were mild to moderate in intensity. The most common CNS TEAEs included dizziness 
(including postural), headache, and somnolence (drowsiness). Common gastrointestinal 
disturbances included dyspepsia, nausea, constipation, and vomiting. Severe nausea and 
vomiting were dose limiting in a few cases. Reported psychiatric conditions included 
agitation, insomnia, and confusional state. 
Clinical and nonclinical safety pharmacology studies of pimavanserin suggest a potential risk 
for QT prolongation. The magnitude of effect in humans has been assessed in a thorough QT 
study with doses of pimavanserin ranging from 17 to 68 mg. In the Phase 3 PDP program, an 
average prolongation of approximately 5 to 8 ms was observed with pimavanserin 34 mg. 
The US package insert for pimavanserin has a boxed warning that elderly patients with 
dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. 
Pimavanserin is not approved in the treatment of patients with dementia-related psychosis 
unrelated to the hallucinations and delusions associated with Parkinson’s disease psychosis. 
Additional information is provided in the pimavanserin Investigator’s brochure and in the 
NUPLAZID® (pimavanserin) US package insert. 
1.3.2 
Alzheimer’s Disease Psychosis 
Evidence from the recently completed Phase 2 study (ACP-103-019) suggests that 
pimavanserin is effective in reducing hallucinations and delusions in subjects with ADP 
(Ballard et al. 2018). 
Study ACP-103-019 was a Phase 2, 12-week randomized, double-blind, placebo-controlled, 
single-center study to assess the safety and efficacy of pimavanserin 34 mg once daily in 
nursing home subjects with ADP. Eligible subjects were required to have a score of 4 or 
greater on either the hallucinations or delusions scale of the Neuropsychiatric Inventory-
Nursing Home Version (NPI-NH) or a combined hallucinations and delusions score of 6 or 
greater. The primary efficacy endpoint was change from Baseline to Day 43 in the NPI-NH 
psychosis score (delusions+hallucinations domains). 
A total of 181 subjects were randomized (n=90 pimavanserin 34 mg and n=91 placebo) with 
178 subjects included in the full analysis set (FAS; n=87 pimavanserin and n=91 placebo). 
The mean (standard error [SE]) age of subjects was 85.9 (0.49) years. The mean (SE) 
Baseline NPI-NH psychosis score for all FAS subjects was 9.8 (0.39) with comparable mean 


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scores in the pimavanserin (9.5) and placebo (10.0) groups. The mean (SE) Mini-mental State 
Examination (MMSE) score for all FAS subjects was 10.1 (0.40). 
Efficacy results for the primary endpoint (NPI-NH psychosis score after 6 weeks of treatment 
(Day 43) demonstrated a significant (p=0.0451) treatment effect for pimavanserin compared 
with placebo. Prespecified subgroup analyses for the primary endpoint at Week 6 confirmed 
the observation of efficacy with the enhancement of the efficacy signal and effect size 
observed in the overall population. Similarly, prespecified responder analyses showed 
significant increases in responder rates at Week 6 in the pimavanserin treatment group 
compared to placebo. On the endpoint of mean change in NPI-NH psychosis score at 
Week 12, pimavanserin generally maintained the achieved improvement on psychosis 
observed at the Week 6 primary endpoint, but the statistical difference from placebo was not 
maintained due to apparent improvement in the placebo group between Weeks 6 and 12. 
NPI-NH psychosis score responder analyses also demonstrate the significant and clinically 
relevant treatment effect of pimavanserin 34 mg compared with placebo in subjects with 
ADP. Furthermore, defining responder as either a 30% or greater improvement or a 50% or 
greater improvement from Baseline NPI-NH psychosis score showed a significantly greater 
proportion of responders in the pimavanserin group (Table 1–2). 
Table 1–2 
NPI-NH Psychosis Score Percent Responder Analysis – Full Analysis Set – 
Week 6 (Day 43) 
 
Percent Improvement from Baseline 
Treatment Group 
(% Responder) 
≥20% 
≥30% 
≥50% 
≥75% 
100% 
 
Pimavanserin 34 mg 
58.6% 
55.2% 
50.6% 
27.6% 
12.6% 
 
Placebo 
46.2% 
37.4% 
34.1% 
16.5% 
9.9% 
p-value for test of group difference 
0.0937 
0.0159 
0.0240 
0.0656 
0.5514 
Source: ACP-103-019 Clinical Study Report 
Note: Missing values were imputed as non-response 
 
With respect to safety, pimavanserin appeared to be well-tolerated with no new safety 
observations in this elderly and frail patient population compared to the pimavanserin PDP 
safety database. An equal number of post-randomization deaths were reported: 4 deaths in the 
pimavanserin group and 4 in the placebo group. 
There were more SAEs reported in pimavanserin group (16.7%) than in the placebo group 
(11.0%). A review of individual SAEs revealed a similar distribution of Medical Dictionary 
for Regulatory Activities (MedDRA) preferred terms between the two treatment groups with 
no clusters or common underlying mechanisms identified. However, there were fewer 


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discontinuations due to AEs in the pimavanserin group (8.9%) compared with the placebo 
group (12.1%). 
The most frequently reported AEs in the pimavanserin group were fall (23.3%), urinary tract 
infection (22.2%), and agitation (21.1%). Agitation was reported more often in the 
pimavanserin group than in the placebo group. 
The mean change from baseline in the QTc interval in subjects treated with pimavanserin was 
9.4 ms at 12 weeks (Day 85) with no significant outliers reported at Day 85 (>500 ms or delta 
≥60 ms). One subject in the pimavanserin group and one subject in the placebo group had a 
delta ≥60 ms at Day 15. Each subject continued in the study. 
Weight data was available for about half of the study participants at Day 85. Mean body 
weight and body mass index (BMI) remained relatively unchanged from Baseline to Day 85 
in both treatment groups. Overall, 1 (1.8%) subject in the placebo group and 7 (14.6%) 
subjects in the pimavanserin group experienced weight decrease of ≥7% and 5 (8.8%) 
subjects in the placebo group and 4 (8.5%) subjects in the pimavanserin group experienced 
weight increase of ≥7%. 
Changes from baseline in MMSE were similar in placebo and pimavanserin group indicating 
that pimavanserin did not affect cognitive function in these patients. Similarly, treatment with 
pimavanserin had no negative effect on motor function as measured by UPDRS Part III 
scores. 
1.4 
Study Rationale 
As discussed above, dementia-related psychosis is an area of high unmet need. Psychosis is a 
common occurrence in the disease evolution of patients with dementia. The reported 
prevalence of psychotic symptoms in patients with dementia ranges from ~20% to 90%. In 
spite of the significant medical need, currently there is no pharmacologic treatment approved 
for dementia-related psychosis. Atypical antipsychotics are frequently used to treat this 
disorder despite significant safety concerns about their use in this population. 
Psychotic symptoms found in the various subtypes of dementia are similar to each other and 
quite different from the psychotic symptoms of major mental illnesses such as schizophrenia. 
The clinical management of dementia-related psychosis does not differ among subtypes of 
dementia. The subtypes of dementia themselves overlap both clinically and pathologically. 
Most patients with dementia receive their diagnosis without further specification of dementia 
subtype. 
Clinical data presented above show pimavanserin to be effective in the acute treatment of 
hallucinations and delusions in subjects with PDP. Positive Phase 2 data in an acute treatment 


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setting in subjects with ADP are also described above. The purpose of this study is to evaluate 
relapse prevention in a broad group of subjects with dementia-related psychosis. 
The relapse prevention design of this study maximizes the duration of exposure to a 
potentially effective treatment and minimizes the duration of exposure to ineffective 
treatment (Temple and Ellenberg 2000; US FDA 2012a). Enrichment is a powerful design to 
demonstrate a drug’s effectiveness using clinical trial data. Furthermore, it is an efficient 
design to determine whether a new drug is safe and effective for its intended use in a 
population with serious illness that lacks good treatment alternatives. 
The advantages of the relapse prevention design stem from the fact that all subjects will 
receive open-label pimavanserin treatment upon entering the study and that there will be 
specific criteria for randomization based on an individual’s response to flexible-dose, open-
label treatment. Subjects who do not respond positively to pimavanserin treatment during the 
open-label period will be withdrawn from the study. Subjects who respond positively (are 
stabilized according to predefined criteria) will be randomized in a double-blind fashion to 
receive either pimavanserin or placebo. During this double-blind period, subjects who meet 
protocol-defined criteria for relapse will be immediately withdrawn from study drug and 
enter the safety follow-up period of the study. Subjects who continue to benefit from 
treatment may continue treatment for the duration of the double-blind period (26 weeks). 


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2 STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objective 
The primary objective of this study is to evaluate relapse prevention in subjects with 
dementia-related psychosis treated with pimavanserin compared to placebo. 
2.1.1 
Primary Endpoint 
The primary endpoint for this study will be time from randomization to relapse in the double-
blind period. 
2.2 
Key Secondary Objective 
The key secondary objective of this study is to evaluate the time to discontinuation of the 
study for any reason in subjects with dementia-related psychosis treated with pimavanserin 
compared to placebo. 
2.2.1 
Key Secondary Endpoint 
The key secondary endpoint for this study will be time from randomization to discontinuation 
from the double-blind period for any reason. 
2.3 
Exploratory Objectives 
The exploratory objectives are to evaluate the benefit of pimavanserin compared to placebo 
in the following domains in subjects with dementia-related psychosis who have been 
stabilized on pimavanserin therapy: 
 symptoms of hallucinations and delusions 
 clinical global impressions 
 caregiver burden 
 daytime sleepiness 
 quality of life 
2.3.1 
Exploratory Endpoints 
The exploratory endpoints for this study are as follows: 
 Change from double-blind Baseline on the following: 
o Scale for the Assessment of Positive Symptoms-Hallucinations+Delusions 
(SAPS-H+D) score 
o SAPS Hallucinations domain score 
o SAPS Delusions domain score 
o Clinical Global Impression-Severity (CGI-S)-dementia-related psychosis 
o Zarit Burden Interview (ZBI) score 


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o Karolinska Sleepiness Scale (KSS) score 
o EQ-5D-5L score 
o Clinical Global Impression-Improvement (CGI-I)-dementia-related psychosis 
2.4 
Safety Objective 
The safety objective for this study is to evaluate the safety and tolerability of pimavanserin 
compared to placebo in subjects with dementia-related psychosis who have been stabilized on 
pimavanserin therapy. 
2.4.1 
Safety Endpoints 
The safety endpoints for this study are as follows: 
 Treatment-emergent adverse events (TEAEs) 
 Serious adverse events (SAEs) 
 Withdrawals due to adverse events (AEs) 
 Potentially clinically important changes in other safety assessments 
 Global Clinician Assessment of Suicidality (GCAS) score 
 Mini-Mental State Examination (MMSE) score 
 Extrapyramidal Symptom Rating Scale A (ESRS-A) score 
2.5 
Pharmacokinetic Objectives 
The pharmacokinetic (PK) objectives for this study are as follows: 
 To characterize the PK of pimavanserin in subjects with dementia-related psychosis 
 To assess the pharmacokinetic/pharmacodynamic (PK/PD) relationship using safety and 
efficacy endpoints in subjects with dementia-related psychosis 
2.5.1 
Pharmacokinetic Endpoints 
The PK endpoints for this study are as follows: 
 Plasma concentration of pimavanserin and AC-279 
 Pimavanserin PK parameters using a population PK approach 
 PK/PD using appropriate PK/PD analysis methods 
3 STUDY DESCRIPTION 
3.1 
Overview of Study Design 
This is a Phase 3, prospective, double-blind, placebo-controlled, multicenter, relapse 
prevention study in subjects with dementia-related psychosis. Approximately 95 study sites 
will participate in this study. 


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The duration of participation for individual study subjects will be up to 47 weeks, consisting 
of a screening period of up to 5 weeks; an open-label period of 12 weeks; a double-blind 
period of up to 26 weeks; and an approximately 4-week safety follow-up period.  
The study discontinuation date is defined as the day on which the Sponsor notifies sites that 
the study is ending (for example, in the event of a positive interim analysis or after 75 
adjudicated relapse events). The study completion date is defined as the day on which the last 
subject completes the last scheduled assessment (i.e., safety follow-up). A study schematic is 
provided in Figure S–1. 
3.2 
Screening Period (3-35 Days) 
During the screening period, subjects will be assessed for study eligibility and prohibited 
medications will be discontinued when medically appropriate. Subjects and 
partner/caregivers will also receive a standardized psychosocial therapy training. 
Investigators should not withdraw a subject’s prohibited medication for the purpose of 
enrolling them into the study. Medications should be discontinued only if it is deemed 
clinically appropriate to do so. 
3.3 
Open-label Period (12 Weeks) 
During the open-label period, eligible subjects will begin receiving pimavanserin 34 mg once 
daily (QD) beginning at Week 0 (open-label Baseline). Subsequent clinic visits will occur at 
Weeks 2, 4, 8, and 12. Dose adjustments are permitted at scheduled or unscheduled visits 
until Week 4. After Week 4, the subject’s dose will remain fixed at either 34 mg or 20 mg 
once daily. 
To enter the double-blind period, eligible subjects must meet the following response criteria 
at Weeks 8 and 12: 
 Subject experiences a ≥30% reduction (improvement) from Week 0 (open-label Baseline) 
on the SAPS-H+D Total Score AND 
 Subject has a CGI-I score of 1 (very much improved) or 2 (much improved), relative to 
Week 0 (open-label Baseline) 
A subject who does not meet response criteria at Weeks 8 and 12 will be withdrawn from 
study drug and enter the safety follow-up period of the study. 
Pharmacokinetic samples will be collected at Weeks 0, 8, and 12. Pharmacokinetic samples 
will also be collected, if possible, at any ET visit or the visit immediately following any SAE 
or following an AE leading to discontinuation. 


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3.4 
Double-blind Period (up to 26 Weeks) 
Randomization will occur at the double-blind Baseline visit (Week 12). Subjects will be 
randomly assigned 1:1 to continue their pimavanserin dose (34 mg or 20 mg) or matching 
placebo. 
The protocol-defined relapse criteria for dementia-related psychosis are designed to identify 
subjects with an impending relapse or relapse of psychosis: 
 Subject experiences a ≥30% increase (worsening) from Week 12 (double-blind Baseline) 
on the SAPS-H+D Total Score AND has a CGI-I score of 6 (much worse) or 7 (very 
much worse), relative to the double-blind Baseline1; OR 
 Subject is treated with an antipsychotic (other than pimavanserin) for dementia-related 
delusions and/or hallucinations; OR 
 Subject stops study drug or withdraws from study for lack of efficacy, (as reported by the 
subject or study partner/caregiver) or the Investigator discontinues study drug due to lack 
of efficacy; OR 
 Subject is hospitalized for worsening dementia-related psychosis 
Relapse criteria will be assessed weekly for the first 2 weeks after randomization (Weeks 13 
and 14), every 2 weeks until Week 26, and every 4 weeks through Week 38. Relapse criteria 
may also be evaluated at unscheduled visits. Any subject who meets any of the relapse 
criteria after randomization will be withdrawn from study drug and enter the safety follow-up 
period of the study. 
All subjects who discontinue the study between randomization and Week 38 should complete 
an ET visit, if possible, and an independent adjudication committee (IAC) will review those 
cases that occurred before the study discontinuation date to determine if protocol-defined 
relapse criteria were met.  
Pharmacokinetic samples will be collected at Weeks 13, 22, and 38/EOT. Pharmacokinetic 
samples will also be collected, if possible, at any ET visit or the visit immediately following 
any SAE or following an AE leading to discontinuation. 
3.5 
Safety Follow-up Period (Approximately 4 Weeks) 
Approximately 4 weeks after the last dose of study drug, subjects will have a safety 
follow-up telephone call visit. 
                                                 
1 For subjects with a Week 12 (double-blind baseline) SAPS H+D total score of “0”, any increase in the 
SAPS H+D total score at any visit after Week 12 will satisfy the criteria for a >30% increase (worsening). 


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The Sponsor will provide investigative sites with 3 months of after-study assistance to 
transition subjects to standard of care therapy after their participation in the study. 
4 SUBJECT ELIGIBILITY AND WITHDRAWAL CRITERIA 
4.1 
Subject Selection and Withdrawal 
To be eligible for this study, subjects must meet all of the inclusion criteria and none of the 
exclusion criteria at Visit 1 (Screening), unless specified otherwise. Subject eligibility criteria 
will be verified prior to Visit 2 (open-label Baseline). This study will randomize up to 
approximately 178 subjects with dementia-related psychosis who meet response criteria 
(Section 3.3). 
In order to participate in the optional pharmacogenomics component of the study, subjects 
must sign a separate pharmacogenomics informed consent form (ICF), indicating their 
willingness to have their DNA sample stored for future use. Refusal to consent for this 
component does not exclude a subject from participation in the clinical study. 
Protocol waivers for eligibility will not be granted by the Sponsor under any circumstances. 
If, during the course of a subject’s post-enrollment participation in the study, it is discovered 
that the subject did not meet all eligibility criteria, she or he will be discontinued, unless the 
discontinuation presents an unacceptable medical risk. The justification to allow the subject 
to continue in the study will be made by the Sponsor, with medical input from the 
Investigator, and will be documented. If allowed to remain in the trial, this will be reported as 
a major protocol deviation and not a waiver. 
Subjects who screen fail will be allowed to rescreen with the permission of the Medical 
Monitor, provided the screen failure was due to a temporary condition that subsequently 
resolved. 
4.2 
Inclusion Criteria 
A subject must meet all of the following inclusion criteria to be eligible for participation in 
the study: 
1. Is a male or female ≥50 and ≤90 years of age 
2. Can understand the nature of the trial and protocol requirements and provide written 
informed consent 
If the subject is deemed not competent to provide informed consent, the following 
requirements for consent must be met: 
a. The subject’s legally acceptable representative (LAR) (or study 
partner/caregiver, if local regulations allow) must provide written informed 
consent 


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b. The subject must provide written (if capable) informed assent 
3. Meets criteria for All-cause Dementia according to NIA-AA guidelines (Appendix A) 
4. Meets clinical criteria for one of the following disorders, with or without 
cerebrovascular disease (CVD): 
a. Dementia associated with Parkinson’s disease (Appendix B) 
b. Dementia with Lewy bodies (Appendix C) 
c. Possible or probable Alzheimer’s disease (Appendix A) 
d. Frontotemporal degeneration spectrum disorders, including possible or 
probable: 
i 
Behavioral variant frontotemporal dementia (Appendix D) 
ii Progressive supranuclear palsy (Appendix E) 
iii Corticobasal degeneration (Appendix F) 
e. Vascular dementia, including post-stroke dementia, multi-infarct dementia 
and/or subcortical ischemic vascular dementia (SIVD) (Appendix G) 
5. Has an MMSE score ≥6 and ≤24 
6. Has sufficient verbal and written ability to understand and answer questions and 
comply with procedures, with corrective measures such as hearing aids and reading 
glasses if necessary, and is willing and able to participate in all scheduled evaluations 
and complete all required tests 
7. Has had psychotic symptoms for at least 2 months 
8. Has all of the following scores at Visit 1 (Screening) and Visit 2 (open-label 
Baseline): 
a. SAPS-H+D total score ≥10; AND 
b. CGI-S ≥4 (moderately ill); AND 
c. SAPS-H+D global item (H7 or D13) score ≥4 (marked) 
9. Has lived at the current place of residence for at least 3 weeks prior to Visit 1 
(Screening) and there are no plans to move to a different location 
10. Has a designated study partner/caregiver who meets the following requirements: 
a. In the Investigator’s opinion, is in contact with the subject frequently enough 
to accurately report on the subject’s symptoms and whether or not the subject 
is taking the study drug 
b. Is fluent in the local language in which study assessments will be administered 


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c. Agrees to participate in study assessments and provides written consent to 
participate in the study 
11. Can come to the clinic for study visits with a study partner/caregiver 
12. Has an MRI or CT scan of the brain (completed within past 3 years) taken during or 
subsequent to the onset of dementia. If not available, a non-contrast brain MRI or 
non-contrast head CT must be done during screening. 
13. If the subject is taking a cholinesterase inhibitor, memantine, or both: 
a. the dose of the medication(s) must be stable for at least 12 weeks prior to Visit 
2 (open-label Baseline) and there must be no current plan to change the dose; 
OR 
b. if the medication(s) was discontinued, the discontinuation must occur no fewer 
than 2 weeks prior to Visit 2 (open-label Baseline) 
14. If the subject is taking an antipsychotic medication at the time of screening, the 
antipsychotic must be discontinued 2 weeks or 5 half-lives (whichever is longer) prior 
to Visit 2. Investigators should not withdraw a subject’s prohibited medication for the 
purpose of enrolling them into the study unless discontinuation of the medication is 
deemed to be clinically appropriate (e.g., symptoms are not well-controlled or the 
subject cannot tolerate the current medication). 
15. If the subject is female, she must not be pregnant or breastfeeding. She must also be 
of non-childbearing potential (defined as either surgically sterilized or at least 1 year 
postmenopausal) or must agree to use a clinically acceptable method of contraception 
or be abstinent for at least 1 month prior to Visit 2 (open-label Baseline), during the 
study, and 1 month following completion of the study. Acceptable methods of birth 
control include the following:  
a. Condom, diaphragm, or cervical cap with spermicide 
b. Hormonal contraception, including oral, injectable, transdermal, or 
implantable methods 
c. Intrauterine device (IUD) 
4.3 
Exclusion Criteria 
1. Is in hospice or end-of-life care 
2. Is confined to bed (subjects who can attend clinic visits using a wheelchair or other 
ambulatory assistive device are permitted) 


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3. Requires skilled nursing care (procedures that can only be administered by a 
registered nurse or doctor, such as but not limited to, intravenous administration of 
medication, procedures related to insertion or care of suprapubic catheters, and 
nasopharyngeal/tracheostomy aspiration) 
4. Has psychotic symptoms that are primarily attributable to delirium, substance abuse, 
or a medical or psychiatric condition (e.g., schizophrenia, bipolar disorder, delusional 
disorder) other than dementia 
5. Has a current major depressive episode (within 3 months of Screening), according to 
the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (DSM-5) 
criteria 
6. Has a Global Clinician Assessment of Suicidality (GCAS) score of 3 or 4 based on 
Investigator’s assessment of behavior within 3 months prior to Visit 1 (Screening) or 
since-last-visit at Visit 2 (open-label Baseline) 
7. Has evidence of a non-neurologic medical comorbidity or medication use that could 
substantially impair cognition 
8. Has a history of ischemic stroke within the last 12 months or any evidence of 
hemorrhagic stroke 
9. Has a known history of cerebral amyloid angiopathy (CAA), epilepsy, CNS 
neoplasm, or unexplained syncope 
10. Has atrial fibrillation unless adequately anticoagulated therapy 
11. Has any of the following: 
a. greater than New York Heart Association (NYHA) Class 2 congestive heart 
failure (Appendix J) 
b. Grade 2 or greater angina pectoris (by Canadian Cardiovascular Society 
[CCS] Angina Grading Scale) (Appendix K) 
c. sustained ventricular tachycardia 
d. ventricular fibrillation 
e. torsade de pointes 
f. syncope due to an arrhythmia 
g. an implantable cardiac defibrillator 
12. Had a myocardial infarction within the 6 months prior to Visit 1 (Screening) 
13. Has a known personal or family history or symptoms of long QT syndrome 
14. Has any of the following ECG results at Visit 1 (Screening) or Visit 2 (open-label 
Baseline): 


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a. If the subject is not on citalopram, escitalopram, or venlafaxine: 
i 
QTcF >450 ms, if QRS duration <120 ms 
ii QTcF >470 ms, if QRS duration ≥120 ms 
b. If the subject is on citalopram, escitalopram, or venlafaxine: 
i 
QTcF >425 ms, if QRS duration is <120 ms 
ii QTcF >450 ms, if QRS duration ≥120 ms 
If the mean QTcF value from the set of ECGs done at Screening is prolonged due to 
an identifiable cause, and it is medically appropriate to address that cause, a repeat set 
of triplicate ECGs may be performed during Screening at the discretion of the 
Medical Monitor.  
15. Has a heart rate <50 beats per minute. If bradycardia is secondary to iatrogenic or 
treatable causes and these causes are addressed, a heart rate assessment can be 
repeated during the screening period. 
16. Has a significant unstable medical condition that could interfere with subject’s ability 
to complete the study or comply with study procedures 
17. Has severe renal impairment, severe or medically significant impairment of hepatic 
function, and/or a clinically significant laboratory abnormality that in the judgment of 
the Investigator or Medical Monitor will interfere with the conduct or interpretation of 
safety or efficacy evaluations in the study 
18. Has one of the following screening laboratory results: 
a. Platelets ≤75,000/mm3 
b. Hemoglobin ≤9.5 g/dL if male, or ≤8.5 g/dL if female 
c. Neutrophils, absolute ≤1000/mm3 
d. Aspartate aminotransferase (AST) >2×upper limit of normal 
e. Alanine aminotransferase (ALT) >2×upper limit of normal 
f. Creatinine ≥2 mg/dL 
g. Hemoglobin A1c (HbA1c) ≥8.5% 
h. Abnormal free thyroxine (T4) 
i. Vitamin B12 deficiency 
Laboratory testing may be repeated during Screening at the discretion of the Medical 
Monitor. 
19. Has a history of a positive test result for HIV or hepatitis C 


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20. Has a clinically significant CNS abnormality that is most likely contributing to the 
dementia or findings on MRI or CT including: 
a. intracranial mass lesion (including but not limited to meningioma [>1 cm3 
with evidence of peritumoral edema] or glioma) 
b. vascular malformation  
c. intracranial aneurysm >4 points by PHASES score (Appendix L) 
d. evidence of >4 hemosiderin deposits (definite microhemorrhage or superficial 
siderosis) 
21. Requires treatment with a medication or other substance that is prohibited by the 
protocol 
22. Has a body mass index (BMI) <18.5 kg/m2 or known unintentional weight loss ≥7% 
of body weight over past 6 months 
23. The urine drug screen result at Visit 1 (Screening) indicates the presence of 
amphetamine/methamphetamine, barbiturates, cocaine, or phencyclidine (PCP). 
Subjects who test positive for amphetamines or barbituates may be retested during 
Screening if they agree to abstain from the medication for the length of their 
participation in the study and if abstinence from medication usage is achieved at least 
7 days prior to Visit 2 (open-label Baseline). The repeat Screening test must be 
negative for them to participate in the study. The presence of benzodiazepines, 
marijuana (THC), or opiates may not exclude the subject from the study. 
24. Has participated in or is participating in a clinical trial of any investigational drug, 
device, or intervention, within 30 days or 5 half-lives, whichever is longer, of Visit 1 
(Screening) OR has participated in a clinical trial for disease-modifying therapy 
within 6 months of Visit 1 
25. Has previously been enrolled in any prior clinical study with pimavanserin or is 
currently taking pimavanserin 
26. Has a significant sensitivity or allergic reaction to pimavanserin or its excipients 
27. Is an employee or is a family member of an employee of ACADIA Pharmaceuticals Inc. 
28. Is judged by the Investigator or the Medical Monitor to be inappropriate for the study 
for any reason 
4.4 
Subject Withdrawal or Termination 
In accordance with the Declaration of Helsinki and other applicable regulations, a subject has 
the right to withdraw from the study at any time, and for any reason, without prejudice to his 
or her future medical care. 


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Subjects may be discontinued or withdrawn from the study for a number of reasons, 
including, but not limited to, those listed below: 
 Relapse of hallucinations and delusions associated with dementia-related psychosis 
 Adverse event 
 Death 
 Lost to follow-up 
 Non-compliance with study drug 
 Use of prohibited medications 
 Physician decision 
 Pregnancy 
 Protocol violation 
 Study terminated by Sponsor 
 Subject withdraws consent 
 Other 
When a subject is found to be appropriate for discontinuation from the trial, the visit during 
which this is determined should immediately be converted to an ET visit (as described in 
Table S–2) and all procedures and assessments listed in the schedule of events for the ET visit 
(Week 38/EOT; Visit 17/ET) should be completed. Safety follow-up should be completed as 
scheduled. 
For subjects who discontinue from the trial between visits, every reasonable effort should be 
made to complete Visit 17/early termination (ET) and the safety follow-up period. 
If a subject is lost to follow-up, every reasonable effort should be made to phone the subject 
approximately 4 weeks after last known contact with the subject in order to assess the 
subject’s current status. All phone contact with the subject should be documented. 
For subjects who continue to be followed for safety, SAEs should continue to be reported as 
described in Section 7.4.2. 
If a subject is discontinued from the study because of an AE, every reasonable attempt should 
be made to follow the subject until the AE resolves or until the Investigator deems the AE to 
be chronic or stable. 
All SAEs will continue to be followed until such events have resolved or the Investigator 
deems them to be chronic or stable. 


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Should a subject request or decide to withdraw, every reasonable effort will be made to 
complete and report observations as thoroughly as possible up to the date of withdrawal, 
including the evaluations specified at the ET visit outlined in Table S–2. Unless the subject 
has withdrawn consent to be contacted for this study, every reasonable effort will be made to 
complete the 4-week safety follow-up telephone call for all subjects who withdraw 
prematurely. All information will be reported on the applicable pages of the electronic case 
report form (eCRF). 
The Sponsor reserves the right to discontinue the study at any time for any reason. Such 
reasons may be any of, but not limited to, the following: 
 Occurrence of AEs unknown to date in respect of their nature, severity, and duration or 
the unexpected incidence of known AEs 
 Medical or ethical reasons affecting the continued performance of the study 
Regulatory Authorities also have the right to terminate the conduct of the study in their region 
for any reason. 
4.5 
Prior and Concomitant Therapy 
Lifetime antipsychotic use and response is to be recorded. All other medications used up to 
24 weeks prior to Visit 2 through Visit 18 (telephone visit) or ET are to be recorded. 
In order to ensure that appropriate concomitant therapy is administered, it is essential that 
subjects be instructed not to take any medication without prior consultation with the 
Investigator (unless the subject is receiving treatment for a medical emergency). 
4.5.1 
Permitted, Restricted, and Prohibited Medications 
Prohibitions and restrictions for concomitant medications, as specified in Appendix H and 
Appendix I, should be followed between Visit 1 (Screening) and Visit 17/ET. Medications 
that can prolong QT interval are prohibited (or restricted if approved by the Medical Monitor 
or appropriate designee) as specified in Appendix H. These appendices do not constitute an 
exhaustive list and any questions regarding prohibited and restricted medications or the use of 
medications that could interfere with study conduct should be discussed with the Medical 
Monitor or appropriate designee. 
If a subject is on a restricted or prohibited medication at screening, the medication should be 
adjusted or discontinued only if it is determined by the Investigator to be clinically 
appropriate (e.g., if the subject's symptoms are not well-controlled or if the subject cannot 
tolerate the current medication). 


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The Investigator may prescribe, adjust, or discontinue appropriate medication to treat or 
manage AEs. Subjects who require current treatment with a prohibited medication will be 
withdrawn from the study. 
Subjects who are discovered to have previously taken a prohibited medication during the 
study will be withdrawn from the study unless:  
• the prohibited medication has been discontinued AND  
• withdrawal from the study presents an unacceptable medical risk to the subject  
The justification to allow the subject to remain in the study will be made by the 
Sponsor/Medical Monitor, with medical input from the Investigator, and will be documented. 
If the subject is allowed to remain in the study, this will be reported as a major protocol 
deviation and not a waiver. 
5 INVESTIGATIONAL PRODUCT 
5.1 
Investigational Product Description 
The investigational product will be pimavanserin 34 mg (provided as 2×17 mg tablets), 
pimavanserin 20 mg (provided as 2×10 mg tablets), and matching placebo (2×placebo 
tablets). Placebo tablets will be size- and color-matched to the pimavanserin tablets 
corresponding to the subject’s dose level at the end of the open-label period. Tablets will be 
administered orally as a single dose once daily (QD). 
5.1.1 
Formulation, Appearance, Packaging, and Labeling 
The Sponsor will supply pimavanserin 17 mg and 10 mg tablets and matching placebo 
tablets. 
Pimavanserin tartrate is a white to off-white powder. Pimavanserin tablets include the active 
compound (pimavanserin) 
 
 
. The 
drug product is formulated with standard pharmaceutical excipients at 17 mg strength (20 mg 
of pimavanserin tartrate) and 10 mg strength (11.8 mg of pimavanserin tartrate). 
Pimavanserin treatment consists of 2 tablets once daily for oral administration. 
Placebo tablets contain all of the same excipients as pimavanserin 17 mg and 10 mg tablets 
but do not contain any pimavanserin. 
Pimavanserin and placebo tablets are manufactured under current Good Manufacturing 
Practice compliance. 


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During the treatment period, study drug will be supplied in treatment kits with blister cards 
containing 20 tablets (10 days of treatment) each. Kits will be distributed in a quantity 
sufficient to ensure the subject has an adequate supply of study drug between study visits. 
5.1.2 
Product Storage and Stability 
Investigational product must be stored at 15°C to 30°C (59°F to 86°F) (see US 
Pharmacopeial Controlled Room Temperature) in a secure area with restricted access and 
according to local and national regulations. 
5.1.3 
Dosing and Administration 
The first dose of study drug will be administered at the clinic; study drug kits will then be 
dispensed to the subject to take home. Each daily dose consists of 2 individual tablets that 
should be taken together. Subjects should be instructed to take 2 whole tablets, orally, once 
each day. Subjects should be instructed to not crush the tablets. The tablets may be taken with 
or without food. 
5.1.4 
Dose Adjustments/Modifications/Delays 
The first dose of open-label pimavanserin 34 mg will be taken at the beginning of the open-
label period (Week 0 [Visit 2]). Pimavanserin will continue daily at this dose level for at least 
the first week of treatment. After the first week, if the subject is unable to tolerate the 34 mg 
dose, the dose may be decreased to 20 mg at any study visit (scheduled or unscheduled) until 
Week 4 (Visit 4). If the dose is decreased to 20 mg it may later be increased to 34 mg based 
on investigator judgment at any study visit (scheduled or unscheduled) until Week 4 (Visit 4). 
After Week 4 (Visit 4), the dose of study drug will remain fixed at either 34 mg or 20 mg 
once daily. 
When the dose is adjusted, subjects should be instructed to return all treatment kits, blister 
cards, and unused tablets from the previous dose level before the next dose level is dispensed. 
Dose adjustments will be recorded in the interactive response technology (IRT) system. 
5.1.5 
Method of Assigning Subjects to Treatment Groups 
At Week 12 (Visit 6), subjects who meet response criteria (Section 3.3) will be randomized in 
a 1:1 ratio to either continue receiving pimavanserin at the current dose level or to receive 
matched placebo. 
5.1.6 
Blinding 
All subjects will receive open-label pimavanserin (34 mg or 20 mg) during the open-label 
period of the study. 
Treatment assignment during the double-blind period will be double-blind such that neither 
the subjects, study partners/caregivers, Sponsor personnel who oversee the study, nor the 


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Investigator and study personnel will know which treatment is assigned to each subject. 
Details regarding medical emergency unblinding procedures are provided in Section 9.6.1. 
5.1.7 
Study Drug Compliance 
If a subject misses 1 dose of study drug, he or she should not take an extra dose the next day. 
5.1.8 
Overdose 
An overdose is a deliberate or inadvertent administration of a treatment at a dose higher than 
specified in the protocol. It must be reported, irrespective of outcome even if toxic effects 
were not observed. All events of overdose are to be captured on the overdose form 
(Section 7.4.4) as protocol deviations. 
5.2 
Investigational Product Accountability Procedures 
The Investigator or designee will keep current and accurate records of the study drug product 
dispensed, used, and returned for each subject to assure the health authority and the Sponsor 
that the study drug is being handled appropriately. Subjects should be instructed to return all 
treatment kits, blister cards, and unused tablets to the Investigator at regularly scheduled 
clinic visits (except Visit 7), any unscheduled visit where a dose change occurs, and any ET 
visits. At Visit 7 (Week 13), the amount of study drug product used since Visit 6 (Week 12) 
will be recorded but no study drug should be returned to the Investigator and no new 
treatment kits will be dispensed to the subject. 
At appropriate intervals during the study, study drug reconciliation will be performed by the 
Sponsor representative who may return appropriate unused study drug and used and unused 
packaging to the Sponsor’s designee for destruction. 
At the conclusion of the study, final study drug reconciliation will be conducted at the site. 
Final study drug accountability documentation will be maintained at both the site and at 
ACADIA. Any remaining unused study drug and all used and unused packaging will be sent 
back to the Sponsor’s designee for destruction, as allowed by country specific regulations. 
Documentation of study drug destruction will be recorded and maintained by both the 
Sponsor and the Sponsor’s designee. 
The Investigator or designee is responsible for taking an inventory of each shipment of study 
drug received and comparing it with the accompanying material shipping form. The 
Investigator or designee will verify the accuracy of the information on the form, sign and date 
it, and provide a copy of it to the Sponsor or designee. Any study drug supplied is for use in 
this study only and should not be used for any other purpose. 


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6 STUDY PROCEDURES 
Study-specific procedures are detailed below. All assessments will be completed according to 
the schedule described in Table S–1 for screening and the open-label period and as described 
in Table S–2 for the double-blind period. Every reasonable effort should be made to complete 
the required procedures and evaluations at the designated visits and times. 
6.1 
Screening Assessments 
6.1.1 
Mini-Mental State Examination 
The MMSE is a brief 30-point questionnaire that is used to quantitatively assess cognition 
(Folstein et al. 1975). The MMSE includes simple questions and problems in a number of 
areas: the time and place of testing, repeating lists of words, arithmetic, language use and 
comprehension, and copying a drawing. The MMSE is being used in this study to screen for 
cognitive impairment and as a safety measure. 
6.1.2 
Medical History and Demographics 
A complete medical history will be obtained from each potential subject, including details of 
the subject’s psychiatric history and treatment (including prior use of and response to 
antipsychotic medication), details of the subject’s dementia diagnosis and treatment 
(including date of onset of cognitive impairment), and details of any neurologic diagnosis and 
treatment. 
Subjects may be asked to provide pharmacy or medical records to substantiate the medication 
history (Section 4.5). 
Demographic information, including date of birth, sex, race, and ethnicity will be recorded as well 
(as allowed by local regulations). Any new medical condition reported after the ICF has been 
signed will be captured as an AE. 
6.1.3 
Brain Imaging 
A non-contrast brain MRI or non-contrast head CT will be completed if the subject has not 
had a CT or MRI scan completed (a) within the past 3 years AND (b) during or subsequent to 
the onset of dementia. If the Investigator believes a brain MRI with contrast or a head CT 
with contrast is clinically warranted, such a study may be done. The purpose of the scan is to 
evaluate criteria excluding a clinically significant CNS abnormality (Section 4). 
6.1.4 
Psychosocial Therapy – Non-pharmacologic Intervention Prior to 
Randomization 
During the screening period, the designated study partner/caregiver will receive instruction 
for engaging in a structured psychosocial interaction with the subject. This psychological 
intervention is intended to aid the subject and caregiver in managing the subject’s 


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neuropsychiatric symptoms. Study partners/caregivers will be instructed on the therapy by 
trained site personnel and will have weekly supportive telephone contacts. It is recommended 
to conduct the intervention at a frequency of 5 times per week (minimum of 3 times per 
week) for the duration of the screening period. 
6.2 
Efficacy Assessments 
6.2.1 
Scale for the Assessment of Positive Symptoms – Hallucinations and Delusions 
The SAPS (Andreasen 1984) was designed to measure positive psychotic symptoms. Positive 
symptoms include hallucinations, delusions, abnormalities in language and behavior, and 
disordered thought processes. The SAPS Hallucinations and Delusions subscales (SAPS-H+D) 
will be administered in this study. The Hallucinations and Delusions subscales consist of 
20 items, including global ratings of severity both of hallucinations (H7) and of delusions 
(D13), respectively. 
All efforts should be made to complete each visit in a single day. In the event of a split visit, the 
CGI-S/CGI-I and the SAPS H+D must be completed on the same day. 
6.2.2 
Clinical Global Impression – Severity and Clinical Global Impression –
Improvement Scales 
The CGI-S scale is a clinician-rated, 7-point scale that is designed to rate the severity of the 
subject’s hallucinations and delusions at the time of assessment using the Investigator’s 
judgment and past experience with subjects who have the same disorder (i.e., dementia-
related psychosis) (Guy 1976). 
The CGI-I is a clinician-rated, 7-point scale that is designed to rate the improvement in the 
subject’s hallucinations and delusions at the time of assessment, relative to the symptoms at 
Baseline (relative to open-label Baseline for response criteria and relative to double-blind 
Baseline for relapse criteria). 
All efforts should be made to complete each visit in a single day. In the event of a split visit, the 
CGI-S/CGI-I and the SAPS H+D must be completed on the same day. 
6.2.3 
Zarit Burden Interview 
The Zarit Burden Interview (ZBI) was designed to assess the stress experienced by caregivers 
of patients with dementia (Zarit et al. 1980). The ZBI will be administered as an interview. 
The interview consists of 22 statements reflecting how people sometimes feel when taking 
care of another person. The statements are phrased as questions for the family member study 
partner/caregiver to indicate how often they feel the way described in the statement. 
Responses are Never, Rarely, Sometimes, Quite Frequently, and Nearly Always. When the 
study partner/caregiver is not a family member, this scale will not be completed. 


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6.2.4 
Karolinska Sleepiness Scale 
The Karolinska Sleepiness Scale (KSS) is a 9-item, self-reported subjective measure of a 
subject’s level of drowsiness (Åkerstedt and Gillberg 1990). Respondents must choose the 
statement that most accurately describes their level of sleepiness over the past few minutes. 
6.2.5 
EQ-5D-5L 
The EQ-5D-5L is a standardized instrument used as a measure of health outcome 
(Kind 1996). It measures 5 dimensions (mobility, self-care, usual activities, pain/discomfort, 
anxiety/depression) each of which has 5 potential responses. The responses record 5 levels of 
severity (no problems/slight problems/moderate problems/severe problems/extreme 
problems) within a particular EQ-5D dimension. The EQ-5D-5L Proxy version 1 will be 
used. For this version, a study partner/caregiver (the proxy) is asked to rate subject's health-
related quality of life in their (the proxy’s) opinion. 
6.3 
Safety Assessments 
6.3.1 
Physical and Neurological Examinations 
A general physical examination will be conducted. The physical exam procedures will 
include the following organ systems: 
 Head, ears, eyes, nose, and throat 
 Skin 
 Cardiovascular 
 Respiratory 
 Abdomen 
 Genitourinary (optional) 
 Musculoskeletal 
 Lymph nodes 
In addition, a neurological exam (cranial nerves, motor, sensory, reflexes, gait, and 
coordination) will be conducted. 
6.3.2 
Vital Signs 
Vital signs will include body temperature, resting respiration rate, sitting systolic and 
diastolic blood pressure, and pulse rate. The resting blood pressure should be measured after 
the subject has been sitting or supine for ≥5 minutes. 
6.3.3 
Height, Weight and Body Mass Index 
Height will be recorded in centimeters or in inches. 
Weight will be recorded in kilograms or in pounds. 


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Body mass index (BMI) will be calculated using the following formula: 
Weight (kg) / [height (m)]2. 
6.3.4 
Electrocardiograms 
All 12-lead electrocardiograms (ECGs) will be complete, standardized recordings. The 
subject must rest in a supine position before the ECG is obtained. ECG tracings (paper or 
electronic) will be reviewed and interpreted by a qualified clinician. All ECGs will be 
centrally read; the interpretation by the central cardiologist is considered the official 
interpretation. ECG tracings and results (ventricular rate, PR, QRS, QT, QTcF and QTcB 
intervals) will be included and summarized in the subject's study records.  
The ECG will be completed in triplicate at Visit 1 (Screening) and as a single tracing at all 
other visits. The following conditions apply: 
 If a site performs additional ECGs beyond the set of triplicate ECGs prescribed at 
Screening or the single ECG prescribed at Baseline, the mean QTcF/QRS values of all the 
tracings of adequate quality will be used to determine eligibility. 
 If the mean QTcF value from the set of ECGs done at Screening is  prolonged  due to an 
identifiable cause, and it is medically appropriate to address that cause, a repeat set of 
triplicate ECGs may be performed during Screening at the discretion of the Medical 
Monitor. In this case, the repeat set of triplicate ECGs will be used in determination of 
subject eligibility. 
 At Baseline, a subject may be enrolled based on the machine read of the locally 
completed ECG. If the interpretation of the ECG by the central cardiologist indicates 
QTcF outside of the allowable range, the subject will be discontinued from the study, but 
enrollment of the subject will not be considered a protocol deviation. 
6.3.5 
Global Clinician Assessment of Suicidality 
The GCAS is a clinician-rated, 5-point scale that is designed to rate the subject’s suicidality 
based on the report of the subject, the report of the study partner/caregiver, and the clinician’s 
global assessment. Ratings can be 0 (“Absent”), 1 (“Feels life is not worth living”), 
2 (“Wishes he/she were dead or any thoughts of possible death to self”), 3 (“Suicidal ideas or 
gesture”), or 4 (“Attempt at suicide”). The Investigator will record a subject rating, a study 
partner/caregiver rating, and a clinician rating. At Visit 1 (Screening) lifetime suicidality and 
suicidality for the past 3 months will be assessed and at all other visits, suicidality since the 
previous visit will be assessed. 
6.3.6 
Extrapyramidal Symptom Rating Scale 
The ESRS (Chouinard and Margolese 2005) was developed to assess drug induced 
movement disorders such as Parkinsonism, akathisia, dystonia and tardive dyskinesia with 


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established reliability, validity and sensitivity. It has demonstrated excellent inter-rater 
reliability in idiopathic Parkinson’s disease (Chouinard et al. 1984). It consists of a 
questionnaire of Parkinsonian symptoms, physician examination of Parkinsonism, dyskinetic 
movements and global impression of tardive dyskinesia. The ESRS-A, an accepted modified 
form of the original ESRS, will be used during treatment to monitor for any worsening in 
extrapyramidal symptoms or signs at scheduled visits. 
6.3.7 
Laboratory Evaluations 
The laboratory evaluations will include, but are not limited to, the following: 
 Clinical chemistry serum tests 
o Sodium (Na), potassium (K), chloride (Cl), phosphorus (P), calcium (Ca), carbon 
dioxide (CO2), blood urea nitrogen (BUN), creatinine (CR), uric acid 
o Alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-
glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), total bilirubin 
(TBIL), lactate dehydrogenase (LDH) 
o Magnesium (Mg) 
 Mg should only be performed at Visit 1 (Screening) 
o Vitamin B12 
 Vitamin B12 should only be performed at Visit 1 (Screening) 
o HbA1c 
 HbA1c should only be performed at Visit 1 (Screening), Visit 6, and 
Visit 17/ET 
o Glucose 
o Albumin (ALB), total protein 
o Prolactin 
o Thyroid stimulating hormone (TSH) and free T4 
 TSH should be performed only at Visit 1 (Screening) 
 Free T4 will be measured only if the TSH is abnormal 
o Lipid Panel 
 Pregnancy test 
o A serum pregnancy test should only be performed at Visit 1 (Table 6–1) for 
women of childbearing potential 
o A urine pregnancy test should be performed at all designated visits after Visit 1 
(Table 6-1) for women of childbearing potential 


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 If urine cannot be obtained in women of childbearing potential, a serum 
pregnancy test should be done 
 Hematology tests 
o Complete blood count (CBC) including: 
 White blood cell (WBC) count 
 Complete differential (relative and absolute) 
 Hematocrit (Hct), hemoglobin, red blood cells (RBC), platelets 
 Reticulocyte count 
 Urinalysis 
o Color, clarity, blood, RBCs, WBCs, protein, glucose, ketones, specific gravity, 
pH, leukocyte esterase, nitrite, microscopic analysis 
o Reasonable efforts should be made to collect a urine sample from all subjects. 
Where collection of a urine sample proves impractical or impossible (e.g., because 
the subject is incontinent), failure to collect a urine sample should be recorded in 
the subject’s CRF, and will not be considered a protocol deviation. 
 Urine toxicity screen 
o Reasonable efforts should be made to collect a urine sample at all other scheduled 
visits as described in ‘Urinalysis’ above 
o In cases of positive drug screens, the Medical Monitor may request confirmatory 
testing of the sample  
o Subjects who test positive for amphetamines or barbituates may be retested during 
Screening if they agree to abstain from the medication for the length of their 
participation in the study and if abstinence from medication usage is achieved at 
least 7 days prior to Visit 2 (open-label Baseline). The repeat Screening test must 
be negative for them to participate in the study. 
o Subjects who test positive for benzodiazepines, THC, or opiates may continue in 
the study and last usage should be noted at visit. In addition, restrictions listed in 
Appendix H should be followed. 
Laboratory evaluations will be completed according to the schedule presented in Table 6–1 
and procedures detailed in the study Manual of Procedures. Additional safety testing may be 
performed at the discretion of the Investigator or designee. 


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Table 6–1 
Safety Laboratory Evaluations 
Visit 
Testsa,b 
Visit 1 (Screening) 
CHEM, CBC, UA, urine toxicity screen, and serum pregnancy test 
Visit 2 (Week 0) 
CHEM, CBC, UA, urine toxicity screen, and urine pregnancy test 
Visit 6 (Week 12) 
CHEM, CBC, UA, urine toxicity screen, and urine pregnancy test 
Visit 10 (Week 18) 
CHEM, CBC, and UA 
Visit 14 (Week 26) 
CHEM, CBC, UA, and urine pregnancy test 
Visit 17/ET (Week 38) 
CHEM, CBC, UA, and urine pregnancy test 
Abbreviations: CBC=complete blood count; CHEM=clinical chemistry serum tests; UA=urinalysis 
a 
A pregnancy test is only required for women of childbearing potential. If urine cannot be obtained in 
women of childbearing potential, a serum pregnancy test should be done. 
b 
Mg, TSH, and vitamin B12 tests are only required at Visit 1 (Screening) and an HbA1c test is only required 
at Visit 1 (Screening), Visit 6, and Visit 17/ET. 
 
6.3.8 
Safety Follow-up 
A 4-week safety follow-up telephone contact is to be completed for all subjects. Subjects will 
have the following completed via telephone approximately 4 weeks after the last dose of 
study drug: 
 Assessment of concomitant medications/treatments 
 Assessment of AEs 
6.4 
Pharmacokinetic Assessments 
Pharmacokinetic samples will be collected for measurement of concentrations of 
pimavanserin and its metabolite AC-279. 
When possible, an additional PK sample will be collected from subjects who experience any 
SAE or experience an AE leading to discontinuation as soon as possible after the occurrence 
of that event. 
For all PK samples (scheduled and unscheduled) the date and time of the last 3 doses of study 
drug, as well as the date and time of the sample draw, should be recorded. For samples 
collected from subjects who experience any SAE or experience an AE leading to 
discontinuation, the date and time of the last dose of study drug prior to the SAE or AE 
should also be recorded. 


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6.4.1 
Pharmacogenomic Assessment 
A single blood draw will be performed for subjects who have signed a separate 
pharmacogenomics consent form indicating their willingness to have their DNA sample 
stored for possible future genetic research related to pimavanserin or the indication(s) for 
which it is developed (where local regulations permit). Stored DNA samples and relevant 
clinical data will be made non-identifiable after the clinical study report has been issued. 
Personal identifiers will be removed and each study subject identifier will be replaced with a 
new number to limit the possibility of linking genetic data to a subject’s identity. 
The pharmacogenomic assessment is an optional component of the study requiring a separate 
informed consent, which may be obtained at any time during the study. The 
pharmacogenomic sample may be collected at any time following informed consent for the 
pharmacogenomic component of the study. 
6.4.2 
Specimen Preparation, Handling, Storage, and Shipment 
Investigators, subjects, and Sponsor personnel will remain blinded to pimavanserin plasma 
concentration data from the double-blind period until the unblinding of the clinical database 
at the end of the study. 
6.5 
Unscheduled Visits 
Unscheduled visits may occur as determined by the Investigator. The following safety 
assessments generally should be recorded at each unscheduled visit: assessment of AEs, 
assessment of concomitant medications/treatments, and measurement of vital signs. The 
Investigator may perform any additional safety evaluations deemed by the Investigator to be 
clinically indicated. Relapse criteria may also be evaluated at unscheduled visits. 
7 ADVERSE EVENTS 
7.1 
Specification of Safety Parameters 
7.1.1 
Definition of Adverse Event 
An AE is defined as “any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related” (US FDA 2012b). 
An AE can therefore be any unfavorable and unintended sign (e.g., an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a drug, without any 
judgment about causality or seriousness. An AE can arise from any use of the drug 
(e.g., off-label use, use in combination with another drug) and from any route of 
administration, formulation, or dose, including an overdose. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
drug caused the AE. 


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AEs do not include the following: 
 Stable or intermittent chronic conditions (such as myopia requiring eyeglasses) that are 
present prior to Baseline and do not worsen during the study 
 Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion). 
The condition that leads to the procedure is an AE if not present at the open-label 
Baseline. 
 Overdose of either study drug (see Section 7.4.4) or concomitant medication without any 
signs or symptoms unless the subject is hospitalized for observation 
 Hospitalization for elective surgery planned prior to study (situation where an untoward 
medical occurrence has not occurred) 
 Pregnancy will not be considered an AE, but if it occurs, it will be reported on a 
pregnancy form 
 
Adverse events will be recorded from the time informed consent is obtained through 30 days 
after the last dose of study drug. 
All AEs must be either resolved or stable at end of study. If ongoing at the end of the study 
the subject should be referred for appropriate treatment. 
Serious AEs occurring after the safety follow-up period should be reported if in the judgment 
of the Investigator, there is “a reasonable possibility” that the event may have been caused by 
the study drug. 
7.1.2 
Definition of Serious Adverse Event 
In addition to the severity rating, each AE will be classified by the Investigator as “serious” 
or “not serious.” The seriousness of an event will be defined according to the applicable 
regulations and generally refers to the outcome of an event. An SAE is one that meets one or 
more of the following: 
 Is fatal 
 Is immediately life threatening 
 Results in disability or permanent damage 
 Requires hospitalization 
 Prolongs existing hospitalization 
 Is a congenital anomaly or birth defect (in an offspring) 
 Is medically significant 


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Definition of Life Threatening 
A life threatening event places the subject at immediate risk of death from the event as it 
occurred. This does not include an AE that might have had an outcome of death had it 
occurred in a more severe form. 
Definition of Hospitalization 
Hospitalization is defined as a full admission to the hospital for diagnosis and treatment. This 
includes prolongation of an existing inpatient hospitalization.  
Examples of visits to a hospital facility that do not meet the serious criteria for hospitalization 
include: 
 Emergency room visits (that do not result in a full hospital admission) 
 Outpatient surgery 
 Preplanned or elective procedures 
 Protocol procedures 
 Social hospitalization, defined as admission to the hospital as a result of inadequate 
family support or care at the subject’s primary residence 
 
Definition of Disability or Permanent Damage 
Disability is defined as a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions. 
Definition of Medically Significant 
Important medical events (medically significant events) that may not result in death, be life 
threatening, or require hospitalization may be considered to be an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject or may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. Examples of 
such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalization or 
development of drug dependency or drug abuse. 
An SAE may also include any other event that the Investigator or Medical Monitor judges to 
be serious or that suggests a significant hazard, contraindication, side effect, or precaution. 


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7.2 
Classification of an Adverse Event 
7.2.1 
Severity of Event 
The severity of each AE will be graded on a 3-point scale and reported in detail as indicated 
on the eCRF: 
 Mild: awareness of sign or symptom but easily tolerated, causing minimal discomfort, 
and not interfering with normal everyday activities 
 Moderate: sufficiently discomforting to interfere with normal everyday activities 
 Severe: incapacitating and/or preventing normal everyday activities 
7.2.2 
Relationship to Study Drug 
The causality of each AE should be assessed and classified by the Investigator as “related” or 
“not related.” An event is considered related if there is a reasonable possibility that the event 
may have been caused by the study drug under investigation (i.e., there are facts, evidence, or 
arguments to suggest possible causation). 
Consider the following when assessing causality: 
 Temporal associations between the agent and the event 
 Response to cessation (de-challenge) or re-challenge 
 Compatibility with known class effect 
 Known effects of concomitant medications 
 Pre-existing risk factors 
 A plausible mechanism 
 Concurrent illnesses 
7.2.2.1 
Duration 
The start and stop dates for AEs will be recorded using the following criteria: 
 Start: Date of the first episode of the AE or date of significant sustained worsening in 
severity 
 Stop: Date when AE either ceased permanently or changed in severity 
7.2.2.2 
Frequency 
The frequency of the AE should be indicated according to the following definitions: 
 Single: Experienced once, without recurrence 
 Recurrent: More than one discrete episode with the same severity 


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7.2.2.3 
Action Taken with Study Drug 
 Dose reduced: Study drug reduced 
 Dose increased: Study drug increased 
 Dose not changed: No change in study drug 
 Drug interrupted: Study drug temporarily stopped 
 Drug withdrawn: Study drug discontinued permanently 
 
7.2.2.4 
Therapy 
 None: No new treatment instituted 
 Medication: New treatment initiated as a direct result of AE 
 Other: Other action required 
 
7.2.2.5 
Outcome 
 Recovered/resolved: Recovered or resolved 
 Recovered/resolved with sequelae: Recovered or resolved with sequelae 
 Not recovered/not resolved: Not recovered or not resolved 
 Fatal: Death related to AE 
 Unknown: Unknown 
 
7.2.2.6 
Seriousness 
 Not serious 
 Serious 
 
7.2.3 
Definition of Unexpectedness 
An AE, the nature or severity of which is not consistent with the information provided in the 
Reference Safety Information section of the current Pimavanserin Investigator’s Brochure. 
7.3 
Time Period and Frequency for Event Assessment and Follow-up 
In the event that a subject is withdrawn from the study because of an AE, the subject should 
be followed and treated by the Investigator until the AE has resolved, stabilized, or a new 
chronic baseline has been established. 


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7.4 
Reporting Procedures 
7.4.1 
Adverse Event Reporting 
The Investigator must record all observed AEs and all reported AEs. At each visit, the 
Investigator should ask the subject a nonspecific question (e.g., “Have you noticed anything 
different since your last visit?”) to assess whether any AEs have been experienced since the 
last report or visit. 
Note that any use of medication (and specifically any newly prescribed medication) during 
the course of a study may indicate the occurrence of an AE that may need to be recorded on 
both the AE and the concomitant medication page. 
All AEs will be coded by Data Management using MedDRA. 
All AEs, serious and not serious, will be recorded on the AE eCRF page using appropriate 
medical terminology. Severity and relationship to study drug will be assessed by the 
Investigator as described above. 
When possible, clinical AEs should be described by diagnosis and not by symptoms (e.g., 
“cold” or “seasonal allergies” instead of “runny nose”). 
All AEs, whether or not related to the study drug, must be fully and completely documented 
on the AE eCRF and in the subject’s notes. 
7.4.2 
Serious Adverse Event Reporting 
The reporting of SAEs by ACADIA to the Regulatory Authorities is a regulatory requirement. 
Each Regulatory Authority has established a timetable for reporting SAEs based upon 
established criteria. 
Serious AEs and other reportable information must be reported within 24 hours of discovery 
to ACADIA or its designee. The SAE (initial and/or follow-up), pregnancy (Section 7.4.3), or 
overdose (Section 7.4.4) of study drug must be reported within 24 hours by completing the 
SAE, pregnancy, or overdose forms, as appropriate (details on how to report SAEs are 
provided in a separate study reference manual). 
At a minimum, events identified by ACADIA to require expedited reporting as serious, 
unexpected, and related to study drug must be brought to the attention of the responsible 
institutional review board (IRB)/ethics committee (EC). For European Union member states, 
ACADIA or its designee will provide reports of suspected unexpected serious adverse 
reactions (SUSARs) directly to the ECs, as required by local legislation. In all other 
countries, it is the Investigator’s responsibility to provide these expedited reports to the 
responsible IRB/EC. It is also the Investigator’s responsibility to notify the responsible 
IRB/EC regarding any new and significant safety information. 


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For this study, sites will complete the paper overdose, SAE, and/or pregnancy form (for 
initial and/or follow-up information), including available supporting documentation relevant 
to the event and send (within 24 hours of discovery) to the contact numbers and/or email 
designated on the SAE form provided to the sites. 
Subjects will be followed until Visit 17/ET for any SAEs and/or other reportable information 
or until such events have resolved or the Investigator, in conjunction with ACADIA, deems 
them to be chronic or stable. 
In the event of any SAE (other than death), the study subject will be instructed to contact the 
Investigator (or designee) using the telephone number provided in the ICF. All subjects 
experiencing an SAE will be seen by the Investigator or designee as soon as is feasible 
following the report of the SAE. 
SAEs should also be reported to the IRB/EC according to local regulations. 
7.4.3 
Reporting of Pregnancy 
Any female subject who becomes pregnant during the study (with or without AEs) must be 
withdrawn from the study and the pregnancy must be reported on the pregnancy form. Any 
female subject who becomes pregnant during the study will be followed through the first 
well-baby visit. 
Any AEs that are the consequence of pregnancy and which meet the criteria for serious 
should also be reported via the SAE form. 
7.4.4 
Reporting of Overdose 
Any overdose (Section 5.1.8) must be reported within 24 hours by completing the overdose 
form. Any AEs that are associated with the event and which meet the criteria for SAEs should 
also be reported via the SAE form. 
8 CLINICAL MONITORING 
Routine monitoring of study sites is described in Section 11. 
Clinical site monitoring is conducted to ensure that the rights and well-being of human 
subjects are protected, that the reported study data are accurate, complete, and verifiable, and 
that the conduct of the study is in compliance with the currently approved protocol and 
amendment(s) as applicable, with GCP, and with applicable regulatory requirements. Details 
of the study site monitoring process are described in a separate clinical monitoring plan 
document. 


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9 STATISTICAL METHODS AND DATA ANALYSIS 
9.1 
Statistical and Analytical Plans 
Statistical methods will be documented in detail in a statistical analysis plan to be approved 
by the Sponsor prior to unblinding for the interim analysis. 
9.2 
Statistical Hypotheses 
The hypotheses for the primary endpoint are stated in terms of the hazard ratio, HR= λPIM / 
λPBO, where λPIM and λPBO denote the hazard rates of relapse for the pimavanserin treatment 
group and the placebo treatment group, respectively. 
 The null hypothesis for the primary efficacy endpoint is: HR = 1 
 The alternative hypothesis for the primary efficacy endpoint is: HR ≠ 1 
 
The hypotheses for the key secondary endpoint are stated in terms of the hazard ratio, HR= 
λPIM / λPBO, where λPIM and λPBO denote the hazard rates of discontinuation from the double-
blind period for any reason (other than termination of the study by the Sponsor) for the 
pimavanserin treatment group and the placebo treatment group, respectively. 
 The null hypothesis for the key secondary efficacy endpoint is: HR = 1 
 The alternative hypothesis for the key secondary efficacy endpoint is: HR ≠ 1 
9.3 
Sample Size Determination 
This study will enroll approximately 356 subjects in order to randomize approximately 
178 subjects with dementia-related psychosis who meet response criteria (Section 3.3). 
The sample size calculation was based on the following assumptions: a placebo relapse event 
rate of 60% over 26 weeks; a pimavanserin relapse event rate of 35% over 26 weeks (hazard 
ratio = 0.47); a dropout rate of 25% over 26 weeks; an overall two-sided alpha level of 0.05; 
use of a one-sided (0.025) O’Brien-Fleming stopping boundary to adjust for a single interim 
analysis that will be performed when one half of the total planned number of post-
randomization relapse events have occurred; and a power of 90%. The total number of post-
randomization relapse events required at the final analysis is 75 and the calculated sample 
size is 89 in each of the two treatment groups (giving a total estimate of 178 subjects). 
Study enrollment will be closed when approximately 178 subjects have been randomized in 
the double-blind period or when 75 adjudicated post-randomization relapse events have 
occurred. In the event that the randomization rate is lower than anticipated and/or the relapse 
event rate is lower than anticipated, the number enrolled and randomized may be increased 
up to a maximum of 400 randomized subjects in order to observe 75 post-randomization 
relapse events. 


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An interim efficacy analysis will be performed (Section 9.5.8), and the study may be 
terminated early if the interim analysis results meet prespecified stopping criteria. 
9.4 
Subject Populations for Analysis 
The open-label safety analysis set includes all subjects who received at least one dose of 
open-label study drug (pimavanserin). Subjects will be analyzed based on the treatment that 
they actually received. The open-label safety analysis set will be used for analyses of the 
open-label data. 
The double-blind safety analysis set includes all subjects who received at least one dose of 
double-blind study drug (pimavanserin or placebo). Subjects will be analyzed based on the 
treatment that they actually received. The double-blind safety analysis set will be used for all 
analyses of the double-blind safety data. 
The primary efficacy analysis will be based on the Intent-to-treat (ITT) population, defined as 
all randomized subjects. Subjects will be analyzed based on their randomized treatment. The 
ITT population will be used for the double-blind analysis of all efficacy endpoints. 
The per-protocol (PP) analysis set will be defined prior to unblinding the study for the final 
analysis. Subjects will be analyzed based on their randomized treatment. The PP analysis set 
will be used for sensitivity analyses of selected efficacy endpoints.  
The PK analysis set includes all subjects in the safety analysis set who have sufficient 
PK data. 
9.5 
Description of Statistical Methods 
For continuous variables, the following summary statistics will be provided: number of 
subjects, mean, standard error of the mean, standard deviation, minimum, maximum, and 
median. For categorical variables, summaries will include the number and percentage of 
subjects in each category, using the number of subjects with non-missing values as the 
denominator for the percentages (unless otherwise specified). 
Unless otherwise specified, all reported p-values will be two-sided. All analyses will be 
performed using SAS® V9.4 (SAS Institute, Inc., Cary, North Carolina) or higher. Validation 
and quality control of the tables, listings, and figures containing the results of the statistical 
analyses will follow appropriate standard operating procedures. 
9.5.1 
Primary Efficacy Analyses 
The time from randomization to relapse in the double-blind period will be compared between 
treatment groups using a Cox regression model with effects for treatment group, dementia 
subtype, and region. The nominal p-value, hazard ratio, and 95% confidence interval will be 
reported. Subjects who discontinue early or complete the study without having experienced a 


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relapse event will be censored at the time of last assessment for relapse. The primary analysis 
will be based on adjudicated relapse events (Section 9.5.7). 
A sensitivity analysis will be performed based on the Investigator assessment of relapse. 
Additional sensitivity analyses to assess the potential impact of informative censoring will be 
specified in the Statistical Analysis Plan. 
Kaplan-Meier curves of time from randomization to relapse will be presented for each 
treatment group. In addition, Kaplan-Meier estimates of the proportion of subjects who 
relapse along with pointwise 95% confidence intervals will be provided for the 26-week 
double-blind period. 
9.5.2 
Key Secondary Analyses 
The key secondary endpoint of time from randomization to discontinuation from the double-
blind period for any reason (other than termination of the study by the Sponsor) will be 
analyzed using the same Cox regression model described above for the primary endpoint 
along with the Kaplan-Meier estimates. 
9.5.3 
Exploratory Efficacy Analyses  
All exploratory efficacy endpoints will be summarized by treatment group using descriptive 
statistics. For all exploratory SAPS endpoints, CGI-S, ZBI, KSS, and EQ-5D-5L, the change 
from double-blind Baseline will be analyzed using mixed model repeated measures 
(MMRM). The independent variables in the model will include the following: treatment 
group (pimavanserin or placebo), visit, treatment by visit interaction, double-blind Baseline 
score, double-blind Baseline score by visit interaction, designated dementia subtype, and 
region. 
CGI-I will be analyzed using an MMRM model with the following independent variables: 
treatment group (pimavanserin or placebo), visit, treatment by visit interaction, double-blind 
Baseline CGI-S score, double-blind Baseline CGI-S score by visit interaction, designated 
dementia subtype, and region. 
The treatment comparisons will be based on the difference in least squares means and will be 
tested at a two-sided alpha level of 0.05. The double-blind Baseline score is defined as the 
last value prior to the first dose of double-blind study drug. 
In addition to the MMRM analyses described above, last observation carried forward (LOCF) 
analyses will also be performed. 
Descriptive summaries of efficacy endpoints, including the number and percent of subjects 
meeting response criteria, will be provided for the open-label period. 


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9.5.4 
Safety Analyses 
All safety results will be summarized using descriptive statistics. Separate summaries will be 
provided for the open-label and double-blind periods. The double-blind summaries will be 
presented by treatment group. Adverse events will be classified into standard terminology 
using MedDRA. Adverse events may also be categorized into categories of special interest. 
Treatment-emergent AEs, TEAEs leading to discontinuation, TEAEs related to study drug, 
TEAEs by maximum severity, serious TEAEs, and serious TEAEs related to study drug will 
all be summarized. Other TEAEs of special interest may also be summarized. 
Descriptive statistics for ECG, vital signs, GCAS, MMSE, ESRS-A total score and all 
subscales, and clinical laboratory parameters, including change from Baseline when 
applicable, will be tabulated by treatment group and timepoint. Additionally, categorical 
analyses will be conducted on the incidence of subjects with prolonged QTc intervals and 
changes in QTc intervals in accordance with ICH guidelines. The incidence of clinically 
significant changes in selected laboratory parameters will also be summarized. 
9.5.5 
Pharmacokinetic Analyses 
Plasma concentration data for pimavanserin and AC-279 will be listed and summarized using 
descriptive statistics. 
If data allow, population PK and PK/PD analyses will be performed to further characterize 
the PK profile and exposure response relationship of pimavanserin using measures of safety 
and efficacy parameters. The results of population PK and PK/PD modeling will be presented 
in a separate report. Investigators, subjects, and Sponsor personnel will remain blinded to 
plasma concentration data from the double-blind period until the unblinding of the clinical 
database at the end of the study. 
9.5.6 
Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) will review safety information 
on a regular basis throughout the study. The DSMB will be independent of the Sponsor and 
will be empowered to recommend stopping the study due to safety concerns. The DSMB may 
review blinded, unblinded, or partially unblinded data, but the Sponsor and the Investigators 
will remain blinded to the data provided to the DSMB until the official unblinding of the 
database at the completion of the study. The membership, activities, responsibilities, and 
frequency of meetings will be described separately in the DSMB charter. 
9.5.7 
Independent Adjudication Committee 
An IAC will be established to perform validation of protocol-defined relapse events. The 
validation is based on review of predefined clinical data related to: 1) a relapse (identified by 
the Investigator) occurring before the study discontinuation date, and 2) all early termination 


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events which occur in the double-blind period before the study discontinuation date 
(Section 3.1). 
Predefined clinical data consist of copies of source documents collected and delivered by the 
investigational sites. The IAC will review copies in English (translated if necessary) of 
medical documentation received in the adjudication packages. The Investigator must provide 
medical documentation as soon as possible after early termination. 
The IAC is composed of permanent members covering required medical specialties. IAC 
members must disclose any potential conflicts of interest and must be independent of the 
Sponsor. 
The events will be reviewed by the IAC in a blinded manner. 
Only events that have been adjudicated will be used in the primary efficacy analysis 
(Section 9.5.1) and the interim analysis (Section 9.5.8). Furthermore, only adjudicated events 
will be used to guide the decision to close enrollment in the study, which is based on the 
number of relapse events observed (Section 9.3). 
The IAC will work in accordance with written guidelines included in the IAC charter 
describing in details the composition, tasks, responsibilities and work processes of the 
committee. 
9.5.8 
Planned Interim Analyses 
An interim efficacy analysis of the primary efficacy endpoint will be performed after 
38 adjudicated relapse events have occurred. The study may be terminated early if the interim 
analysis results meet prespecified stopping criteria. For example, if there are exactly 38 
relapse events at the interim analysis, the significance level will be 0.0054. If the study is not 
stopped early and the final analysis includes exactly 75 relapse events (including the 38 
events from the interim analysis), the significance level for the final analysis will be 0.0479. 
The actual significance levels to be used at the interim and final analyses will be calculated 
based on the actual number of adjudicated events observed. The interim efficacy analysis will 
be performed by an independent statistician. Investigators, subjects, and Sponsor personnel 
will remain blinded throughout the study. 
9.5.9 
Additional Subgroup Analyses 
Selected analyses will be performed in subgroups defined by dementia subtype: 
 AD or FTD-spectrum disorders 
 VaD 
 PDD or DLB 
Subgroup analyses by region will also be provided. 


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Additional subgroup analyses may be specified in the statistical analysis plan. Subgroup 
analyses will be performed for both the open-label and double-blind periods. 
9.5.10 
Multiple Comparisons/Multiplicity 
Adjustment of the primary efficacy analysis to account for the interim efficacy analysis is 
described in Section 9.5.8. 
A hierarchical testing procedure will be used to control the overall type I error rate for the 
primary and key secondary efficacy endpoints. Hypothesis testing will occur in the following 
sequential order: 
1. Primary endpoint 
2. Key secondary endpoint 
Statistical significance for the key secondary endpoint may only be claimed if the primary 
endpoint is statistically significant. The stopping boundary to be used for the key secondary 
endpoint will be specified in the SAP. 
9.6 
Enrollment, Randomization, and Masking Procedures 
Eligible subjects will be randomized into 1 of 2 treatment groups (pimavanserin or placebo) 
in a 1:1 ratio using an interactive response technology (IRT) system. Randomization will be 
stratified by: 
1. Most likely dementia subtype or most prominent cause of dementia: 
 AD or FTD-spectrum disorders 
 VaD 
 PDD or DLB 
2. Region 
The assignments will be based on a pre-generated permuted-block randomization schedule. 
Blinding will be assured by restricting access of Investigators and Sponsor personnel and/or 
designee to the treatment codes, and providing identical tablets and packaging for the 
pimavanserin and placebo treatments. 
9.6.1 
Breaking the Study Blind/Subject Code 
For the final analysis, the treatment codes for all subjects will be released to the Sponsor after 
all subjects have completed the study and the clinical database is locked. 
For DSMB safety reviews, and for the interim efficacy analysis, the treatment codes will be 
released to an independent statistician/programmer to produce unblinded statistical outputs. 
The Sponsor and the Investigators will remain blinded. 


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Unblinding of individual treatment assignment during the study is discouraged. The 
Investigator may break the blind in the event of a medical emergency if it is considered 
necessary for the care of the subject. The Investigator should contact the study Medical 
Monitor to discuss the event, but this need not be prior to unblinding the subject. In an 
emergency situation, the subject’s treatment assignment may be obtained by the Investigator 
from the IRT system. Details of the process to be followed are provided in the IRT Manual. 
In the event that the IRT system is used to perform a code break, the Sponsor or designee will 
be notified immediately via an automated notification from the IRT system that an unblinding 
has occurred. The notification only alerts the Sponsor or designee that the unblinding 
occurred, and does not include any information about the unblinded subject’s treatment 
assignment. 
10 STUDY MANAGEMENT AND DATA COLLECTION 
10.1 Data Collection and Management Responsibilities 
All documents required for the conduct of the study as specified in the ICH GCP guidelines 
will be maintained by the Investigator in an orderly manner and made available for 
monitoring and/or auditing by the Sponsor and regulatory agencies. 
The Investigator and institution must permit authorized representatives of the Sponsor or 
designees (including monitors and auditors), Regulatory Agencies (including inspectors), and 
the IRB/EC direct access to source documents (such as original medical records). Direct 
access includes permission to examine, analyze, verify, and reproduce any records and 
reports that are needed for the evaluation of the study. The Investigator must ensure the 
reliability and availability of source documents from which the information on the eCRF was 
derived. 
10.2 Source Documents 
All study specific information obtained at each study visit must be recorded in the subject’s 
record (source documentation), and then entered into a validated electronic data capture 
database by trained site personnel. The source documentation may consist of source notes 
captured by site personnel as well as laboratory reports, ECG reports, and electronic source 
data. 
10.3 Case Report Forms 
Subject data required by this protocol are to be recorded in an electronic data capture system 
on eCRFs. The Investigator and his or her site personnel will be responsible for completing 
the eCRFs. The Investigator is responsible for the accuracy and reliability of all the 
information recorded on the eCRFs. All information requested on the eCRFs needs to be 
supplied, including subject identification data, visit date(s), assessment values, etc., and any 


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omission or discrepancy will require explanation. All information on eCRFs must be 
traceable to source documentation at the site. 
10.4 Confidentiality 
The Investigator must ensure that each subject’s anonymity is maintained. On the eCRFs or 
other documents submitted to the Sponsor or designees, subjects must be identified by a 
Subject Identification Number only. Documents that are not for submission to the Sponsor or 
designees (e.g., signed ICFs) should be kept in strict confidence by the Investigator in 
compliance with Federal regulations or other applicable laws or ICH Guidance on GCP. 
10.5 Study Records Retention 
Investigators are required to maintain all essential study documentation as per ICH GCP 
guidelines. This includes, but is not limited to, copies of signed, dated and completed eCRFs, 
documentation of eCRF corrections, signed ICFs, audio recordings, subject-related source 
documentation, and adequate records for the receipt and disposition of all study drug. 
Investigators should maintain all essential study documentation, for a period of at least 
2 years following the last approval of marketing application in an ICH region (US, Europe, 
and Japan), or until at least 2 years after the drug investigational program is discontinued, 
unless a longer period is required by applicable law or regulation. Only the Sponsor can 
notify an Investigator or vendor when any records may be discarded. Investigators should 
contact the Sponsor before destroying any files. 
10.6 Protocol Exceptions and Deviations 
No prospective entry criteria protocol deviations are allowed; all subjects must meet all 
eligibility criteria in order to participate in the study. 
Protocol waivers for eligibility and use of prohibited medication during the study 
(Section 4.5.1) will not be granted by the Sponsor under any circumstances. If, during the 
course of a subject’s post-enrollment participation in the trial it is discovered that the subject 
did not meet all eligibility criteria, he or she will be discontinued, unless the discontinuation 
presents an unacceptable medical risk. The justification to allow the subject to continue in the 
trial will be made by the Sponsor, with medical input from the Investigator, and will be 
documented. If allowed to remain in the trial, this will be reported as a major protocol 
deviation and not a waiver. All follow-up safety assessments must be completed and 
documented as outlined in the protocol (Section 6.3.8). The Investigator must report any 
protocol deviation to the Sponsor and, if required, to the IRB/EC in accordance with local 
regulations, within reasonable time. 


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10.7 Protocol Amendments 
Changes to the protocol may be made only by the Sponsor (with or without consultation with 
the Investigator). All protocol modifications must be submitted to the site IRB/EC in 
accordance with local requirements and, if required, to Regulatory Agencies, as either an 
amendment or a notification. Approval for amendments must be awaited before any changes 
can be implemented, except for changes necessary to eliminate an immediate hazard to trial 
subjects, or when the changes involve only logistical or administrative aspects of the trial. No 
approval is required for notifications. 
11 STUDY MONITORING, AUDITING, AND INSPECTING 
11.1 Quality Control and Quality Assurance 
The Sponsor or designee and Regulatory Agency inspectors are responsible for contacting 
and visiting the Investigator for the purpose of inspecting the facilities and, upon request, 
inspecting the various records of the trial (e.g., eCRFs and other pertinent data) provided that 
subject confidentiality is respected. 
The Sponsor’s or designee’s monitor is responsible for inspecting the eCRFs at regular 
intervals throughout the study to verify adherence to the protocol; completeness, accuracy, 
and consistency of the data; and adherence to local regulations on the conduct of clinical 
research. The monitor should have access to subject medical records and other study-related 
records needed to verify the entries on the eCRFs. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in 
the course of these monitoring visits are resolved. 
In accordance with ICH Guidance on GCP and the Sponsor’s audit plans, a certain 
percentage of sites participating in this study will be audited. These audits may include a 
review of site facilities (e.g., pharmacy, drug storage areas, and laboratories) and review of 
study-related records may occur in order to evaluate the trial conduct and compliance with 
the protocol, ICH Guidance on GCP, and applicable regulatory requirements. 
The Sponsor’s or designee’s representatives, Regulatory Agency inspectors, and IRB/EC 
representatives who obtain direct access to source documents should also respect subject 
confidentiality, taking all reasonable precautions in accordance with applicable regulatory 
requirements to maintain the confidentiality of subjects’ identities. 
12 ETHICAL CONSIDERATIONS 
12.1 Ethical Standard 
The study will be conducted in compliance with the protocol, the Declaration of Helsinki, 
ICH GCP, and other applicable regulatory requirements. 


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The study will be performed in accordance with Health Insurance Portability and 
Accountability Act (HIPAA) regulations, US FDA GCP Regulations (US CFR 21 parts 50, 
54, 56, and 312), and ICH Guidance on GCP (E6) and clinical safety data management 
(E2A). 
In accordance with Directive 75/318/EEC, as amended by Directive 91/507/EEC, the final 
clinical study report will be signed by an Investigator and/or Coordinating Investigator who 
will be designated prior to the writing of the clinical study report. 
12.2 Institutional Review Board/Ethics Committee 
The Investigator or designee will provide the IRB/EC with all requisite material, including a 
copy of the protocol, informed consent, and any subject information or advertising materials. 
The study will not be initiated until the IRB/EC provides written approval of the protocol and 
the informed consent and until approved documents have been obtained by the Investigator 
and copies received by the Sponsor. All amendments will be sent to the IRB/EC for 
information (minor amendment) or for submission (major amendment) before 
implementation. The Investigator will supply the IRB/EC and the Sponsor with appropriate 
reports on the progress of this study, including any necessary safety updates, in accordance 
with the applicable government regulations and in agreement with policy established by the 
Sponsor. 
12.3 Informed Consent Process 
Properly executed, written informed consent must be obtained from each subject or subject’s 
LAR prior to any screening procedures. When a subject lacks capacity to consent, and 
consent is being provided by an LAR, subject assent for participation must be documented. 
The subject’s study partner/caregiver must also provide written consent prior to any 
screening procedures. 
The informed consent must, at a minimum, include the elements of consent described in the 
ICH Guidance on GCP and the US CFR 21 Part 50.25. A copy of the ICF planned for use 
will be reviewed by the Sponsor or designee for acceptability and must be submitted by the 
Investigator or designee together with the protocol, to the appropriate IRB/EC for review and 
approval prior to the start of the study at that investigational site. Consent forms must be in a 
language fully comprehensible to the prospective subject. The Investigator must provide the 
Sponsor or designee with a copy of the IRB/EC letter approving the protocol and the ICF 
before the study drug supplies will be shipped and the study can be initiated. 
The consent form must be revised if new information becomes available during the study that 
may be relevant to the subject. Any revision must be submitted to the appropriate IRB/EC for 
review and approval in advance of use. 


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12.3.1 
Consent and Other Informational Documents Provided to Subjects 
Copies of signed forms must be given to the signatories and original forms must be 
maintained in the designated location at the site. 
12.3.2 
Consent Procedures and Documentation 
It is the Investigator or designee’s responsibility to obtain written informed consent from the 
subject or LAR after adequate explanation of the aims, methods, anticipated benefits, and 
potential hazards of the study. The subject or LAR must be given ample time to decide about 
study participation and opportunity to inquire about details of the study. The IRB/EC-
approved consent form must be personally signed and dated by the subject or LAR with 
subject assent and by the person who conducted the informed-consent discussion. The 
Investigator or appropriate site personnel must document the details of obtaining informed 
consent in the subject’s study documents. 
The subject’s study partner/caregiver must also indicate their understanding of the study and 
their role as a study partner/caregiver to the subject during the study. The subject’s study 
partner/caregiver must provide written consent prior to any Screening visit procedures being 
performed indicating their agreement to participate in the study in the study partner/caregiver 
role. 
Consent for pharmacogenomic testing is optional. Subjects (and LAR, if applicable) must 
sign a separate pharmacogenomics consent form prior to blood draws. The pharmacogenomic 
ICF may be signed at any time during the study. 
Copies of signed forms must be given to the signatories and original forms must be 
maintained in the designated location at the site. 
13 PUBLICATION PLAN 
All publication rights are delineated in the Clinical Study Agreement and/or other separate 
agreements with the Investigator and/or Institution, as applicable. 
14 CONFLICT OF INTEREST POLICY 
14.1 Finance, Insurance, and Indemnity 
Arrangements for finance, insurance and indemnity are delineated in the Clinical Study 
Agreement and/or other separate agreements with the Investigator and/or Institution, as 
applicable. 
 
 


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16 APPENDICES 
Appendix A NIA-AA Guidelines for All-cause Dementia and Alzheimer’s Disease 
All-cause Dementia 
Dementia is diagnosed when there are cognitive or behavioral (neuropsychiatric) symptoms 
that: 
1. Interfere with the ability to function at work or at usual activities; and 
2. Represent a decline from previous levels of functioning and performing; and 
3. Are not explained by delirium or major psychiatric disorder; 
4. Cognitive impairment is detected and diagnosed through a combination of (1) history-
taking from the patient and a knowledgeable informant and (2) an objective cognitive 
assessment, either a “bedside” mental status examination or neuropsychological 
testing. Neuropsychological testing should be performed when the routine history and 
bedside mental status examination cannot provide a confident diagnosis. 
5. The cognitive or behavioral impairment involves a minimum of two of the following 
domains: 
a. Impaired ability to acquire and remember new information––symptoms 
include: repetitive questions or conversations, misplacing personal belongings, 
forgetting events or appointments, getting lost on a familiar route. 
b. Impaired reasoning and handling of complex tasks, poor judgment––symptoms 
include: poor understanding of safety risks, inability to manage finances, poor 
decision-making ability, inability to plan complex or sequential activities. 
c. Impaired visuospatial abilities––symptoms include: inability to recognize faces 
or common objects or to find objects in direct view despite good acuity, 
inability to operate simple implements, or orient clothing to the body. 
d. Impaired language functions (speaking, reading, writing)––symptoms include: 
difficulty thinking of common words while speaking, hesitations; speech, 
spelling, and writing errors. 
e. Changes in personality, behavior, or comportment––symptoms include: 
uncharacteristic mood fluctuations such as agitation, impaired motivation, 
initiative, apathy, loss of drive, social withdrawal, decreased interest in 
previous activities, loss of empathy, compulsive or obsessive behaviors, 
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Probable Alzheimer’s Disease Dementia 
Meets criteria for all-cause dementia (see above) and in addition, has the following 
characteristics: 
1. Insidious onset. Symptoms have a gradual onset over months to years, not sudden over 
hours or days; 
2. Clear-cut history of worsening of cognition by report or observation; and 
3. The initial and most prominent cognitive deficits are evident on history and 
examination in one of the following categories: 
a. Amnestic presentation: It is the most common syndromic presentation of AD 
dementia. The deficits should include impairment in learning and recall of 
recently learned information. There should also be evidence of cognitive 
dysfunction in at least one other cognitive domain, as defined earlier in the 
text. 
b. Nonamnestic presentations: 
i. Language presentation: The most prominent deficits are in word-
finding, but deficits in other cognitive domains should be present. 
ii. Visuospatial presentation: The most prominent deficits are in spatial 
cognition, including object agnosia, impaired face recognition, 
simultanagnosia, and alexia. Deficits in other cognitive domains should 
be present. 
iii. Executive dysfunction: The most prominent deficits are impaired 
reasoning, judgment, and problem solving. Deficits in other cognitive 
domains should be present. 
4. The diagnosis of probable AD dementia should not be applied when there is evidence 
of  
a. substantial concomitant cerebrovascular disease, defined by a history of a 
stroke temporally related to the onset or worsening of cognitive impairment; or 
the presence of multiple or extensive infarcts or severe white matter 
hyperintensity burden; or 
b. core features of dementia with Lewy bodies other than dementia itself; or 
c. prominent features of behavioral variant frontotemporal dementia; or 
d. prominent features of semantic variant primary progressive aphasia or 
nonfluent/agrammatic variant primary progressive aphasia; or  
e. evidence for another concurrent, active neurological disease, or a non-
neurological medical comorbidity or use of medication that could have a 
substantial effect on cognition. 


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Possible Alzheimer’s Disease Dementia 
A diagnosis of possible AD dementia should be made in either of the circumstances 
mentioned in the following paragraphs. 
Atypical course 
Atypical course meets the core clinical criteria in terms of the nature of the cognitive deficits 
for AD dementia, but either has a sudden onset of cognitive impairment or demonstrates 
insufficient historical detail or objective cognitive documentation of progressive decline, 
OR 
Etiologically mixed presentation 
Etiologically mixed presentation meets all core clinical criteria for AD dementia but has 
evidence of (a) concomitant cerebrovascular disease, defined by a history of stroke temporally 
related to the onset or worsening of cognitive impairment; or the presence of multiple or 
extensive infarcts or severe white matter hyperintensity burden; or (b) features of dementia 
with Lewy bodies other than the dementia itself; or (c) evidence for another neurological 
disease or a non-neurological medical comorbidity or medication use that could have a 
substantial effect on cognition. 
Source: McKhann et al. 2011 
Abbreviations: AD=Alzheimer’s disease; NIA-AA=National Institute on Aging-Alzheimer’s Association 


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Appendix B Movement Disorder Society’s Task Force Clinical Diagnostic Criteria for 
Dementia Associated with Parkinson’s Disease 
I. 
Core features 
a. Diagnosis of Parkinson’s disease according to Queen Square Brain Bank 
criteria 
b. A dementia syndrome with insidious onset and slow progression, 
developing within the context of established Parkinson’s disease and 
diagnosed by history, clinical, and mental examination, defined as: 
o Impairment in more than one cognitive domain 
o Representing a decline from premorbid level 
o Deficits severe enough to impair daily life (social, occupational, or 
personal care), independent of the impairment ascribable to motor or 
autonomic symptoms 
II. 
Associated Clinical features 
a. Cognitive features: 
o Attention: Impaired. Impairment in spontaneous and focused attention, 
poor performance in attentional tasks; performance may fluctuate during 
the day and from day to day 
o Executive functions: Impaired. Impairment in tasks requiring initiation, 
planning, concept formation, rule finding, set shifting or set 
maintenance; impaired mental speed (bradyphrenia) 
o Visuo-spatial functions: Impaired. Impairment in tasks requiring visual-
spatial orientation, perception, or construction 
o Memory: Impaired. Impairment in free recall of recent events or in tasks 
requiring learning new material, memory usually improves with cueing, 
recognition is usually better than free recall 
o Language: Core functions largely preserved. Word finding difficulties 
and impaired comprehension of complex sentences may be present 
b. Behavioral features: 
o Apathy: decreased spontaneity; loss of motivation, interest, and effortful 
behavior 
o Changes in personality and mood including depressive features and 
anxiety 
o Hallucinations: mostly visual, usually complex, formed visions of 
people, animals or objects 
o Delusions: usually paranoid, such as infidelity, or phantom boarder 
(unwelcome guests living in the home) delusions 
o Excessive daytime sleepiness 


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III. 
Features which do not exclude PDD, but make the diagnosis uncertain 
 Coexistence of any other abnormality which may by itself cause cognitive 
impairment, but judged not to be the cause of dementia (e.g., presence of 
relevant vascular disease in imaging) 
 Time interval between the development of motor and cognitive symptoms not 
known 
IV. 
Features suggesting other conditions or diseases as cause of mental 
impairment, which, when present make it impossible to reliably diagnose 
PDD: 
 Cognitive and behavioral symptoms appearing solely in the context of other 
conditions such as: 
o Acute confusion due to 
a. Systemic diseases or abnormalities 
b. Drug intoxication 
o Major Depression according to DSM IV 
 Features compatible with “Probable Vascular dementia” criteria according to 
NINDS-AIREN (dementia in the context of cerebrovascular disease as 
indicated by focal signs in neurological exam such as hemiparesis, sensory 
deficits, and evidence of relevant cerebrovascular disease by brain imaging 
AND a relationship between the two as indicated by the presence of one or 
more of the following: onset of dementia within 3 months after a recognized 
stroke, abrupt deterioration in cognitive functions, and fluctuating, stepwise 
progression of cognitive deficits) 
Source: Emre et al. 2007 
Abbreviations: DSM=Diagnostic and Statistical Manual of Mental Disorders; NINDS-AIREN=National 
Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et 
l’Enseignement en Neurosciences; PDD=Parkinson’s disease dementia 


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Appendix C Dementia with Lewy Bodies Consortium Clinical Diagnostic Criteria 
1. Central feature (essential for a diagnosis of possible or probable DLB) 
a. Dementia defined as progressive cognitive decline of sufficient magnitude 
to interfere with normal social or occupational function. 
b. Prominent or persistent memory impairment may not necessarily occur in 
the early stages but is usually evident with progression. 
c. Deficits on tests of attention, executive function, and visuospatial ability 
may be especially prominent. 
2. Core features (two core features are sufficient for a diagnosis of probable DLB, 
one for possible DLB) 
a. Fluctuating cognition with pronounced variations in attention and alertness 
b. Recurrent visual hallucinations that are typically well formed and detailed 
c. Spontaneous features of parkinsonism 
3. Suggestive features (If one or more of these is present in the presence of one or 
more core features, a diagnosis of probable DLB can be made. In the absence of 
any core features, one or more suggestive features is sufficient for possible DLB. 
Probable DLB should not be diagnosed on the basis of suggestive features alone.) 
a. REM sleep behavior disorder 
b. Severe neuroleptic sensitivity 
c. Low dopamine transporter uptake in basal ganglia demonstrated by SPECT 
or PET imaging 
4. Supportive features (commonly present but not proven to have diagnostic 
specificity) 
a. Repeated falls and syncope 
b. Transient, unexplained loss of consciousness 
c. Severe autonomic dysfunction (e.g., orthostatic hypotension, urinary 
incontinence) 
d. Hallucinations in other modalities 
e. Systematized delusions 
f. Depression 
g. Relative preservation of medial temporal lobe structures on CT/MRI scan 
h. Generalized low uptake on SPECT/PET perfusion scan with reduced 
occipital activity 
i. Abnormal (low uptake) MIBG myocardial scintigraphy 
j. Prominent slow wave activity on EEG with temporal lobe transient sharp 
waves 


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5. A diagnosis of DLB is less likely 
a. In the presence of cerebrovascular disease evident as focal neurologic signs 
or on brain imaging 
b. In the presence of any other physical illness or brain disorder sufficient to 
account in part or in total for the clinical picture 
c. If parkinsonism only appears for the first time at a stage of severe dementia 
6. Temporal sequence of symptoms 
 DLB should be diagnosed when dementia occurs before or concurrently 
with parkinsonism (if it is present). The term Parkinson disease dementia 
(PDD) should be used to describe dementia that occurs in the context of 
well-established Parkinson disease. In a practice setting the term that is most 
appropriate to the clinical situation should be used and generic terms such as 
LB disease are often helpful. In research studies in which distinction needs 
to be made between DLB and PDD, the existing 1-year rule between the 
onset of dementia and parkinsonism DLB continues to be recommended. 
Adoption of other time periods will simply confound data pooling or 
comparison between studies. In other research settings that may include 
clinicopathologic studies and clinical trials, both clinical phenotypes may be 
considered collectively under categories such as LB disease or alpha-
synucleinopathy. 
Source: McKeith et al. 2005 
Abbreviations: CT=computed tomography; DLB=dementia with Lewy bodies; EEG=electroencephalography; 
LB=Lewy body; MIBG=metaiodobenzylguanidine; MRI=magnetic resonance imaging; PDD=Parkinson’s 
disease dementia; PET=positron emission tomography; SPECT=single photon emission computed 
tomography 


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Appendix D International Consensus Criteria for Behavioral Variant Frontotemporal 
Dementia 
I. 
Neurodegenerative disease 
The following symptom must be present to meet criteria for bvFTD 
A. Shows progressive deterioration of behavior and/or cognition by observation or 
history (as provided by a knowledgeable informant) 
II. 
Possible bvFTD 
Three of the following behavioral/cognitive symptoms (A-F) must be present to meet 
criteria. Ascertainment requires that symptoms be persistent or recurrent, rather than single 
or rare events. 
A. Early* behavioral disinhibition [one of the following symptoms (A.1-A.3) must 
be present]: 
A.1. 
Socially inappropriate behavior 
A.2. 
Loss of manners or decorum 
A.3. 
Impulsive, rash or careless actions 
B. Early apathy or inertia [one of the following symptoms (B.1-B.2) must be 
present]: 
B.1. 
Apathy 
B.2. 
Inertia 
C. Early loss of sympathy or empathy [one of the following symptoms (C.1-C.2) 
must be present]: 
C.1. 
Diminished response to other people’s needs and feelings 
C.2. 
Diminished social interest, interrelatedness or personal warmth 
D. Early perseverative, stereotyped or compulsive/ritualistic behavior [one of the 
following symptoms (D.1–D.3) must be present]: 
D.1. 
Simple repetitive movements 
D.2. 
Complex, compulsive or ritualistic behaviors 
D.3. 
Stereotypy of speech 
E. Hyperorality and dietary changes [one of the following symptoms (E.1-E.3) 
must be present]: 
E.1. 
Altered food preferences 
E.2. 
Binge eating, increased consumption of alcohol or cigarettes 
E.3. 
Oral exploration or consumption of inedible objects 
F. Neuropsychological profile: executive/generation deficits with relative sparing 
of memory and visuospatial functions [all of the following symptoms (F.1-F.3) 
must be present]: 
F.1. 
Deficits in executive tasks 
F.2. 
Relative sparing of episodic memory 
F.3. 
Relative sparing of visuospatial skills 


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III. 
Probable bvFTD 
All of the following symptoms (A-C) must be present to meet criteria. 
A. Meets criteria for possible bvFTD 
B. Exhibits significant functional decline (by caregiver report or as evidenced by 
Clinical Dementia Rating Scale or Functional Activities Questionnaire scores) 
C. Imaging results consistent with bvFTD [one of the following (C.1-C.2) must be 
present]: 
C.1. 
Frontal and/or anterior temporal atrophy on MRI or CT 
C.2. 
Frontal and/or anterior temporal hypoperfusion or hypometabolism 
on PET or SPECT 
IV. 
Behavioral variant FTD with definite FTLD Pathology 
Criterion A and either criterion B or C must be present to meet criteria. 
A. Meets criteria for possible or probable bvFTD 
B. Histopathological evidence of FTLD on biopsy or at post-mortem 
C. Presence of a known pathogenic mutation 
V. 
Exclusionary criteria for bvFTD 
Criteria A and B must be answered negatively for any bvFTD diagnosis. Criterion C can be 
positive for possible bvFTD but must be negative for probable bvFTD. 
A. Pattern of deficits is better accounted for by other non-degenerative nervous 
system or medical disorders 
B. Behavioral disturbance is better accounted for by a psychiatric diagnosis 
C. Biomarkers strongly indicative of Alzheimer’s disease or other 
neurodegenerative process 
Source: Rascovsky et al. 2011 
Abbreviations: bvFTD=behavioral variant frontotemporal dementia; CT=computed tomography; 
FTLD=frontotemporal lobar degeneration; MRI=magnetic resonance imaging; PET=positron emissions 
tomography; SPECT=single photon emission computed tomography 
*As a general guideline “early” refers to symptom presentation within the first 3 years 


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Appendix E Neuroprotection and Natural History in Parkinson Plus Syndromes 
Diagnostic Criteria for Progressive Supranuclear Palsy 
Inclusion Criteria 
Exclusion Criteria 
All of the following: 
 Supranuclear ophthalmoplegia 
 Postural instability or falls (within 
3 years from disease onset) 
 Akinetic-rigid syndrome 
 Disease duration (12 months to 8 
years) 
 Age at disease onset ≥30 years 
Any of the following: 
 Idiopathic Parkinson’s disease 
 Evidence of any other neurological 
disease that could explain signs 
 History of repeated strokes with 
stepwise progression of parkinsonian 
features 
 History of major stroke 
 Any history of severe or repeated 
head injury 
 History of encephalitis 
 History of neuroleptic use for a 
prolonged period of time or within the 
past 6 months 
 Street-drug–related parkinsonism 
 Significant other neurological disease 
on CT scan/MRI 
 Oculogyric crises 
 Signs of corticobasal degeneration 
 Signs of Lewy body disease 
 Cerebellar ataxia 
 Symptomatic autonomic dysfunction 
 Tremor at rest 
Source: Respondek et al. 2013 
Abbreviations: CT=computed tomography; MRI=magnetic resonance imaging 


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Appendix F Corticobasal Degeneration Diagnostic Criteria 
Clinical Criteria for Possible Corticobasal Degeneration 
Presentation: 
Insidious onset and gradual progression 
Minimum duration of 
symptoms: 
1 year 
Age at onset: 
No minimum 
Family history (2 or more 
relatives): 
Permitted 
Genetic mutation affecting 
tau (e.g., MAPT): 
Permitted 
Permitted phenotypes: 
Possible 
CBS:  
May be symmetric: 1 of: a) limb rigidity or akinesia, b) limb 
dystonia, c) limb myoclonus plus 1 of: d) orobuccal or limb 
apraxia, e) cortical sensory deficit, f) alien limb phenomena 
(more than simple levitation) 
FBS: 
Two of: a) executive dysfunction, b) behavioral or personality 
changes, c) visuospatial deficits 
NAV: 
Effortful, agrammatic speech plus at least one of: a) impaired 
grammar/sentence comprehension with relatively preserved 
single word comprehension, or b) groping, distorted speech 
production (apraxia of speech) 
PSPS: 
(PLUS ≥1 
CBS feature 
b-f) 
Three of: a) axial or symmetric limb rigidity or akinesia, b) 
postural instability or falls, c) urinary incontinence, d) 
behavioral changes, e) supranuclear vertical gaze palsy or 
decreased velocity of vertical saccades 
Exclusion Criteria: 
1 
Evidence of Lewy body disease: classic 4-Hz Parkinson disease resting 
tremor, excellent and sustained levodopa response, or hallucinations 
2) Evidence of multiple system atrophy: dysautonomia or prominent 
cerebellar signs 
3) Evidence of amyotrophic lateral sclerosis: presence of both upper and 
lower motor neuron signs 
4) Semantic- or logopenic-variant primary progressive aphasia 
5 
Structural lesion suggestive of focal cause. 
6) Granulin mutation or reduced plasma progranulin levels; TDP-43 
mutations; FUS mutations. 
7) Evidence of Alzheimer disease 
Source: Armstrong et al. 2013 
Abbreviations: CBS=corticobasal syndrome; FBS=frontal behavioral-spatial syndrome; 
NAV=Nonfluent/agrammatic variant of primary progressive aphasia; PSPS=progressive supranuclear palsy 
syndrome 
 


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Appendix G VASCOG Criteria for Vascular Dementia 
A. One of the following clinical features: 
1. The onset of the cognitive deficits is temporally related to one or more 
cerebrovascular events (CVE). [Onset is often abrupt with a stepwise or fluctuating 
course owing to multiple such events, with cognitive deficits persisting beyond three 
months after the event. However, subcortical ischemic pathology may produce a 
picture of gradual onset and slowly progressive course, in which case A2 applies]. 
The evidence of CVEs is one of the following: 
a. Documented history of a stroke, with cognitive decline temporally associated 
with the event 
b. Physical signs consistent with stroke (e.g., hemiparesis, lower facial 
weakness, Babinski sign, sensory deficit including visual field defect, 
pseudobulbar syndrome – supranuclear weakness of muscles of face, tongue 
and pharynx, spastic dysarthria, swallowing difficulties and emotional 
incontinence) 
2. Evidence for decline is prominent in speed of information processing, complex 
attention and/or frontal-executive functioning in the absence of history of a stroke or 
transient ischemic attack. One of the following features is additionally present: 
a. Early presence of a gait disturbance (small step gait or marche petits pas, or 
magnetic, apraxic-ataxic or parkinsonian gait); This may also manifest as 
unsteadiness and frequent, unprovoked falls 
b. Early urinary frequency, urgency, and other urinary symptoms not explained 
by urologic disease 
c. Personality and mood changes: abulia, depression, or emotional incontinence 
B. Presence of significant neuroimaging (MRI or CT) evidence of cerebrovascular disease 
(one of the following): 
1. One large vessel infarct is sufficient for Mild VCD, and two or more large vessel 
infarcts are generally necessary for VaD (or Major VCD). 
2. An extensive or strategically placed single infarct, typically in the thalamus or basal 
ganglia may be sufficient for VaD (or Major VCD). 
3. Multiple lacunar infarcts (> two) outside the brainstem; 1–2 lacunes may be 
sufficient if strategically placed or in combination with extensive white matter 
lesions. 
4. Extensive and confluent white matter lesions 
5. Strategically placed intracerebral hemorrhage, or two or more intracerebral 
hemorrhages 
6. Combination of the above 


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Exclusion criteria (for Mild and Major VCD) 
1. History 
a. Early onset of memory deficit and progressive worsening of memory and 
other cognitive functions such as language (transcortical sensory aphasia), 
motor skills (apraxia), and perception (agnosia), in the absence of 
corresponding focal lesions on brain imaging or history of vascular events. 
b. Early and prominent parkinsonian features suggestive of Lewy body disease 
c. History strongly suggestive of another primary neurological disorder such as 
multiple sclerosis, encephalitis, toxic or metabolic disorder, etc. sufficient to 
explain the cognitive impairment. 
2. Neuroimaging 
a. Absent or minimal cerebrovascular lesions on CT or MRI 
3. Other medical disorders severe enough to account for memory and related symptoms 
a. Other disease of sufficient severity to cause cognitive impairment (e.g., brain 
tumor, multiple sclerosis, encephalitis) 
b. Major depression, with a temporal association between cognitive impairment 
and the likely onset of depression. 
c. Toxic and metabolic abnormalities, all of which may require specific 
investigations 
4. Other medical disorders severe enough to account for memory and related symptoms 
a. Other disease of sufficient severity to cause cognitive impairment (e.g., brain 
tumor, multiple sclerosis, encephalitis) 
b. Major depression, with a temporal association between cognitive impairment 
and the likely onset of depression. 
c. Toxic and metabolic abnormalities, all of which may require specific 
investigations 
Source: Sachdev et al. 2014 
Abbreviations: CT=computed tomography; CVE=cerebrovascular events; MRI=magnetic resonance imaging; 
VaD=vascular dementia; VASCOG=International Society for Vascular Behavioral and Cognitive Disorders; 
VCD=vascular cognitive disorder 
 


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Appendix H Prohibited and Restricted Medications 
The table below lists prohibitions and restrictions by medication class, including 
representative medications within class. A prohibited medication is not allowed. 
A restricted medication is allowed only under certain conditions. Details regarding 
procedures for subjects who take a prohibited medication during the study are provided in 
Section 4.5.1. 
Medication Class 
Medication1 
Prohibition/restrictions 
Antipsychotics other 
than pimavanserin 
PROHIBITED 
All in class 
 
Must be washed out 2 weeks or 5 half-lives 
(whichever is longer) prior to open-label Baseline 
 
Prohibited throughout the study 
Anticholinergics 
PROHIBITED 
 
Centrally acting 
anticholinergics 
o 
benztropine 
o 
biperiden 
o 
trihexiphenidyl 
o 
Oral 
diphenhydramine 
 
Anticholinergic medications whose primary 
mechanism of action is centrally acting are 
prohibited and should be washed out and 
discontinued at least 2 weeks or 5 half-lives 
(whichever is longer) prior to open-label Baseline 
UNRESTRICTED 
 
Peripherally acting 
anticholinergics 
 
Topical 
diphenhydramine 
 
Peripherally acting anticholinergic medications 
and topical diphenhydramine are allowed without 
restriction 
Anticonvulsant and 
mood stabilizers 
PROHIBITED 
 
carbamazepine 
 
lamotrigine 
 
lithium 
 
phenytoin 
 
Must be washed out 5 half-lives prior to Baseline 
 
Prohibited throughout the study 
RESTRICTED 
 
valproate 
 
Valproate may be used if dose unchanged for at 
least 4 weeks prior to Baseline and dose should 
be expected to remain unchanged until the 
subject’s final visit. 


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Medication Class 
Medication1 
Prohibition/restrictions 
Antidepressants 
PROHIBITED 
 
mirtazapine 
 
nefazadone 
 
fluvoxamine 
 
mianserin 
 
trazodone 
 
amitriptyline 
 
nortriptyline 
 
imipramine 
 
trimipramine 
 
desipramine 
 
clomipramine 
 
Prohibited throughout the study 
 
Must be discontinued at least 2 weeks or 5 half-
lives (whichever is longer) prior to the Baseline 
visit 
RESTRICTED 
 
citalopram 
 
escitalopram 
 
venlafaxine 
 
If subject is remaining on these medications, the 
dose of the permitted antidepressants on the left 
must be unchanged for at least 4 weeks prior to 
Baseline and should be expected to remain 
unchanged until the subject’s final visit. If the 
medication is being discontinued, it must be 
discontinued at least 2 weeks or 5 half-lives 
(whichever is longer) prior to the Baseline visit. 
o 
Citalopram is restricted to a 
maximum dose of 20 mg/day  
o 
Escitalopram is restricted to a 
maximum dose of 10 mg/day  
o 
Venlafaxine is restricted to a 
maximum dose of 225 mg/day 
Anxiolytics 
PROHIBITED 
 
chlordiazepoxide 
 
diazepam 
 
flurazepam 
 
Prohibited at study entry and throughout the study 
RESTRICTED 
 
alprazolam 
 
clonazepam 
 
lorazepam 
 
oxazepam 
 
temazepam 
 
midazolam 
 
triazolam 
 
Short- or medium-acting benzodiazepine may be 
used for acute anxiety. Reasonable efforts should 
be made to use minimum dose necessary for 
symptom management. 
 
May not be used within 12 hours prior to an 
assessment visit 
Hypnotics and 
sleeping agents 
PROHIBITED 
 
zolpidem 
 
zopiclone 
 
eszopiclone 
 
Prohibited at study entry and throughout the study


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Medication Class 
Medication1 
Prohibition/restrictions 
RESTRICTED 
 
zaleplon 
 
ramelteon 
 
May not be used within 12 hours of a cognitive 
assessment, and efforts should be made to limit 
agents to lowest dose for the shortest time 
needed. 
Stimulants and wake-
promoting agents 
PROHIBITED 
 
methylphenidate 
 
modafinil 
 
armodafinil 
 
Prohibited at study entry and throughout the study 
(see Section 6.3.7 for procedures related to a 
positive amphetamine test at study entry) 
Non-stimulant 
ADHD medications 
PROHIBITED 
 
atomoxetine 
 
Prohibited at study entry and throughout the study 
Serotonin antagonists  PROHIBITED 
 
cyproheptadine 
 
Prohibited throughout the study 
 
Must be discontinued at least 3 weeks prior to the 
Baseline visit 
Antiarrhythmic drugs 
PROHIBITED 
 
ajmaline 
 
amakalant, semantilide 
 
amiodarone 
 
bretylium 
 
disopyramide 
 
dofetilide 
 
dronedarone 
 
flecainide 
 
ibutilide 
 
procainamide 
 
propafenone 
 
quinidine 
 
sotalol, d-sotalol 
 
Prohibited at study entry and throughout the study 
Opioids 
PROHIBITED 
 
methadone 
 
Prohibited at study entry and throughout the study 


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Medication Class
Medication1
Prohibition/restrictions
Antimicrobials, 
antifungals, and 
antimalarials 
PROHIBITED 

clarithromycin

erythromycin

levofloxacin

moxifloxacin

pentamidine

roxithromycin

Prohibited at study entry and throughout the study
RESTRICTED 

artenimol/piperaquine

azithromycin

bedaquiline

ciprofloxacin

gemifloxacin

norfloxacin

ofloxacin

fluconazole

telavancin

telithromycin

Prohibited at Baseline but may be used during the
course of the study to treat a bacterial infection
(e.g., urinary tract infection, respiratory
infection), post-Baseline at the discretion of the
Principal Investigator.

The medications on the left are only allowed
under the following conditions:
o
The subject has a Baseline ECG with a QTcF
<425 ms IF QRS duration is <120 ms OR
o
The subject has a QTcF <450 ms at Baseline
IF QRS duration ≥120 ms
1 
Medications within each class include but are not limited to the examples listed in this table.


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Appendix I 
Prohibited and Restricted Concomitant Medications: Inhibitors and 
Inducers of Cytochrome P450 Enzyme 3A4 
The information presented here is intended to provide guidance and does not constitute an 
exhaustive list of strong CYP 3A4 enzyme (CYP3A4) inhibitors and inducers. Any questions 
should be discussed with the Medical Monitor or appropriate designee. Details regarding 
procedures for subjects who take a prohibited medication during the study are provided in 
Section 4.5.1. 
The metabolism of pimavanserin is affected by strong CYP3A4 inhibitors, resulting in an 
increase in maximum plasma concentration (Cmax) and area under the plasma concentration-
time curve (AUC) of approximately 3-fold. 
Strong inhibitors of CYP3A4 are to be stopped at least 7 days or 5 half-lives prior to 
investigational product administration, whichever is longer. Strong inducers of CYP3A4 are 
to be stopped 30 days or 5 half-lives prior to investigational product administration, 
whichever is longer. 
Moderate inhibitors and inducers of CYP3A4 may be allowed but should be used with 
caution. 
STRONG 
INHIBITORS 
grapefruit juice
a 
boceprevir (Victrelis®) 
clarithromycin (Biaxin®) 
cobicistat (part of Stribild®) 
conivaptan (Vaprisol®) 
fluvoxamine (Luvox®) 
indinavir (Crixivan®) 
itraconazole (Sporanox®) 
ketoconazole (Nizoral®) 
lopinavir and ritonavir (Kaletra®) 
mibefradil (Posicor®) 
nefazodone (Serzone®) 
nelfinavir (Viracept®) 
posaconazole (Noxafil®) 
quinupristin (Synercid®) 
ritonavir (Norvir®, part of Viekira Pak™) 
saquinavir (Invirase®) 
telaprevir (Incivek®) 
telithromycin (Ketek®) 
voriconazole (Vfend®) 
MODERATE 
INHIBITORS 
grapefruit juice
a 
amprenavir (Agenerase®) 
aprepitant (Emend®) 
atazanavir (Reyataz®) 
ciprofloxacin (Cipro®) 
darunavir/ritonavir 
(Prezista®/Ritonavir) 
diltiazem 
erythromycin (Erythrocin® 
Lactobionate) 
fluconazole (Diflucan®) 
fosamprenavir (Lexiva®) 
imatinib (Gleevec®) 
verapamil (Calan®) 


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STRONG 
INDUCERS 
avasimibe 
carbamazepine (Tegretol®) 
phenobarbital (Luminal®, Solfoton®) 
phenytoin (Dilantin®)  
rifampin (Rifadin®, Rifadin® IV, 
Rimactane®) 
St. John's Wort 
MODERATE 
INDUCERS 
bosentan (Tracleer®) 
efavirenz (Sustiva®) 
etravirine (Intelence®) 
modafinil (Provigil®) 
nafcillin (Unipen®, Nallpen®) 
a 
The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-
dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain 
preparation was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when another 
preparation was used (e.g., low dose, single strength). (FDA Drug Development and Drug Interactions 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabelin
g/ucm093664.htm#classInhibit). 
 


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Appendix J 
New York Heart Association Classification of Heart Failure 
Class 
Patient Symptoms 
I 
No limitation of physical activity. Ordinary physical activity does 
not cause undue fatigue, palpitation, dyspnea (shortness of breath). 
II 
Slight limitation of physical activity. Comfortable at rest. Ordinary 
physical activity results in fatigue, palpitation, dyspnea (shortness of 
breath).  
III 
Marked limitation of physical activity. Comfortable at rest. Less 
than ordinary activity causes fatigue, palpitation, or dyspnea.  
IV 
Unable to carry on any physical activity without discomfort. 
Symptoms of heart failure at rest. If any physical activity is 
undertaken, discomfort increases.  
Source: American Heart Association 


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Appendix K Canadian Cardiovascular Society Angina Grading Scale 
Grade 
Description 
I 
Ordinary physical activity does not cause angina, such as walking 
and climbing stairs. Angina with strenuous or rapid or prolonged 
exertion at work or recreation 
II 
Slight limitation of ordinary activity. Walking or climbing stairs 
rapidly, walking uphill, walking or stair climbing after meals, or 
in cold, or in wind, or under emotional stress, or only during the 
few hours after awakening. Walking more than two blocks on the 
level and climbing more than one flight of ordinary stairs at a 
normal pace and in normal conditions 
III 
Marked limitation of ordinary physical activity. Walking one or 
two blocks on the level and climbing one flight of stairs in normal 
conditions and at normal pace 
IV 
Inability to carry on any physical activity without discomfort, 
anginal syndrome may be present at rest 
Sources: Campeau L 1976 
 
 


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Appendix L Predictors Composing the PHASES Aneurysm Rupture Risk Score 
PHASES aneurysm risk score 
Points 
(P) Population 
North American, European (other than Finnish) 
0 
Japanese 
3 
Finnish 
5 
(H) Hypertension 
No 
0 
Yes 
1 
(A) Age 
<70 years 
0 
≥70 years 
1 
(S) Size of aneurysm 
<7.0 mm 
0 
7.0-9.9 mm 
3 
10.0-19.9 mm 
6 
≥20 mm 
10 
(E) Earlier SAH from another aneurysm 
No 
0 
Yes 
1 
(S) Site of aneurysm 
ICA 
0 
MCA 
2 
ACA/Pcom/posterior 
4 
Source: Greving et al. 2014 
Abbreviations: ACA=anterior cerebral arteries (including the anterior cerebral artery, anterior communicating 
artery, and pericallosal artery); ICA=internal carotid artery; MCA=middle cerebral artery; Pcom=posterior 
communicating artery; posterior=posterior circulation (including the vertebral artery, basilar artery, 
cerebellar arteries, and posterior cerebral artery); SAH=subarachnoid haemorrhage  
Note: To calculate the PHASES risk score for an individual, the number of points associated with each indicator 
can be added up to obtain the total risk score. 
 

SAP_001.pdf: 
Official Title: A Double-blind, Placebo-controlled, Relapse Prevention Study of 
Pimavanserin for the Treatment of Hallucinations and Delusions Associated With 
Dementia-related Psychosis 
NCT Number: NCT03325556 
Document Date: 26 Jul 2019 
 


 
 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Protocol No.: 
ACP-103-045 
Protocol Title: 
A Double-blind, Placebo-controlled, Relapse 
Prevention Study of Pimavanserin for the Treatment of 
Hallucinations and Delusions Associated With 
Dementia-related Psychosis 
Drug: 
Pimavanserin 
Sponsor:  
ACADIA Pharmaceuticals Inc. 
 
Version No. and Date 
Version 1.0, 26JUL2019 
 
 
 
 
 
 
 
 
 


Protocol ACP-103-045 
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SIGNATURE/APPROVAL PAGE 
AUTHOR 
 
See electronic signature page     
_____________________________________________ 
____________ 
 
Date 
Associate Director, Biostatistics  
ACADIA Pharmaceuticals Inc. 
 
 
APPROVERS 
 
 
See electronic signature page     
_____________________________________________ 
____________ 
 
Date 
Vice President, Biometrics 
ACADIA Pharmaceuticals Inc. 
 
 
 
 


Signature Page for ACP-103-045 SAP
Signature Page for ACP-103-045 SAP
Approve
29-Jul-2019 15:57:16 GMT+0000
Approve
29-Jul-2019 16:05:45 GMT+0000


Protocol ACP-103-045 
 Version 1.0 
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 26 July 2019 
 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ........................................................................................................... 4 
LIST OF TABLES ..................................................................................................................... 8 
LIST OF FIGURES ................................................................................................................... 8 
ABBREVIATIONS .................................................................................................................... 9 
1 INTRODUCTION ............................................................................................................. 11 
2 STUDY OBJECTIVES AND ENDPOINTS ..................................................................... 11 
2.1 
Primary Objective .......................................................................................................... 11 
2.1.1 
Primary Endpoint ....................................................................................................... 11 
2.2 
Key Secondary Objective .............................................................................................. 11 
2.2.1 
Key Secondary Endpoint ........................................................................................... 11 
2.3 
Exploratory Objectives .................................................................................................. 11 
2.3.1 
Exploratory Endpoints ............................................................................................... 12 
2.4 
Safety Objective ............................................................................................................ 12 
2.4.1 
Safety Endpoints ........................................................................................................ 12 
2.5 
Pharmacokinetic Objectives .......................................................................................... 13 
2.5.1 
Pharmacokinetic Endpoints ....................................................................................... 13 
3 STUDY DESIGN ............................................................................................................... 13 
3.1 
General Study Design .................................................................................................... 13 
3.2 
Randomization ............................................................................................................... 21 
3.3 
Blinding ......................................................................................................................... 21 
3.4 
Determination of Sample Size ....................................................................................... 21 
4 ANALYSIS SETS .............................................................................................................. 22 
4.1 
Intent-to-treat (ITT) Analysis Set .................................................................................. 22 
4.2 
Open-label Safety Analysis Set ..................................................................................... 22 
4.3 
Double-blind Safety Analysis Set .................................................................................. 22 
4.4 
Per-protocol Analysis Set .............................................................................................. 23 
4.5 
Open-label Pharmacokinetic Analysis Set ..................................................................... 23 
4.6 
Double-blind Pharmacokinetic Analysis Set ................................................................. 23 
5 DATA HANDLING CONVENTIONS .............................................................................. 23 
5.1 
General Data Reporting Conventions ............................................................................ 23 


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5.1.1 
Open-label Period ...................................................................................................... 24 
5.1.2 
Double-blind Period .................................................................................................. 24 
5.2 
Derived Variables........................................................................................................... 25 
5.2.1 
Open-label Baseline ................................................................................................... 25 
5.2.2 
Double-blind Baseline ............................................................................................... 25 
5.2.3 
Time from Randomization to Relapse in the Double-blind Period ........................... 25 
5.2.4 
Time from Randomization to Discontinuation from the Double-blind Period for 
Any Reason ................................................................................................................ 26 
5.2.5 
Scale for the Assessment of Positive Symptoms-Hallucinations + Delusions .......... 27 
5.2.6 
Clinical Global Impressions – Severity Scale ........................................................... 27 
5.2.7 
Clinical Global Impressions – Improvement Scale ................................................... 28 
5.2.8 
Zarit Burden Interview .............................................................................................. 28 
5.2.9 
Karolinska Sleepiness Scale ...................................................................................... 28 
5.2.10 
EQ-5D-5L Proxy Version 1 ....................................................................................... 29 
5.2.11 
Global Clinician Assessment of Suicidality .............................................................. 29 
5.2.12 
Mini-Mental State Examination ................................................................................ 30 
5.2.13 
Extrapyramidal Symptom Rating Scale-Abbreviated ............................................... 30 
5.3 
Analysis Visit Windows ................................................................................................. 31 
5.3.1 
Open-label Period ...................................................................................................... 31 
5.3.2 
Double-blind Period .................................................................................................. 32 
5.3.3 
Unscheduled Assessments ......................................................................................... 32 
5.3.4 
Multiple Measurements within Visit Windows ......................................................... 33 
5.4 
Data Handling Conventions........................................................................................... 33 
5.4.1 
Missing or Incomplete Dates for Prior or Concomitant Medications ....................... 34 
5.4.2 
Missing or Incomplete Dates for Adverse Events ..................................................... 34 
5.4.3 
Missing Severity Assessment for Adverse Events ..................................................... 34 
5.4.4 
Missing Relationship to Study Drug for Adverse Events .......................................... 34 
5.4.5 
Character Values of Clinical Laboratory Variables.................................................... 35 
6 SUBJECT DISPOSITION ................................................................................................. 35 
6.1 
Analysis for the Open-label Period ............................................................................... 35 
6.2 
Analysis for the Double-blind Period ............................................................................ 36 
6.3 
Screen Failure ................................................................................................................ 36 
7 PROTOCOL DEVIATIONS .............................................................................................. 37 
8 DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS .......................... 37 
8.1 
Demographics ................................................................................................................ 37 
8.2 
Disease Characteristics .................................................................................................. 38 


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9 MEDICAL HISTORY ....................................................................................................... 38 
10 PRIOR, CONCOMITANT AND POST-TREATMENT MEDICATION .......................... 38 
10.1 Prior Medication ............................................................................................................ 39 
10.2 Concomitant Medication ............................................................................................... 39 
10.2.1 
Analysis for the Open-label Period ........................................................................... 39 
10.2.2 
Analysis for the Double-Blind Period ....................................................................... 39 
10.3 Analysis for Post-Treatment Medication ....................................................................... 39 
11 EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE ................................... 40 
11.1 Exposure to Study Drug ................................................................................................ 40 
11.1.1 
Analysis for the Open-label Period ........................................................................... 40 
11.1.2 
Analysis for the Double-blind Period ........................................................................ 40 
11.2 Study Drug Compliance ................................................................................................ 41 
11.2.1 
Analysis for the Open-label Period ........................................................................... 41 
11.2.2 
Analysis for the Double-blind Period ........................................................................ 41 
12 EFFICACY ANALYSES ................................................................................................... 41 
12.1 Efficacy Variables .......................................................................................................... 42 
12.1.1 
Primary Endpoint ....................................................................................................... 42 
12.1.2 
Key Secondary Endpoint ........................................................................................... 42 
12.1.3 
Exploratory Study Endpoints ..................................................................................... 42 
12.2 Adjustment for Covariates ............................................................................................. 42 
12.3 Handling of Informative Censoring ............................................................................... 43 
12.4 Multiple Comparisons/Multiplicity ............................................................................... 43 
12.5 Examination of Subgroups ............................................................................................ 43 
12.5.1 
Double-Blind Period .................................................................................................. 43 
12.5.2 
Open-Label Period ..................................................................................................... 44 
13 METHODS OF EFFICACY ANALYSES ........................................................................ 44 
13.1 Primary Efficacy Analysis ............................................................................................. 44 
13.1.1 
Deviations From Non-Informative Censoring ........................................................... 46 
13.1.2 
Sensitivity Analyses ................................................................................................... 48 
13.2 Key Secondary Efficacy Analysis ................................................................................. 49 
13.2.1 
Deviations From Non-Informative Censoring ........................................................... 51 
13.2.2 
Sensitivity Analysis ................................................................................................... 51 
13.3 Exploratory Efficacy Analysis ....................................................................................... 52 
13.3.1 
Analysis for the Double-blind Period ........................................................................ 52 


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13.3.1.1 
Mixed Model Repeated Measures ......................................................................... 52 
13.3.1.2 
ANCOVA ............................................................................................................... 53 
13.3.1.3 
Treatment Comparisons ......................................................................................... 53 
13.3.2 
Analysis for the Open-label Period ........................................................................... 54 
13.3.3 
SAPS-H+D ................................................................................................................ 54 
13.3.4 
SAPS Hallucinations Domain ................................................................................... 55 
13.3.5 
SAPS Delusions Domain ........................................................................................... 55 
13.3.6 
CGI-S Dementia-Related Psychosis .......................................................................... 56 
13.3.7 
Responder Analysis ................................................................................................... 56 
13.3.8 
ZBI Score ................................................................................................................... 56 
13.3.9 
KSS Score .................................................................................................................. 56 
13.3.10 CGI-I Dementia-Related Psychosis ........................................................................... 57 
13.3.11 EQ-5D VAS ............................................................................................................... 57 
13.3.12 EQ-5D 5L Descriptive System .................................................................................. 57 
13.3.13 Pareto Classification of Health Change ..................................................................... 58 
14 SAFETY ANALYSES ....................................................................................................... 58 
14.1 Adverse Events .............................................................................................................. 59 
14.2 Clinical Laboratory Variables ........................................................................................ 60 
14.2.1 
Analysis for the Open-label Safety Analysis set ....................................................... 62 
14.2.2 
Analysis for the Double-blind Safety Analysis Set ................................................... 63 
14.3 Vital Signs ...................................................................................................................... 66 
14.3.1 
Analysis for the Open-label Safety Analysis Set ....................................................... 66 
14.3.2 
Analysis for the Double-blind Safety Analysis Set ................................................... 67 
14.4 Electrocardiogram ......................................................................................................... 68 
14.4.1 
Analysis for the Open-label Safety Analysis Set ....................................................... 68 
14.4.2 
Analysis for the Double-blind Safety Analysis Set ................................................... 69 
14.5 Physical and Neurological Examinations ...................................................................... 71 
14.5.1 
Analysis for the Open-label Safety Analysis Set ....................................................... 71 
14.5.2 
Analysis for the Double-blind Safety Analysis Set ................................................... 71 
14.6 Global Clinician Assessment of Suicidality .................................................................. 71 
14.6.1 
Analysis for the Open-label Safety Analysis Set ....................................................... 71 
14.6.2 
Analysis for the Double-blind Safety Analysis Set ................................................... 72 
14.7 Mini-Mental State Examination .................................................................................... 72 
14.7.1 
Analysis for the Open-label Safety Analysis Set ....................................................... 72 
14.7.2 
Analysis for the Double-blind Safety Analysis Set ................................................... 72 
14.8 Extrapyramidal Symptom Rating Scale - Abbreviated.................................................. 73 


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14.8.1 
Analysis for the Open-label Safety Analysis Set ....................................................... 73 
14.8.2 
Analysis for the Double-blind Safety Analysis Set ................................................... 73 
15 CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES ........ 73 
15.1 Analysis for the Open-label Pharmacokinetic Analysis Set .......................................... 74 
15.2 Analysis for the Double-blind Pharmacokinetic Analysis Set....................................... 74 
16 UNBLINDED INTERIM EFFICACY ANALYSIS .......................................................... 74 
16.1 Primary Efficacy Endpoint ............................................................................................ 75 
16.2 Key Secondary Efficacy Endpoint ................................................................................ 77 
16.2.1 
Overrunning of Relapse Events at Interim Analysis ................................................. 78 
16.2.2 
Analysis Following a Sequential Test ........................................................................ 78 
17 DATA AND SAFETY MONITORING BOARD .............................................................. 78 
18 INDEPENDENT ADJUDICATION COMMITTEE ......................................................... 79 
19 COMPUTER METHODS ................................................................................................. 79 
20 CHANGES TO ANALYSES SPECIFIED IN PROTOCOL ............................................. 79 
21 REFERENCES .................................................................................................................. 80 
22 APPENDICES ................................................................................................................... 81 
Appendix 1 Summary of Version Changes .............................................................................. 81 
 
LIST OF TABLES 
Table 1 Schedule of Assessments for Screening and Open-label Period ................................. 17 
Table 2 Schedule of Assessments for Double-blind Period ..................................................... 19 
Table 3 Analysis Visit Windows for the Open-label Period .................................................... 32 
Table 4 Analysis Visit Windows for the Double-Blind Period ................................................ 32 
Table 5 Criteria for PCI Laboratory Values – Hematology and Chemistry ............................. 65 
Table 6 Criteria for PCI Laboratory Values - Urinalysis ......................................................... 66 
Table 7 Criteria for PCI Vital Signs ......................................................................................... 68 
Table 8 Criteria for PCI ECG Values ....................................................................................... 71 
Table 9 O’Brien-Fleming Stopping Boundary Information .................................................... 75 
 
LIST OF FIGURES 
Figure 1 Schematic of Study Design ....................................................................................... 14 


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ABBREVIATIONS 
AE 
adverse event 
ATC 
Anatomical Therapeutic Chemical 
BMI 
body mass index 
CI 
confidence interval 
CGI-I 
Clinical Global Impression-Improvement 
CGI-S 
Clinical Global Impression-Severity 
DB 
double-blind 
DSMB 
Data and Safety Monitoring Board 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
EOT 
end-of-treatment 
FDA 
Food and Drug Administration 
FTD 
frontotemporal dementia 
GCAS 
Global Clinician Assessment of Suicidality 
IAC 
Independent Adjudication Committee 
ISG 
Independent Statistical Group 
ITT 
intent-to-treat 
KSS 
Karolinska Sleepiness Scale 
LLOQ 
lower limit of quantification 
LS 
least squares 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed model repeated measures 
MMSE 
Mini-Mental State Examination 
msec 
milliseconds 
OL 
open-label 
PCI 
potentially clinically important 
PK 
pharmacokinetic 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAPS-H+D 
Scale for Assessment of Positive Symptoms-Hallucinations + Delusions 
SAS® 
Statistical Analysis System 
SD 
standard deviation 


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SE 
standard error 
SOC 
system organ class 
TEAE   
treatment-emergent adverse event 
ZBI 
Zarit Burden Interview 


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1 INTRODUCTION 
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the 
statistical analyses of efficacy and safety data as described in Protocol Amendment 1 dated 
16 August 2018. Specifications for tables, figures, and listings are contained in a separate 
document. 
2 STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objective 
The primary objective is to evaluate relapse prevention in subjects with dementia-related 
psychosis treated with pimavanserin compared to placebo. 
2.1.1 
Primary Endpoint 
The primary endpoint for this study will be time from randomization to relapse in the 
double-blind period. 
2.2 
Key Secondary Objective 
The key secondary objective is to evaluate the time to discontinuation of the study for any 
reason in subjects with dementia-related psychosis treated with pimavanserin compared to 
placebo. 
2.2.1 
Key Secondary Endpoint 
The key secondary endpoint for this study will be time from randomization to discontinuation 
from the double-blind period for any reason. 
2.3 
Exploratory Objectives 
The exploratory objectives are to evaluate the benefit of pimavanserin compared to placebo 
in the following domains in subjects with dementia-related psychosis who have been 
stabilized on pimavanserin therapy: 
• symptoms of hallucinations and delusions  
• clinical global impression  
• caregiver burden  


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• daytime sleepiness  
• quality of life  
2.3.1 
Exploratory Endpoints 
The exploratory endpoints for this study are as follows: 
• Change from double-blind Baseline on the following: 
o Scale for the Assessment of Positive Symptoms-Hallucinations+Delusions 
(SAPS-H+D) score 
o SAPS Hallucinations domain score 
o SAPS Delusions domain score 
o Clinical Global Impression-Severity (CGI-S)-dementia-related psychosis 
o Zarit Burden Interview (ZBI) score 
o Karolinska Sleepiness Scale (KSS) score 
o EQ-5D-5L score 
o Clinical Global Impression-Improvement (CGI-I)-dementia-related psychosis  
2.4 
Safety Objective 
The safety objective for this study is to evaluate the safety and tolerability of pimavanserin 
compared to placebo in subjects with dementia-related psychosis who have been stabilized on 
pimavanserin therapy. 
2.4.1 
Safety Endpoints 
The safety endpoints for this study are as follows: 
• Treatment-emergent adverse events (TEAEs) 
• Serious adverse events (SAEs) 
• Withdrawals due to adverse events (AEs) 
• Potentially clinically important changes in other safety assessments 
• Global Clinician Assessment of Suicidality (GCAS) score 
• Mini-Mental State Examination (MMSE) score 
• Extrapyramidal Symptom Rating Scale A (ESRS-A) score 


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2.5 
Pharmacokinetic Objectives 
The pharmacokinetic (PK) objectives for this study are as follows: 
• To characterize the PK of pimavanserin in subjects with dementia-related psychosis 
• To assess the pharmacokinetic/pharmacodynamics (PK/PD) relationship with safety and 
efficacy endpoints in subjects with dementia-related psychosis 
2.5.1 
Pharmacokinetic Endpoints 
The PK endpoints for this study are as follows: 
• Plasma concentration of pimavanserin and AC-279 
• Pimavanserin PK parameters using a population PK approach 
• PK/PD using appropriate PK/PD analysis methods 
3  STUDY DESIGN 
3.1 
General Study Design 
This is a Phase 3, prospective, double-blind, placebo-controlled, multicenter, relapse 
prevention study in subjects with dementia-related psychosis. Approximately 95 study sites 
will participate in this study. 
The duration of participation for individual study subjects will be up to 47 weeks, consisting 
of a screening period of up to 5 weeks; an open-label (OL) period of 12 weeks; a 
double-blind (DB) period of up to 26 weeks; and an approximately 4-week safety follow-up 
period.  
The study discontinuation date is defined as the day on which the Sponsor notifies sites that 
the study is ending (for example, in the event of a positive interim analysis or after 75 
adjudicated relapse events). The study completion date is defined as the day on which the last 
subject completes the last scheduled assessment (i.e., safety follow-up). A study schematic is 
provided in Figure 1. 


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Figure 1 Schematic of Study Design 
 
Screening Period (3-35 Days) 
During the screening period, subjects will be assessed for study eligibility and prohibited 
medications will be discontinued when medically appropriate. Subjects and 
partner/caregivers will also receive a standardized psychosocial therapy training.  
Investigators should not withdraw a subject’s prohibited medication for the purpose of 
enrolling them into the study. Medications should be discontinued only if it is deemed 
clinically appropriate to do so. 
Open-label Period (12 Weeks) 
During the open-label period, eligible subjects will begin receiving pimavanserin 34 mg once 
daily (QD) beginning at Week 0 (open-label Baseline). Subsequent clinic visits will occur at 
Weeks 2, 4, 8, and 12. Dose adjustments are permitted at scheduled or unscheduled visits 
until Week 4. After Week 4, the subject’s dose will remain fixed at either 34 mg or 20 mg 
once daily. 
To enter the double-blind period, eligible subjects must meet the following response criteria 
at Weeks 8 and 12: 
• Subject experiences a ≥30% reduction (improvement) from Week 0 (open-label Baseline) 
on the Scale for the Assessment of Positive Symptoms – Hallucinations + Delusions 
(SAPS-H+D) Total Score AND 


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• Subject has a Clinical Global Impression – Improvement (CGI-I) score of 1 (very much 
improved) or 2 (much improved), relative to Week 0 (open-label Baseline) 
A subject who does not meet response criteria at Weeks 8 and 12 will be withdrawn from 
study drug and enter the safety follow-up period of the study. 
Pharmacokinetic samples will be collected at Weeks 0, 8, and 12. Pharmacokinetic samples 
will also be collected, if possible, at any ET visit or the visit immediately following any SAE 
or following an AE leading to discontinuation. 
Double-blind Period (up to 26 Weeks) 
Randomization will occur at the double-blind Baseline visit (Week 12). Subjects will be 
randomly assigned 1:1 to continue their pimavanserin dose (34 mg or 20 mg) or matching 
placebo.  
The protocol-defined relapse criteria for dementia-related psychosis are designed to identify 
subjects with an impending relapse or relapse of psychosis:  
• Subject experiences a ≥30% increase (worsening) from Week 12 (double-blind Baseline) 
on the SAPS-H+D Total Score AND has a CGI-I score of 6 (much worse) or 7 (very 
much worse), relative to the double-blind Baseline; OR 
• Subject is treated with an antipsychotic (other than pimavanserin) for dementia-related 
delusions and/or hallucinations; OR  
• Subject stops study drug or withdraws from study for lack of efficacy, (as reported by the 
subject or study partner/caregiver) or the Investigator discontinues study drug due to lack 
of efficacy; OR  
• Subject is hospitalized for worsening dementia-related psychosis  
Relapse criteria will be assessed weekly for the first 2 weeks after randomization (Weeks 13 
and 14), every 2 weeks until Week 26, and every 4 weeks through Week 38. Relapse criteria 
may also be evaluated at unscheduled visits. Any subject who meets any of the relapse 
criteria after randomization will be withdrawn from study drug and enter the safety follow-up 
period of the study.  


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All subjects who discontinue the study between randomization and Week 38 should complete 
an ET visit, if possible. The Independent Adjudication Committee (IAC) will adjudicate early 
termination and relapse events that occurred before the study discontinuation date. Early 
termination and relapse events that occur in the double-blind period after the study 
discontinuation date will not be adjudicated.  
An interim and final analysis will be planned after 38 and 75 adjudicated relapse events have 
occurred, respectively. The study may be terminated early if the interim analysis results 
establish the efficacy and safety of pimavanserin for the treatment of hallucinations and 
delusions associated with dementia-related psychosis.  
The Data Safety Monitoring Board (DSMB) will monitor, review, and evaluate the unblinded 
safety data on a periodic basis. In addition, the DSMB will review the results of the 
pre-planned unblinded interim analysis conducted by the Independent Statistical Group. 
Pharmacokinetic samples will be collected at Weeks 13, 22, and 38/EOT. Pharmacokinetic 
samples will also be collected, if possible, at any ET visit or the visit immediately following 
any SAE or following an AE leading to discontinuation. 
Safety Follow-up Period (Approximately 4 Weeks) 
Approximately 4 weeks after the last dose of study drug, subjects will have a safety 
follow-up telephone call visit.  
The Sponsor will provide investigative sites with 3 months of after-study assistance to 
transition subjects to standard of care therapy after their participation in the study. 
 
 


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Table 1 Schedule of Assessments for Screening and Open-label Period   
 
Screening 
Open-label Period 
Visit week 
-5 to 0 
0 
2 
4 
8 
12a 
Allowable visit window (# days) 
 
 
±3 
±3 
±3 
+7 
Visit Number 
1 
2 
3 
4 
5 
6 
Informed consent 
X 
 
 
 
 
 
Inclusion/exclusion criteria assessment 
X 
X 
 
 
 
 
Medical history and demographics 
X 
 
 
 
 
 
Mini-Mental State Examination 
X 
X 
X 
X 
X 
X 
MRI or CTb 
X 
 
 
 
 
 
Psychosocial therapy training 
X 
 
 
 
 
 
Physical and neurological examinations 
X 
X 
 
 
 
X 
Vital signs and weight 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
12-lead electrocardiogramc 
X 
X 
X 
 
 
X 
Clinical laboratory tests 
X 
X 
 
 
 
X 
Pregnancy testd 
X 
X 
 
 
 
X 
SAPS-H+D 
X 
X 
X 
X 
X 
X 
Clinical Global Impression-Improvemente 
 
 
X 
X 
X 
X 
Clinical Global Impression-Severity 
X 
X 
X 
X 
X 
X 
Zarit Burden Interviewf 
 
X 
 
 
 
X 
Karolinska Sleepiness Scale 
 
X 
 
 
 
X 
EQ-5D-5L 
 
X 
 
 
 
X 
Assessment for response criteria 
 
 
 
 
X 
X 
Assessment for concomitant medications 
X 
X 
X 
X 
X 
X 
Global Clinician Assessment of Suicidality 
X 
X 
X 
X 
X 
X 
Extrapyramidal Symptom Rating Scale A 
 
X 
 
 
 
X 
Assessment for adverse events 
X 
X 
X 
X 
X 
X 
Pharmacokinetic sample collectiong 
 
X 
 
 
X 
X 
Pharmacogenomic sample collectionh 
 
X 
 
 
 
 
Drug dispensation 
 
X 
X 
X 
X 
Xi 
Drug return and accountability 
 
 
X 
X 
X 
X 
Randomization 
 
 
 
 
 
X 
Footnotes for Table 1 on next page 


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Abbreviations: CT=computed tomography; MRI=magnetic resonance imaging;  
                  SAPS-H+D=Scale for the Assessment of Positive Symptoms, Hallucinations and Delusions  
                  subscales 
Note: All efforts should be made to complete visits in a single day. In the event of a split visit, the CGI-S/CGI-I 
and the SAPS H+D must be completed on the same day (pertinent for all visits). 
Note: When a subject is found to be appropriate for discontinuation from the trial, the visit during which this is 
determined should immediately be converted to an ET visit (as described in Table 2) and all procedures and 
assessments done at the ET visit (Week 38/EOT; Visit 17/EOT) should be completed (additional details 
provided in Section 4.4 of the protocol). Safety follow-up should be completed as scheduled. 
For additional details on study procedures, see Section 6 of the protocol. 
 
a 
Visit 6 (Week 12) will serve as both the final visit of the open-label period and the Baseline visit of the 
double-blind period (Table 2). 
b 
A non-contrast brain MRI or non-contrast head CT will be completed if the subject has not had a CT or 
MRI scan completed (a) within the past 3 years AND (b) during or subsequent to the onset of dementia. 
c 
The ECG will be completed in triplicate at Visit 1 (Screening). A single ECG will be completed at all other 
visits. 
d 
A pregnancy test (serum at Visit 1 and urine at all other visits) is only required for women of child-bearing 
potential. If urine cannot be obtained in women of child-bearing potential, a serum pregnancy test should be 
done in its place. 
e 
The CGI-I should be scored relative to Visit 2, the subject’s open-label Baseline. 
f 
The ZBI should only be administered to study partners/caregivers who are family members. 
g 
Pharmacokinetic samples will also be collected, if possible, at any ET visit (Table 2) or the visit 
immediately following any SAE or following an AE leading to discontinuation. 
h 
A separate informed consent (and assent, if applicable) must be given for the pharmacogenomic component 
of the study. This consent may be obtained at any time during the study. If informed consent is given in 
time for sample collection at Visit 2, a pre-dose sample should be collected at Visit 2. If informed consent 
for pharmacogenomics is not given in time for sample collection at Visit 2, a sample may be collected any 
time after informed consent for pharmacogenomics is given. 
i 
Blinded study drug will be dispensed after randomization at Visit 6 (Week 12). 


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Table 2 Schedule of Assessments for Double-blind Period   
Visit week 
13 
14 
16 
18 
20 
22 
24 
26 
30 
34 
38/EOT 
42 
Allowable visit window (# days) 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
+7 
+3 
Visit Number 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17/ET 
18 
Visit Type (Clinic [C] or Telephone [T]) 
C 
C 
C 
C 
T 
C 
T 
C 
C 
C 
C 
T 
Mini-Mental State Examination 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Physical and neurological examinations 
 
 
 
 
 
X 
 
 
 
 
X 
 
Vital signs and weight 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
12-lead electrocardiogram 
 
 
 
X 
 
 
 
X 
 
 
X 
 
Clinical laboratory tests 
 
 
 
X 
 
 
 
X 
 
 
X 
 
Pregnancy testa 
 
 
 
 
 
 
 
X 
 
 
X 
 
SAPS-H+D 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Clinical Global Impression-Improvementb 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Clinical Global Impression-Severity 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Zarit Burden Interviewc 
 
 
 
X 
 
 
 
X 
 
 
X 
 
Karolinska Sleepiness Scale 
 
 
 
X 
 
 
 
X 
 
 
X 
 
EQ-5D-5L 
 
 
 
X 
 
 
 
X 
 
 
X 
 
Assessment for protocol-defined relapse criteria 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Assessment for concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Global Clinician Assessment of Suicidality 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Extrapyramidal Symptom Rating Scale A 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
Assessment for adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetic sample collectiond 
X 
 
 
 
 
X 
 
 
 
 
X 
 
Drug dispensation 
 
X 
X 
X 
 
X 
 
X 
X 
X 
 
 
Drug return and accountability 
Xe 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
 
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Abbreviations: EOT=end-of-treatment; ET=early termination; SAPS-H+D=Scale for the Assessment of Positive 
                 Symptoms, Hallucinations and Delusions subscales 
For additional details on study procedures, see Section 6 of the protocol. 
Note: All efforts should be made to complete visits in a single day. In the event of a split visit, the CGI-S/CGI-I 
and the SAPS H+D must be completed on the same day (pertinent for all visits). 
Note: When a subject is found to be appropriate for discontinuation from the trial, the visit during which this is 
determined should immediately be converted to an ET visit (as described in Table 2) and all procedures and 
assessments done at the ET visit (Week 38/EOT; Visit 17/EOT) should be completed (additional details 
provided in Section 4.4 of the protocol). Safety follow-up should be completed as scheduled.  
 
a 
A urine pregnancy test is only required for women of child-bearing potential. If urine cannot be obtained in 
women of child-bearing potential, a serum pregnancy test should be done in its place 
b 
The CGI-I should be scored relative to Visit 6 (Week12), the subject’s double-blind Baseline. 
c 
The ZBI should only be administered to study partners/caregivers who are family members. 
d 
Pharmacokinetic samples will also be collected, if possible, at the visit immediately following any SAE or 
following an AE leading to discontinuation. 
e 
Only drug accountability will be completed at this visit. 
 


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3.2 
Randomization 
At Week 12 (Visit 6), subjects who meet response criteria will be randomized in a 1:1 ratio to 
either continue receiving pimavanserin at the current dose level or to receive matched 
placebo, using an interactive response technology system. Randomization will be stratified 
by: 
• Most likely dementia subtype or most prominent cause of dementia (defined as 
designated dementia subtype): 
• Alzheimer’s disease or frontotemporal dementia (FTD) spectrum disorders 
• Vascular dementia 
• Parkinson’s disease dementia or dementia with Lewy bodies 
• Region (North America, Western Europe, Eastern Europe, Asia Pacific, Latin America) 
The assignments will be based on a pre-generated permuted-block randomization schedule. 
Blinding will be assured by restricting access of Investigators and Sponsor personnel and/or 
designee to the treatment codes, and providing identical tablets and packaging for the 
pimavanserin and placebo treatments. 
3.3 
Blinding 
All subjects will receive open-label pimavanserin (34 mg or 20 mg) during the open-label 
period of the study. 
Treatment assignment during the double-blind period will be double-blind such that neither 
the subjects, study partners/caregivers, Sponsor personnel who oversee the study, nor the 
Investigator and study personnel will know which treatment is assigned to each subject. 
3.4 
Determination of Sample Size 
This study will enroll approximately 356 subjects in order to randomize approximately 
178 subjects with dementia-related psychosis who meet response criteria at Weeks 8 and 12 
of the open-label period. 
The sample size calculation was based on the following assumptions: a placebo relapse event 
rate of 60% over 26 weeks; a pimavanserin relapse event rate of 35% over 26 weeks (hazard 
ratio = 0.47); a dropout rate of 25% over 26 weeks; an overall two-sided alpha level of 0.05; 
use of a one-sided (0.025) O’Brien-Fleming stopping boundary to adjust for a single interim 


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analysis that will be performed when one half of the total planned number of 
post-randomization relapse events have occurred; and a power of 90%. The total number of 
post-randomization relapse events required at the final analysis is 75 and the calculated 
sample size is 89 in each of the two treatment groups (giving a total estimate of 178 subjects). 
Study enrollment will be closed when approximately 178 subjects have been randomized in 
the double-blind period or when 75 adjudicated post-randomization relapse events have 
occurred. In the event that the randomization rate is lower than anticipated and/or the relapse 
event rate is lower than anticipated, the number enrolled and randomized may be increased 
up to a maximum of 400 randomized subjects in order to observe 75 post-randomization 
relapse events. If fewer than 75 post-randomization relapse events have been observed after 
400 randomized subjects have completed the study or terminated early, the study will end. 
An interim efficacy analysis will be performed, and the study may be terminated early if the 
interim analysis results meet prespecified stopping criteria.(see Section 16) 
4 ANALYSIS SETS 
4.1 
Intent-to-treat (ITT) Analysis Set 
The ITT Analysis Set will include all randomized subjects. Subjects will be analyzed based 
on their randomized treatment. The ITT Analysis Set will be used for analyses of the 
double-blind efficacy data. 
4.2 
Open-label Safety Analysis Set 
The Open-label Safety Analysis set will include all subjects who received at least one dose of 
open-label study drug (pimavanserin). The Open-label Safety Analysis Set will be used for 
analyses of the open-label data. 
4.3 
Double-blind Safety Analysis Set 
The Double-blind Safety analysis set will include all subjects who received at least one dose 
of double-blind study drug (pimavanserin or placebo). Subjects will be analyzed based on the 
treatment that they actually received. The Double-blind Safety Analysis Set will be used for 
all analyses of the double-blind safety data. 


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4.4 
Per-protocol Analysis Set 
The Per-protocol Analysis Set will consist of those subjects in the ITT Analysis Set without 
any protocol deviations which could potentially have a substantial impact on the primary 
efficacy outcome. The precise reasons for excluding subjects from the Per-protocol Analysis 
Set will be fully defined and documented prior to the clinical database lock. Subjects will be 
analyzed based on their randomized treatment.  
4.5 
Open-label Pharmacokinetic Analysis Set 
The Open-label Pharmacokinetic (PK) Analysis Set includes all subjects who have at least 
one measurable pimavanserin plasma concentration collected in the open-label period.  
4.6 
Double-blind Pharmacokinetic Analysis Set 
The Double-blind PK Analysis Set includes all subjects who have at least one measurable 
pimavanserin plasma concentration collected in the double-blind period. 
5 DATA HANDLING CONVENTIONS 
All data collected in the study will be listed. 
5.1 
General Data Reporting Conventions 
In general, listings will be sorted by randomized treatment group (placebo, pimavanserin), 
enrolled but not randomized, screen failure (screened but not enrolled), and subject ID, and 
all relevant data will be presented.  Data from screen failures will be included in listings 
where available.   
For continuous variables, the following summary statistics will be provided: number of 
subjects, mean, standard error of the mean (SE), standard deviation (SD), minimum, 
maximum, and median. For pharmacokinetic data, the geometric mean will also be provided. 
Unless specified otherwise, means, medians, and confidence intervals (CIs) will be presented 
to one more decimal place than the raw data, and the standard deviations and standard errors 
will be presented to 2 more decimal places than the raw data. 
For categorical variables, summaries will include the number and percentage of subjects in 
each category, using the number of subjects with non-missing values as the denominator for 


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the percentages (unless otherwise specified). Categories with zero counts will not have zero 
percentages displayed. Percentages will be presented to 1 decimal place.  
Unless specified otherwise, all statistical tests will be 2-sided hypothesis tests and all CIs will 
be 2-sided 95% CIs. Two-sided P-values will generally be presented to 4 decimal places; 
values less than 0.0001 will be presented as <0.0001. 
When converting number of days to months, it will be calculated as the number of days 
divided by 365.25 and then multiplied by 12. When converting number of days to years, it 
will be calculated as the number of days divided by 365.25. 
5.1.1 
Open-label Period 
In general, dates associated with open-label data will be accompanied on the listings by the 
study day relative to the date of first dose of open-label pimavanserin. Open-label study day 1 
is the date of first dose of open-label pimavanserin. 
For assessments occurring on or after the open-label study day 1, open-label study day is 
calculated for a given subject as 
assessment date – first open-label dose date + 1.  
For assessments occurring prior to the open-label study day 1, open-label study day is 
calculated for a given subject as 
assessment date – first open-label dose date. 
Unless specified otherwise, the following summaries will be provided: 
1. all subjects combined;  
2. by randomization status (not randomized and randomized);   
3. by final dose level (20 and 34 mg) of open-label pimavanserin administered during 
the open-label period.  
5.1.2 
Double-blind Period 
In general, dates associated with double-blind data points will be accompanied on the listings 
by the study day relative to the date of first dose of double-blind study drug. Double-blind 
study day 1 is the date of first dose of double-blind study drug. 


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For assessments occurring on or after the double-blind study day 1, double-blind study day is 
calculated for a given subject as  
assessment date – first double-blind dose date + 1. 
For assessments occurring prior to the double-blind study day 1, double-blind study day is 
calculated for a given subject as  
assessment date – first double-blind dose date.  
Unless specified otherwise, the following summaries will be provided:  
1. by treatment group (placebo and pimavanserin);     
2. by dose level (20 and 34 mg) of double-blind pimavanserin administered during the 
double-blind period for the pimavanserin group. 
5.2 
Derived Variables 
In general, the total scores and subscores for assessment scales will be derived within the 
analysis datasets. In the event that total scores and/or subscores are also collected on the 
electronic case report form (eCRF), the derived values will be used for all analyses. Both the 
raw and derived scores will be presented in listings. 
5.2.1 
Open-label Baseline 
Open-Label Baseline is defined as the last non-missing assessment, including those from 
repeated and unscheduled measurements, before the date of first dose of open-label 
pimavanserin. 
5.2.2 
Double-blind Baseline 
Double-Blind Baseline is defined as the last non-missing assessment, including those from 
repeated and unscheduled measurements, on or before the date of first dose of double-blind 
study drug. 
5.2.3 
Time from Randomization to Relapse in the Double-blind Period 
For subjects who experience a relapse event, the time to relapse will be calculated as  
date of relapse – date of randomization + 1. 
For the primary efficacy endpoint the date of relapse is determined by the IAC. 


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Subjects who complete the 26-week double-blind period, those who discontinue early, and 
those who are ongoing at the time of the applicable analysis cutoff, without experiencing a 
relapse event, will be censored at the time of the last applicable SAPS-H+D assessment. See 
Section 13.1 for further details regarding the analysis cutoffs, and Section 13.2.2 for 
censoring times for sensitivity analyses. The censored follow-up time will be calculated as:  
date of last applicable SAPS-H+D assessment – date of randomization + 1. 
Subjects who have not experienced a relapse event and do not have any post-baseline 
SAPS-H+D assessments in the double-blind period, will be censored at the time of 
randomization. The censored follow-up time will have a value of 1 day.  
5.2.4 
Time from Randomization to Discontinuation from the Double-blind Period for 
Any Reason  
For subjects who experience a relapse event, the time to discontinuation will be calculated as: 
date of relapse – date of randomization + 1. 
For subjects who don’t experience a relapse event and who discontinue early from the 
double-blind period, prior to the study discontinuation date, for any reason other than 
termination of the study by the sponsor, the time to discontinuation will be calculated as: 
date of last dose  – date of randomization + 1. 
Subjects who don’t experience a relapse event and who complete the 26-week double-blind 
period will be censored at the date of last dose. The censored follow-up time will be 
calculated as: 
date of last dose  – date of randomization + 1. 
All subjects who are ongoing in the 26-week double-blind period at the time of study 
discontinuation by the sponsor will be censored at the study discontinuation date. The 
censored follow-up time will be calculated as 
study discontinuation date – date of randomization + 1. 
All subjects who are ongoing in the 26-week double-blind period at the time of the database 
cutoff for the interim analysis will be censored at the database cutoff date. The censored 
follow-up time will be calculated as 


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date of database cutoff – date of randomization + 1. 
5.2.5 
Scale for the Assessment of Positive Symptoms-Hallucinations + Delusions 
The Scale for the Assessment of Positive Symptoms-Hallucinations + Delusions (SAPS-H+D) 
is assessed at Screening, Baseline (Week 0), and Weeks 2, 4, 8, and 12 during the open-label 
period, and at Weeks 13, 14, 16, 18, 22, 26, 30, 34, and 38 during the double-blind period. 
The SAPS was designed to measure positive psychotic symptoms. Positive symptoms include 
hallucinations, delusions, abnormalities in language and behavior, and disordered thought 
processes. The SAPS-H+D subscales will be administered in this study. The Hallucinations and 
Delusions subscales consist of 20 items, including 2 global ratings of severity for hallucinations 
(H7) and delusions (D13). Each of the 20 items is scored on a 6-point scale (0=none, 
1=questionable, 2=mild, 3=moderate, 4=marked, 5=severe). The SAPS-H+D total score is the 
sum of the 20 item scores with a possible range of 0 to 100. Higher scores denote more severe 
symptoms. The hallucinations score (SAPS-H) is the sum of the 7 hallucinations item scores 
and the delusions score (SAPS-D) is the sum of the 13 delusions item scores. 
Missing SAPS-H+D item scores will not be imputed. The total score will be missing if any 
item score is missing. Similarly, the SAPS-H and SAPS-D scores will be missing if any 
component item score is missing. 
5.2.6 
Clinical Global Impressions – Severity Scale 
The Clinical Global Impressions – Severity (CGI-S) scale is assessed at Screening, Baseline 
(Week 0), and Weeks 2, 4, 8, and 12 during the open-label period, and at Weeks 13, 14, 16, 18, 
22, 26, 30, 34, and 38 during the double-blind period. 
The CGI-S scale is a clinician-rated, 7-point scale that is designed to rate the severity of the 
subject’s hallucinations and delusions at the time of assessment using the Investigator’s 
judgment and past experience with subjects who have the same disorder (i.e., 
dementia-related psychosis).  The possible scores are 1=normal, not at all ill, 2=borderline ill, 
3=mildly ill, 4=moderately ill, 5=markedly ill, 6=severely ill, 7=among the most extremely 
ill patients. 
Missing CGI-S scores will not be imputed. 


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5.2.7 
Clinical Global Impressions – Improvement Scale 
The Clinical Global Impressions – Improvement (CGI-I) scale is assessed at Weeks 2, 4, 8, 
and 12 during the open-label period, and at Weeks 13, 14, 16, 18, 22, 26, 30, 34, and 38 during 
the double-blind period. 
The CGI-I scale is a clinician-rated, 7-point scale that is designed to rate the improvement in 
the subject’s hallucinations and delusions at the time of assessment, relative to the symptoms 
at Baseline (relative to open-label Baseline for response criteria and relative to double-blind 
Baseline for relapse criteria). The possible scores are 1=very much improved, 2=much 
improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, 7=very 
much worse. 
Missing CGI-I scores will not be imputed. 
5.2.8 
Zarit Burden Interview 
The Zarit Burden Interview (ZBI) is assessed at Baseline (Week 0) and Week 12 during the 
open-label period, and at Weeks 18, 26, and 38 during the double-blind period.  
The ZBI was designed to assess the stress experienced by caregivers of patients with 
dementia. The ZBI will be administered as an interview. The interview consists of 22 
statements reflecting how people sometimes feel when taking care of another person. The 
statements are phrased as questions for a caregiver who is a family member to indicate how 
often they feel the way described in the statement. Responses are Never, Rarely, Sometimes, 
Quite Frequently, and Nearly Always. When the study caregiver is not a family member or 
when the study caregiver changes, this scale will not be completed. Each of the responses is 
scored from 0 to 4. The ZBI total score is the sum of the 22 item scores with a possible range 
of 0 to 88. Higher scores denote greater stress.  
Missing scores will not be imputed. The total score will be missing if any item score is 
missing. 
5.2.9 
Karolinska Sleepiness Scale 
The Karolinska Sleepiness Scale (KSS) is assessed at Baseline (Week 0) and Week 12 during 
the open-label period, and at Weeks 18, 26, and 38 during the double-blind period. 


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The KSS is a self-reported subjective measure of a subject’s level of drowsiness.  Scoring is 
based on a 9-point verbally anchored scale going from “1 = extremely alert” to “9 = very 
sleepy, great effort to keep awake, fighting sleep”.  
Missing KSS scores will not be imputed. 
5.2.10 EQ-5D-5L Proxy Version 1 
The EQ-5D-5L Proxy Version 1 is assessed at Baseline (Week 0) and Week 12 during the 
open-label period, and at Weeks 18, 26, and 38 during the double-blind period. 
The EQ-5D-5L is a standardized instrument used as a measure of health outcome. The 
EQ-5D-5L Proxy version 1 will be used. For this version, the study partner/caregiver (the 
proxy) is asked to rate subject's health-related quality of life in their (the proxy’s) opinion. 
The EQ-5D consists of the EQ-5D-5L descriptive system and the EQ-5D Visual Analogue 
scale (EQ-5D VAS). 
The EQ-5D-5L descriptive system consists of 5 dimensions: mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels (responses): 
no problem (1), slight problems (2), moderate problems (3), severe problems (4), and 
extreme problems (5). The digits for the 5 dimensions are combined into a 5-digit code that 
describes the subject’s health state. 
The EQ-5D VAS records the subject’s health on a vertical visual analogue scale, where the 
upper endpoint is labelled “The best health you can imagine” and is numbered 100, while the 
lower endpoint is labelled “The worst health you can imagine” and is numbered 0. The 
EQ-5D VAS will be treated as a continuous endpoint. 
Missing values will not be imputed for either the EQ-5D-5L descriptive system or EQ-5D 
VAS. 
5.2.11 Global Clinician Assessment of Suicidality 
The Global Clinician Assessment of Suicidality (GCAS) is assesse d at Screening, Baseline 
(Week 0), and Weeks 2, 4, 8, and 12 during the open-label period, and at Weeks 13, 14, 16, 
18, 20, 22, 24, 26, 30, 34, and 38 during the double-blind period. 


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GCAS is a clinician-rated, 5-point scale that is designed to rate the subject’s suicidality based 
on the report of the subject, the report of the study partner/caregiver, and the clinician’s 
global assessment. Ratings can be 0 (“Absent”), 1 (“Feels life is not worth living”), 
2 (“Wishes he/she were dead or any thoughts of possible death to self”), 3 (“Suicidal ideas or 
gesture”), or 4 (“Attempt at suicide”). The Investigator will record a subject rating, a study 
partner/caregiver rating, and a clinician rating (only the clinician rating is entered in the 
database). At Screening visit, lifetime suicidality and suicidality for the past 3 months will be 
assessed and at all other visits suicidality since the previous visit will be assessed. 
Missing GCAS scores will not be imputed. 
5.2.12 Mini-Mental State Examination 
The Mini-Mental State Examination (MMSE) is assessed at Screening, Baseline (Week 0), 
and Weeks 2, 4, 8, and 12 during the open-label period, and at Weeks 13, 14, 16, 18, 22, 26, 
30, 34, and 38 during the double-blind period. 
The MMSE consists of an 11-domain, 30-point questionnaire that is used to quantitatively 
assess cognition. The MMSE is being used in this study to screen for cognitive impairment 
and as a safety measure. Total score of MMSE is calculated as the sum of the 11 area scores. 
Lower scores denote more severe cognitive impairment.  
Missing scores will not be imputed. The total score will be missing if any area score is 
missing. 
5.2.13 Extrapyramidal Symptom Rating Scale-Abbreviated 
The Extrapyramidal Symptom Rating Scale-Abbreviated (ESRS-A) is assessed at Baseline 
(Week 0) and Week 12 during the open-label period, and at Weeks 13, 14, 16, 18, 22, 26, 30, 
34, and 38 during the double-blind period.  
ESRS-A, derived from the original ESRS, was designed as a more concise instrument for 
assessing the four types of drug-induced movement disorders Parkinsonism, akathisia, 
dystonia, and dyskinesia.  ESRS-A consists of 4 subscales and 4 clinical global impression 
movement severity (CGI-S) scales of Parkinsonism, dyskinesia, dystonia, and akathisia. 


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The Parkinsonism subscale consists of 10 items, the dyskinesia subscale consists of 6 items, the 
dystonia subscale consists of 6 items, and the akathisia subscale consists of 2 items. Each item 
is scored on a 6-point scale (0=absent, 1=minimal, 2=mild, 3=moderate, 4=severe, 5=extreme). 
The ESRS-A total score is the sum of the 24 item scores with a possible range of 0 to 120. 
Higher scores denote more severe symptoms of a movement disorder. 
Missing ESRS-A item scores of the 4 subscales will not be imputed. The ESRS-A total score 
will be missing if any item score of the 4 subscales is missing.  
Each CGI-S scale of Parkinsonism, dyskinesia, dystonia, and akathisia is a single-item 6-point 
scale (0=absent, 1=minimal, 2=mild, 3=moderate, 4=severe, 5=extreme). The score ranges 
from 0 to 5, with higher scores indicating more severe movement disorders.  Missing CGI-S 
score will not be imputed. 
5.3 
Analysis Visit Windows 
5.3.1 
Open-label Period 
Efficacy, safety and pharmacokinetic assessments for the open-label (OL) period will be 
summarized by analysis visit as presented in Table 3. For exploratory efficacy endpoints and 
MMSE, assessments more than 14 days after last dose of study drug will be assigned an 
analysis visit but will not be selected for the by-visit analyses.  
 
 


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Table 3 Analysis Visit Windows for the Open-label Period 
Study Visit 
Analysis Visit 
Target OL Study Daya 
Study Day Interval 
Week 0 
OL Baseline 
1 
<1 
Week 2 
OL Week 2 
15 
2 to 21 
Week 4 
OL Week 4 
29 
22 to 42 
Week 8 
OL Week 8 
57 
43 to 70 
Week 12 
OL Week 12 
85 
71 to 98 (or day of first dose of 
double-blind study drugb) 
aDerivation of open-label study day is described in Section 5.1.1. Open-label study day 1 is the date of first dose   
 of open-label pimavanserin. 
bFor subjects who are randomized in the double-blind period. 
5.3.2 
Double-blind Period 
Efficacy, safety, and pharmacokinetic assessments for the double-blind (DB) period will be 
summarized by analysis visit as presented in Table 4. For exploratory efficacy endpoints and 
MMSE, assessments more than 14 days after last dose of study drug will be assigned an 
analysis visit but will not be selected for the by-visit analyses. 
Table 4 Analysis Visit Windows for the Double-Blind Period 
Study Visit 
Analysis Visit 
Target DB Study Daya 
Study Day Interval 
Week 12 
DB Baseline 
1  
≤1 
Week 13 
DB Week 1 
8 
2 to 11 
Week 14 
DB Week 2 
15 
12 to 21 
Week 16 
DB Week 4 
29 
22 to 35 
Week 18 
DB Week 6 
43 
36 to 49 
Week 20 
DB Week 8 
57 
50 to 62 
Week 22 
DB Week 10 
71 
63 to 77 
Week 24 
DB Week 12 
85 
78 to 91 
Week 26 
DB Week 14 
99 
92 to 112 
Week 30 
DB Week 18 
127 
113 to 140 
Week 34 
DB Week 22 
155 
141 to 168 
Week 38 
DB Week 26 
183 
169 to 197 
aDerivation of double-blind study day is described in Section 5.1.2. Double-blind study day 1 is the date of first 
dose of double-blind study drug.  
5.3.3 
Unscheduled Assessments 
Unscheduled assessments, including the assessments at early termination visits, will be 
considered for planned time point analyses. All assessments will be presented in data listings. 


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5.3.4 
Multiple Measurements within Visit Windows 
For endpoints other than the exploratory efficacy endpoints and MMSE, if more than one 
assessment falls within a study visit then the assessment closest to the target study day will be 
selected for the by-visit analyses. For exploratory efficacy endpoints and MMSE, if more 
than one assessment falls within a study visit and each of them were collected within 14 days 
of last dose of study drug then the assessment closest to the target study day will be selected 
for the by-visit analyses.  In these analyses, if two eligible assessments are equidistant from 
the target day then the chronologically last assessment will be used. Exceptions may be made 
for incomplete assessments, in which case, more complete assessments may be given 
priority.  Details are provided in a separate programming conventions document. 
For both open-label and double-blind safety analysis where the most extreme values should 
be selected (e.g. overall post-baseline minimum, overall post-baseline maximum, and 
potentially clinically important values), all non-missing post-baseline values should be 
considered, regardless of whether the value is selected for the by-visit summaries. All results 
will be presented in data listings. 
When ECG is collected in triplicate at screening, the average of the triplicate will be 
considered as one assessment for the analysis. 
5.4 
Data Handling Conventions 
In the Open-label and Double-blind Safety Analysis Set, if the last dose date of study drug is 
missing for a subject who completed or early terminated from the study, then the date of the 
end-of-study/early termination visit will be used in the calculation of treatment duration. For 
the incomplete last dose date of the study drug with respect to the open-label or double-blind 
period, the imputation algorithms will be detailed in the analysis dataset specification 
document. The missing or incomplete dates will be displayed in the data listings as reported 
on the eCRF rather than the imputed dates. 
For the data summarization at the time of the database cutoff for the interim analysis, if a 
subject is still ongoing, then this subject’s last dose date will be imputed using the database 
cutoff date. 


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5.4.1 
Missing or Incomplete Dates for Prior or Concomitant Medications 
Missing or incomplete medication start or end dates will be imputed for the purpose of 
determining whether the medications are taken concomitantly (see Section 10 for definition). 
When the chronological order of medication use relative to the study drug treatment period is 
unclear due to missing or incomplete date(s), the medication will be considered as 
concomitant. The imputation algorithms will be detailed in the analysis dataset specification 
document. The missing or incomplete dates will be displayed in the data listings as reported 
on the eCRF rather than the imputed dates. 
5.4.2 
Missing or Incomplete Dates for Adverse Events  
Missing or incomplete adverse event (AE) start dates will be imputed for the purpose of 
determining whether the AEs are treatment-emergent (see Section 14.1 for definition). When 
the chronological order of an AE onset relative to the study drug treatment period is unclear 
due to missing or incomplete date(s), the AE will be considered as treatment-emergent. The 
imputation algorithms will be detailed in the analysis dataset specification document. The 
missing or incomplete dates will be displayed in the data listings as reported on the eCRF 
rather than the imputed dates. 
5.4.3 
Missing Severity Assessment for Adverse Events 
If severity is missing for an AE starting prior to the date of the first dose of study drug, then a 
severity of “Mild” will be assigned. If the severity is missing for an AE starting on or after 
the date of the first dose of study drug, then a severity of “Severe” will be assigned. The 
imputed values for severity assessment will be used for incidence summaries, and the actual 
values will be used in data listings. 
5.4.4 
Missing Relationship to Study Drug for Adverse Events 
If the relationship to study drug is missing for an AE starting on or after the date of the first 
dose of study drug, a causality of “Related” will be assigned. The imputed values for 
relationship to study drug will be used for incidence summaries, and the actual values will be 
presented in data listings. 


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5.4.5 
Character Values of Clinical Laboratory Variables  
If the reported value of a clinical laboratory variable cannot be used in a statistical analysis 
due to, for example, a character string reported for a numeric variable, an appropriately 
determined coded value may be used in the statistical analysis. The coding algorithms will be 
detailed in the analysis dataset specification document. The actual values as reported in the 
database will be presented in data listings. 
6 SUBJECT DISPOSITION 
The number and percentage of sites that screened at least 1 subject, enrolled at least 1 subject, 
and randomized at least 1 subject will be summarized by region and all regions combined. 
The number and percentage of subjects screened, unique subjects screened, subjects enrolled, 
and subjects randomized will be summarized by region and all regions combined. 
6.1 
Analysis for the Open-label Period 
Subject disposition for the open-label period will be summarized for the Open-label Analysis 
Set. The number and percentage of subjects who were randomized to the double-blind period, 
completed 12 weeks of open-label period, discontinued, or are ongoing at the time of 
database cutoff will be presented. The number and percentage of subjects meeting the 
following discontinuation reasons will be tabulated: 
• Lack of response in open-label; 
• Adverse event; 
• Death; 
• Non-compliance with study drug; 
• Used of prohibited medications; 
• Physician decision; 
• Pregnancy; 
• Protocol violation; 
• Study terminated by Sponsor; 
• Subject withdrew consent; 
• Lost to follow-up; 
• Other. 


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6.2 
Analysis for the Double-blind Period 
Subject disposition for the double-blind period will be summarized for the ITT Analysis Set, 
Per-protocol Analysis Set, and Double-blind Safety Analysis Set. The number and percentage 
of subjects who completed the study, discontinued, or are ongoing at the time of database 
cutoff will be presented. The number and percentage of subjects meeting the following 
discontinuation reasons will be tabulated: 
• Relapse of hallucinations and delusions associated with dementia-related psychosis; 
• Adverse event; 
• Death; 
• Non-compliance with study drug; 
• Used of prohibited medications; 
• Physician decision; 
• Pregnancy; 
• Protocol violation; 
• Study terminated by Sponsor; 
• Subject withdrew consent; 
• Lost to follow-up; 
• Other. 
The number and percentage of subjects in the ITT Analysis Set who are excluded from the 
Per-protocol Analysis Set will be presented in a summary table by exclusion reason. 
6.3 
Screen Failure 
For subjects who participate in the screening phase and are screen failures, their 
demographics information (including age, sex, and primary race), screen failure reasons (the 
specific inclusion/exclusion criterion (or criteria) not met or other reason) and protocol 
version will be listed. If a subject is re-screened, then the re-screening subject ID and the 
final enrollment status (whether eventually enrolled) will also be displayed in this listing. In 


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addition, the frequency that the screen failure reasons are reported will also be summarized. 
Note that a subject may be deemed ineligible for multiple inclusion/exclusion criteria and 
may be allowed to rescreen with the permission of the Medical Monitor, provided the screen 
failure was due to a temporary condition that subsequently resolved.    
7 PROTOCOL DEVIATIONS 
Protocol deviations will be reviewed periodically over the course of the study. The review 
process, definition of the deviation categories, and the classification of a deviation as major 
or minor are detailed in the Protocol Deviation Management Plan. 
A protocol deviation for a given subject that occurs on or after the date of first dose of 
double-blind study drug will be assigned to double-blind period, otherwise it will be assigned 
to the open-label period.  A summary of the number and percentage of subjects with major 
protocol deviations for each deviation category will be presented. A listing of protocol 
deviations by site and subject will also be provided. 
Major protocol deviations occurring in the open-label period will be summarized for the 
Open-label Safety Analysis Set. Summaries for the ITT Analysis Set will include major 
protocol deviations from both open-label and double-blind study periods. 
8 DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
8.1 
Demographics 
Demographic variables will be summarized using descriptive statistics for the Open-label 
Safety Analysis Set, ITT Analysis Set, Double-blind Safety Analysis Set, and Per-protocol 
Analysis Set. Demographic variables include age, sex, primary race (subjects of multi-racial 
background can only identify/select one primary race on eCRF, or choose “other” and 
specify), ethnicity, height, weight, BMI, region, subject living situation, and partner/caregiver 
relationship.  
The reported age reflects a subject’s age at the informed consent date. Age will be presented 
as both continuous and categorical variables. Age categories will be presented as <65, 65 – 
74, 75 – 84, and ≥85 years old.  


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8.2 
Disease Characteristics 
Disease characteristics will be summarized descriptively for the Open-label Safety Analysis 
Set, ITT Analysis Set, Double-blind Safety Analysis Set, and Per-protocol Analysis Set. 
Dementia subtype: Alzheimer’s disease, FTD spectrum disorders, vascular dementia, 
Parkinson’s disease dementia, and dementia with Lewy bodies; and dementia severity will be 
presented as a categorical variable. Open-label and double-blind Baseline MMSE total score, 
SAPS-H+D total score, ZBI score, KSS score, EQ-5D VAS score, and CGI-S score will be 
presented as continuous variables. In addition, open-label and double-blind Baseline CGI-S 
score will be presented as categorical variables using categories of 1 to 7.  
Neuropsychiatric history will be summarized descriptively for continuous and categorical 
variables.  
9 MEDICAL HISTORY 
Medical history will be summarized descriptively for the Open-label Safety Analysis Set, ITT 
Analysis Set, Double-blind Safety Analysis Set, and Per-protocol Analysis Set.  
Medical history data will be coded using Medical Dictionary for Regulatory activities 
(MedDRA) version 20.0 or newer. The subject incidence will be summarized for each system 
organ class (SOC) and preferred term. A subject will be counted only once per SOC or per 
preferred term for the summary. 
A listing of the SOC, preferred term, body system, verbatim term for the medical history 
condition/event, start and stop dates (when available), and an indicator for whether or not the 
condition is ongoing will be provided. 
10 PRIOR, CONCOMITANT AND POST-TREATMENT MEDICATION 
Medications will be coded using WHO Drug Dictionary (WHODrug-DDE-B2) 2017 March 
or newer version. The number and percentage of subjects taking each drug class (ATC Level 
3) and medication preferred term will be tabulated. Multiple medication usage by a subject in 
the same category will be counted only once. Prior, concomitant, and post-treatment 
medications will be summarized separately.  


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10.1 Prior Medication 
Prior medication is defined as any medication with a start and stop date prior to the date of 
the first dose of open-label pimavanserin.  Summaries of prior medications will be provided 
for the Open-label Safety Analysis Set and Double-blind Safety Analysis Set. 
10.2 Concomitant Medication 
10.2.1 Analysis for the Open-label Period 
Concomitant medication during the open-label period is defined as any medication with a 
start date prior to the date of first dose of open-label pimavanserin and continuing after the 
date of first dose of open-label pimavanserin or with a start date between the date of the first 
dose of open-label pimavanserin and before the date of the first dose of double-blind study 
drug for subjects randomized into the double-blind period or last dose in the open-label 
period for subjects not randomized, inclusive. Concomitant medications during the 
open-label period will be summarized for the Open-label Safety Analysis Set. 
10.2.2 Analysis for the Double-Blind Period 
Concomitant medication during the double-blind period is defined as any medication with a 
start date prior to the date of first dose of double-blind study drug and continuing after the 
date of first dose of double-blind study drug or with a start date between the dates of the first 
and last doses of double-blind study drug, inclusive. Concomitant medications during the 
double-blind period will be summarized for the Double-blind Safety Analysis Set. 
10.3 Analysis for Post-Treatment Medication 
Post-treatment medication is defined as any medication with a start date after the date of the 
last dose of open-label pimavanserin for non-randomized subjects and after the date of the 
last dose of double-blind study drug for randomized subjects. Summaries of post-treatment 
medications will be provided for the Open-label Safety Analysis Set. 


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11 EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE 
11.1 Exposure to Study Drug 
The duration of exposure during the open-label period and the double-blind period for a 
given subject will be calculated separately. Duration of exposure to study drug will be 
summarized descriptively as both continuous and categorical variables for the open-label 
period and the double-blind period. 
11.1.1 Analysis for the Open-label Period  
Duration of exposure during the open-label period for a given subject is calculated as 
follows: 
OL Duration of exposure = last OL dose date – first OL dose date + 1. 
For the categorical presentation of duration of exposure during the open-label period, the 
number and percentage of subjects in each of the following categories will be displayed: 
<1 week, 1 to <2 weeks, 2 to <4 weeks, 4 to <8 weeks, 8 to <12 weeks, and ≥12 weeks. 
Summaries of duration of exposure will be provided for the Open-label Safety Analysis Set. 
Kaplan-Meier curves of duration of exposure will also be provided. 
11.1.2 Analysis for the Double-blind Period 
Duration of exposure during the double-blind period for a given subject is calculated as 
follows: 
DB Duration of exposure = last DB dose date – first DB dose date + 1 
For the categorical presentation of duration of exposure during the double-blind period, the 
number and percentage of subjects in each of the following categories will be displayed: 
<1 week, 1 to <2 weeks, 2 to <4 weeks, 4 to <8 weeks, 8 to <12 weeks, 12 to <18 weeks, 18 
to <26 weeks, and ≥26 weeks. Summaries of duration of exposure will be provided for the 
Double-blind Safety Analysis Set. In addition, Kaplan-Meier curves of duration of exposure 
will be provided.  


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11.2 Study Drug Compliance 
Study drug dosing compliance (in percentage) for the open-label period and the double-blind 
period for a given subject will be calculated separately. Study drug compliance will be 
summarized descriptively as both continuous and categorical variables for the open-label 
period and the double-blind period. For the categorical presentation, the number and 
percentage of subjects in each of the following categories will be presented: <80%, 80 to 
120%, and >120%. 
11.2.1 Analysis for the Open-label Period 
Study drug compliance during the open-label (OL) period for a given subject is calculated as 
follows: 
Compliance = ൤OL tablets dispensed −OL tablets returned
2 × OL duration of exposure
൨× 100% 
Summaries of compliance will be provided for the Open-label Safety Analysis Set.  
11.2.2 Analysis for the Double-blind Period 
Study drug compliance (in percentage) during the double-blind (DB) period for a given 
subject is calculated as follows: 
Compliance = ൤DB tablets dispensed −DB tablets returned
2 × DB duration of exposure
൨× 100% 
Summaries of compliance will be provided for the Double-blind Safety Analysis Set. 
12 EFFICACY ANALYSES 
Efficacy analyses of the primary and key secondary endpoints for the double-blind period 
will be performed on the ITT Analysis Set and the Per-protocol Analysis Set. Efficacy 
analyses of the exploratory efficacy endpoints for  double-blind period will be performed on 
the ITT Analysis Set. The following summaries will be provided: 
1. by treatment group (placebo and pimavanserin); 
2. by dose level (20 and 34 mg) of double-blind pimavanserin administered during the 
double-blind period for the pimavanserin group. No formal comparisons between the 
dose levels (20 and 34 mg) will be performed. 


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12.1   Efficacy Variables 
12.1.1 Primary Endpoint 
The primary endpoint is the time from randomization to relapse in the double-blind period.  
12.1.2 Key Secondary Endpoint 
The key secondary endpoint is time from randomization to discontinuation from the 
double-blind period for any reason (other than termination of the study by the sponsor). 
12.1.3 Exploratory Study Endpoints 
Change from double-blind Baseline on the following: 
• Scale for the Assessment of Positive Symptoms-Hallucinations+Delusions 
(SAPS-H+D) score 
• SAPS Hallucinations domain score 
• SAPS Delusions domain score 
• Clinical Global Impression-Severity (CGI-S)-dementia-related psychosis 
• Zarit Burden Interview (ZBI) score 
• Karolinska Sleepiness Scale (KSS) score 
• EQ-5D VAS score and EQ-5D-5L descriptive system 
• Clinical Global Impression-Improvement (CGI-I)-dementia-related psychosis 
12.2 Adjustment for Covariates 
For time-to-event variables analyzed using the Cox regression model, region and designated 
dementia subtype (as defined by randomization strata) will be included as covariates as 
described in Section 13. 
For continuous variables (except CGI-I) analyzed using a mixed model for repeated measures 
(MMRM) or an analysis of covariance (ANCOVA), the Baseline value of the endpoint being 
analyzed, region, and designated dementia subtype will be included as covariates as 
described in Section 13.3. For CGI-I, the Baseline CGI-S score, region, and designated 
dementia subtype will be included as covariates in the MMRM and ANCOVA analyses. 


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12.3 Handling of Informative Censoring 
The primary time-to-event analysis using the Cox regression model assumes the censoring 
times are independent of the event times (i.e., the censoring is non-informative). The 
robustness of the primary analysis results to certain deviations from non-informative 
censoring will be evaluated using a reference-based multiple imputation method (Lu et. 
al.,2015).  Further details are provided in Section 13.1.1. 
12.4 Multiple Comparisons/Multiplicity 
A hierarchical testing procedure will be used to control the overall type I error rate for the 
primary and key secondary efficacy endpoints. Hypothesis testing will occur in the following 
sequential order: 
1. Primary endpoint 
2. Key secondary endpoint 
Adjustment of the analyses of the primary and key secondary efficacy endpoints to account 
for the interim efficacy analysis is described in Section 16. 
12.5 Examination of Subgroups 
12.5.1 Double-Blind Period 
Treatment comparisons will be made with respect to the primary and key secondary efficacy 
variables using the Cox regression described in Sections 13.1 and 13.2 for the following 
subgroups:  
• Region (North America, Western Europe, Eastern Europe, Asia Pacific, Latin 
America) 
• Designated dementia subtype (Alzheimer’s disease or FTD spectrum disorders, 
Vascular dementia, Parkinson’s disease dementia or dementia with Lewy bodies) 
• Parkinson’s disease dementia (yes) 
• Alzheimer’s disease (yes) 
• FTD spectrum disorders (yes) 


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• Dementia with Lewy bodies (yes) 
• Age group (<75 or ≥75 years old) 
• Sex (male or female) 
• Primary race (white or non-white) 
• Screening dementia severity (mild, moderate, severe) 
• OL Baseline antidementia medication (memantine and/or acetylcholinesterase 
inhibitors) use (yes, no) 
• Antipsychotic use within 14 days of screening (yes, no).  
• OL Baseline MMSE (<18, ≥18) 
For each subgroup, Kaplan-Meier curves of time to relapse and time to discontinuation from 
the double-blind period for any reason (other than termination of the study by the sponsor) 
will be presented for each treatment group. The hazard ratios with corresponding 95% CIs 
obtained from the Cox regression model for each subgroup will be presented in forest plots 
for the primary and key secondary efficacy variables. 
12.5.2 Open-Label Period 
For each subgroup listed above, the number and percentage of subjects in the Open-label 
Safety Analysis Set who met the response criteria for randomization will be summarized. 
SAPS-H+D, SAPS-H, and SAPS-D assessments from the open-label period for the 
Open-label Safety Analysis Set will be descriptively summarized (Section 13.3.2) by 
designated dementia subtype.  
13 METHODS OF EFFICACY ANALYSES 
13.1 Primary Efficacy Analysis 
The primary efficacy endpoint is the time from randomization to relapse in the double-blind 
period. The hypotheses are stated in terms of the hazard ratio, HR= λPIM / λPBO, where λPIM 
and λPBO denote the hazard rates of relapse for the pimavanserin group (20 mg and 34 mg 
combined) and the placebo group, respectively.  


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The null hypothesis for the primary efficacy endpoint is: HR = 1 
The alternative hypothesis for the primary efficacy endpoint is: HR ≠ 1  
The primary efficacy analysis will be based on adjudicated relapse events determined by the 
IAC for the ITT Analysis Set. If the study is stopped at the interim analysis, the primary 
efficacy analysis will be based on the interim analysis dataset (see Section 16 for additional 
details). If the study is not stopped at the interim analysis, the primary analysis will be based 
on all data collected up until the study discontinuation date; data collected after the study 
discontinuation date will not be used in the primary analysis. 
The treatment effect will be measured by the HR. The pimavanserin group includes all 
subjects taking pimavanserin irrespective of the dose (20 mg or 34 mg). The time from 
randomization to relapse in the double-blind period will be compared between treatment 
groups using a Cox regression model with effects for treatment group, designated dementia 
subtype (Alzheimer’s disease or FTD spectrum disorders, Vascular dementia, Parkinson’s 
disease dementia or dementia with Lewy bodies), and region (levels: North America, Western 
Europe, Eastern Europe, Asia Pacific, Latin America) as covariates in the model. A robust 
sandwich-type variance method will be applied to compute the variance of the estimated HR 
(Lin et. al., 1989), which can be computed as DʹD where D is the matrix of DFBETA 
residuals. The Cox exact discrete method will be used to compute the partial likelihood 
function to account for tied relapse times. The estimated HR, SE, 95% confidence interval, 
and p-value obtained from the Cox regression model will be presented. The algorithm for 
censoring of subjects who discontinued early, completed the study without having 
experienced a relapse event, or were ongoing at the time of database cutoff is described in 
Section 5.2.3. The number and percentage of subjects having the following possible reasons 
for censoring will be tabulated for each treatment group: 
• Completed Week 26 without relapse; 
• Prematurely discontinued prior to Week 26, for reasons other than termination of the 
study by the sponsor; 
• Ongoing at the time of database cutoff (for the interim analysis only); 
• Termination of the study by the sponsor (for the final analysis only). 


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Kaplan-Meier curves of time from randomization to relapse will be presented for each 
treatment group. In addition, Kaplan-Meier estimate of median survival (relapse free time) 
and probability estimates at the double-blind Weeks 4, 8, 12, 18, and 26 along with pointwise 
95% confidence intervals will be provided. The confidence intervals will be calculated using 
a log-log transformation and Greenwood’s variance formula.  
The number and percentage of subjects meeting at least one of the following relapse criteria 
will be tabulated for each treatment group: 
• Experienced a ≥30% increase (worsening) on the SAPS-H+D total score AND has a 
CGI-I score of 6 (much worse) or 7 (very much worse),  relative to the double-blind 
Baseline; 
• Treated with an antipsychotic (other than pimavanserin) for dementia-related 
delusions and/or hallucinations; 
• Stopped study drug or withdrew from study for lack of efficacy, (as reported by the 
subject or study partner/caregiver) or the Investigator discontinues study drug due to 
lack of efficacy; 
• Hospitalized for worsening dementia-related psychosis. 
The number and percentage of subjects meeting each of the relapse criteria will be tabulated. 
A subject who meets more than one of the relapse criteria will be counted once for each of 
the relapse criteria that were met.  
13.1.1 Deviations From Non-Informative Censoring 
One of the assumptions underlying the primary analysis is that the censoring mechanism is 
non-informative. In order to assess the sensitivity of the primary analysis to deviations from 
this assumption, a reference-based multiple imputation method will be used (Lu et. al., 2015). 
Subjects who don’t relapse but who discontinue from the study prior to the Week 26 
assessment, for any reason other than termination of the study by the sponsor, will have time 
to relapse values imputed conditionally on their observed censored values. Censoring due to 
completion of the 26 week double-blind period, study being terminated by the sponsor or 
ongoing at the time of the interim analysis datacut (for the interim analysis only), will be 
treated as non-informative and no imputation will be performed for these subjects. The 


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imputation algorithm will be based on the assumption that the risk of relapse (i.e. hazard rate) 
for pimavanserin subjects who prematurely discontinue is the same as that for placebo 
subjects. If the imputed event time exceeds the applicable cutoff date for a planned analysis, 
or the date corresponding to Week 26 for the subject, whichever comes first, the 
time-to-event will be right censored at the earlier of the two dates. Random number seeds of 
201938 and 202075 will be used for the posterior draw of model parameters from the 
imputation model and for imputation of censored event times, respectively. A total of 1000 
imputed datasets will be created.  
The imputation model will be a Cox regression model with piecewise exponential baseline 
hazards fit to the ITT Analysis Set with treatment, designated dementia subtype, and region 
as covariates. A noninformative improper prior for the baseline hazard parameters and an 
improper uniform prior for the regression coefficients will be assumed. For the piecewise 
constant baseline hazards, the post-baseline follow-up time axis will be partitioned into 
2 disjoint intervals, where the interval cut-points will be such that there will be a similar 
amount of relapse events in each interval. Sampling of model parameters will set the burn-in 
to 200 and every 10th sample will be kept. 
 
  
 
 
 
 
 
 
 
When imputing censored event times, posterior samples for the treatment parameter will be 
set to 0 so that the assumption that the risk of relapse (i.e. hazard rate) for pimavanserin 
subjects who prematurely discontinue is the same as that for placebo subjects. Additional 
details of how censored event times will be imputed can be found in Lu et. al. (2015). If the 
imputation model cannot be fit due to sparse covariate data, this will be documented and the 
imputation model will be modified to include only treatment as a covariate.  
For each of the 1000 imputed datasets, a Cox regression model with effects for treatment 
group, designated dementia subtype, and region will be used to obtain an estimate of the log 


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hazard ratio and associated standard error. These estimates will be combined using Rubin’s 
rule to obtain an overall hazard ratio, standard error, 95% confidence interval, and p-value 
(Rubin, 1976). 
13.1.2 Sensitivity Analyses 
If the study is stopped at the interim analysis, the following sensitivity analyses will be 
performed: 
• Time to relapse based on adjudicated relapse events using data collected up to the 
study discontinuation date (ITT analysis set). Subjects without any such relapse event 
will be censored at the last SAPS-H+D assessment prior to the study discontinuation 
date.  
• Time to relapse based on adjudicated relapse events occurring up to the study 
discontinuation date, plus any additional investigator determined relapse events that 
occur after the study discontinuation date (ITT analysis set). Subjects without any 
such relapse event will be censored at the last SAPS-H+D assessment. 
• Time to relapse based on investigator determined relapse events using data collected 
up to the study discontinuation date (ITT analysis set). Subjects without any such 
relapse event will be censored at the last SAPS-H+D assessment prior to the study 
discontinuation date. 
• Time to relapse based on adjudicated relapse events using the interim analysis dataset 
and using the Per-protocol analysis set. Subjects without any such relapse event will 
be censored at the last SAPS-H+D assessment. 
If the study is not stopped at the interim analysis, the following sensitivity analyses will be 
performed: 
• Time to relapse based on adjudicated relapse events occurring up to the study 
discontinuation date, plus any additional investigator determined relapse events that 
occur after the study discontinuation date (ITT analysis set). Subjects without any 
such relapse event will be censored at the last SAPS-H+D assessment. 


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• Time to relapse based on investigator determined relapse events using data collected 
up to the study discontinuation date (ITT analysis set). Subjects without any such 
relapse event will be censored at the last SAPS-H+D assessment prior to the study 
discontinuation date. 
• Time to relapse based on adjudicated relapse events occurring up to the study 
discontinuation date using the Per-protocol analysis set. Subjects without any such 
relapse event will be censored at the last SAPS-H+D assessment prior to the study 
discontinuation date. 
The same Cox regression model as described in Section 13.1 will be used for each of the 
sensitivity analyses. The results will be presented in a summary table similar to that described 
for the primary efficacy analysis. The estimated HRs with corresponding 95% CIs from the 
primary efficacy analysis and the sensitivity analyses will be presented in a forest plot.  
13.2 Key Secondary Efficacy Analysis 
The key secondary endpoint is time from randomization to discontinuation from the 
double-blind period for any reason (other than termination of the study by the sponsor). The 
hypotheses are stated in terms of the hazard ratio, HR= λPIM / λPBO, where λPIM and λPBO 
denote the hazard rates of discontinuation from the double-blind period for any reason (other 
than termination of the study by the sponsor) for the pimavanserin group and the placebo 
group, respectively.  
The null hypothesis for the key secondary endpoint is: HR = 1 
The alternative hypothesis for the key secondary endpoint is: HR ≠ 1 
The key secondary efficacy endpoint will be analyzed using the same Cox regression model 
described for the primary efficacy endpoint. The null hypothesis for the key secondary 
efficacy endpoint cannot be rejected unless the null hypothesis for the primary efficacy 
endpoint has been rejected. Adjustment of stopping boundaries for the key secondary 
endpoint analysis to account for multiple endpoints and group sequential testing is described 
in Section 16. 
The estimated HR, SE, 95% confidence interval, and p-value obtained from the Cox 
regression model will be presented. The algorithm for censoring of subjects who completed 


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the 26-week double-blind period without experiencing a relapse event, or who 
administratively exited the study due to study termination by the sponsor, or who were 
ongoing at the time of database cutoff is described in Section 5.2.4. The number and 
percentage of subjects having the following possible reasons for censoring will be tabulated 
for each treatment group: 
• Completed Week 26 without relapse; 
• Termination of the study by the sponsor  (for the final analysis only); 
• Ongoing at the time of the interim database cutoff (for the interim analysis only). 
Kaplan-Meier curves of time from randomization to discontinuation from the double-blind 
period for any reason (other than termination of the study by the sponsor) will be presented 
for each treatment group. In addition, Kaplan-Meier probability estimates of median survival 
and at the double-blind Weeks 4, 8, 12, 18, and 26 along with pointwise 95% confidence 
intervals will be provided. The confidence intervals will be calculated using a log-log 
transformation and Greenwood’s variance formula. 


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The number and percentage of subjects meeting the following discontinuation reasons for the 
double-blind period will be tabulated for each treatment group: 
• Relapse of hallucinations and delusions associated with dementia-related psychosis 
adjudicated by the IAC; 
• Adverse event; 
• Death; 
• Non-compliance with study drug; 
• Used of prohibited medications; 
• Physician decision; 
• Protocol violation; 
• Pregnancy; 
• Subject withdrew consent; 
• Lost to follow-up; 
• Other. 
13.2.1 Deviations From Non-Informative Censoring 
For the key secondary endpoint, censoring can only occur among those subjects who 
complete the 26 week double-blind period or who discontinue due to the study being 
terminated by the sponsor.  This censoring is non-informative and therefore sensitivity 
analyses to address informative censoring are not needed.  
13.2.2 Sensitivity Analysis 
Sensitivity analysis for the key secondary efficacy endpoint will be performed on the 
Per-protocol Analysis Set. The results will be presented in a summary table similar to that 
described for the key secondary efficacy analysis.  


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13.3 Exploratory Efficacy Analysis 
13.3.1 Analysis for the Double-blind Period 
Exploratory efficacy variables SAPS-H+D, SAPS Hallucinations domain, SAPS Delusions 
domain, CGI-S, ZBI, KSS, EQ-5D VAS, and EQ-5D-5L descriptive system evaluated in the 
double-blind period will be analyzed for the ITT Analysis Set. For each exploratory efficacy 
variable other than the EQ-5D-5L descriptive system, observed and change from 
double-blind Baseline values at each analysis visit will be summarized using descriptive 
statistics by treatment group (placebo and pimavanserin). In addition, the descriptive 
summaries will be provided by pimavanserin dose level (20 and 34 mg) for the double-blind 
pimavanserin group. 
For each exploratory efficacy variable other than the EQ-5D-5L descriptive system, treatment 
comparisons will be made between the placebo group and the pimavanserin group (20 mg 
and 34 mg combined) using a MMRM and an ANCOVA. No adjustment for multiple 
comparisons will be made among the exploratory efficacy variables. At each post-baseline 
analysis visit, LS means and standard errors (SE), the corresponding 95% confidence interval 
and p-value will be presented. In addition, plots of LS mean ± SE versus analysis visit will be 
provided. 
13.3.1.1 
Mixed Model Repeated Measures  
For each exploratory efficacy variable other than the EQ-5D-5L descriptive system, the 
change from baseline will be analyzed using mixed model repeated measures (MMRM) 
method with missing data assumed to be missing at random. The dependent variable will be 
the change from double-blind Baseline. Assessments more than 14 days after last dose of 
study drug will be excluded from the analysis. The independent variables in the model will 
include treatment group (placebo or pimavanserin), designated dementia subtype, region, 
analysis visit, treatment group by analysis visit interaction, double-blind Baseline score, and 
double-blind Baseline score by analysis visit interaction. An unstructured covariance matrix 
will be used and the Kenward-Roger approximation will be used to adjust the denominator 
degrees of freedom. Observed cases will be analyzed in the model and least squares (LS) 
adjusted means will be estimated using observed margins. 


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In the event that the model fails to converge using the unstructured covariance matrix, then 
the following covariance structures will be modeled in the following order:  
• Heterogeneous Toeplitz; 
• Heterogeneous compound symmetry; 
• Heterogeneous autoregressive(1); 
• Toeplitz; 
• Compound symmetry 
• Autoregressive(1); 
• Variance components.  
The first covariance structure that allows for convergence will be selected for the final model. 
13.3.1.2 
ANCOVA 
For each exploratory efficacy variable other than the EQ-5D-5L descriptive system, the 
change from baseline will be analyzed using an analysis of covariance (ANCOVA) at each 
post-baseline analysis visit and using the last observation carried forward (LOCF) method of 
imputation for missing data. The LOCF method will carry forward the double-blind Baseline 
value if necessary; assessments more than 14 days after last dose of study drug will not be 
carried forward. The dependent variable will be the change from double-blind Baseline. The 
independent variables in the model will include treatment group (placebo or pimavanserin), 
designated dementia subtype, region, and double-blind Baseline score. Least squares (LS) 
adjusted means will be estimated using observed margins. 
13.3.1.3 
Treatment Comparisons 
For each exploratory efficacy variable other than the EQ-5D-5L descriptive system, the 
treatment comparisons will be based on the difference in LS means obtained from the 
statistical model (MMRM or ANCOVA) at each post-baseline analysis visit for the respective 
exploratory efficacy variable and will be tested at a 2-sided alpha level of 0.05.  
Summary statistics for the observed and change from Baseline values will be presented for all 
analysis visits. For the change from double-blind Baseline values at each post-baseline 
analysis visit, LS means and standard errors (SE), the between-group difference in LS means 


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with the corresponding 95% confidence interval, p-value and effect size will be presented. In 
addition, LS mean ± SE over time for the change from Baseline values by treatment group 
will be presented in line plots. 
At each post-baseline analysis visit, the effect size (Cohen’s d) for the change from double-
blind Baseline between the treatment groups will be calculated using the following formula: 
𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠= 𝐿𝐿𝐿𝐿 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑
√𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣
 
 
where the variance at a given visit will be obtained from the covariance matrix estimated for 
the MMRM model or the mean squared error obtained from the ANCOVA model. The sign 
(+ or -) of the effect size will be chosen so that a positive value favors pimavanserin. 
13.3.2 Analysis for the Open-label Period 
Exploratory variables SAPS-H+D, SAPS Hallucinations domain, SAPS Delusions domain, 
CGI-S, ZBI, KSS, EQ-5D VAS, and EQ-5D-5L descriptive system assessed in the open-label 
period will be summarized for the Open-label Safety Analysis Set.  
For each exploratory variable other than the EQ-5D-5L descriptive system, the observed and 
change from open-label Baseline values at each analysis visit will be summarized using 
descriptive statistics. The following summaries will be provided: 
1. 
all subjects combined;  
2. 
by randomization status (not randomized and randomized);  
3. 
by final dose level (20 and 34 mg) of open-label pimavanserin. 
The mean change from open-label Baseline to each analysis visit and 95% CI will be 
provided for the following exploratory endpoints: SAPS-H+D, SAPS Hallucinatins domain, 
SAPS Delusions domain, CGI-S, ZBI, KSS and EQ-5D VAS. 
13.3.3 SAPS-H+D 
For the double-blind period, observed SAPS-H+D total score will be summarized using 
descriptive statistics at double-blind Baseline, double-blind Weeks 1, 2, 4, 6, 10, 14, 18, 22, 
and 26. The change from double-blind Baseline values will also be summarized at the 
double-blind Weeks 1, 2, 4, 6, 10, 14, 18, 22, and 26. The change from double-blind Baseline 


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in SAPS-H+D total score will be analyzed using the MMRM and ANCOVA models as 
described in Sections 13.3.1.1, 13.3.1.2, and 13.3.1.3.  
For the open-label period, observed SAPS-H+D total score will be summarized using 
descriptive statistics at open-label Baseline, open-label Weeks 2, 4, 8, and 12. The change 
from open-label Baseline values will also be summarized at the open-label Weeks 2, 4, 8, and 
12.  
13.3.4 SAPS Hallucinations Domain 
For the double-blind period, observed SAPS Hallucinations domain score will be 
summarized using descriptive statistics at the double-blind Baseline and Weeks 1, 2, 4, 6, 10, 
14, 18, 22, and 26. The change from double-blind Baseline values will also be summarized at 
the double-blind Weeks 1, 2, 4, 6, 10, 14, 18, 22, and 26. The change from double-blind 
Baseline in SAPS Hallucinations domain score will be analyzed using the MMRM and 
ANCOVA models as described in Sections 13.3.1.1, 13.3.1.2, and 13.3.1.3. 
For the open-label period, observed SAPS Hallucinations domain score will be summarized 
using descriptive statistics at the open-label Baseline, Weeks 2, 4, 8, and 12. The change from 
open-label Baseline values will also be summarized at the open-label Weeks 2, 4, 8, and 12.  
13.3.5 SAPS Delusions Domain 
For the double-blind period, observed SAPS Delusions domain score will be summarized 
using descriptive statistics at the double-blind Baseline and Weeks 1, 2, 4, 6, 10, 14, 18, 22, 
and 26. The change from double-blind Baseline values will also be summarized at the 
double-blind Weeks 1, 2, 4, 6, 10, 14, 18, 22, and 26. The change from double-blind Baseline 
in SAPS Delusions domain score will be analyzed using the MMRM and ANCOVA models 
as described in Sections 13.3.1.1, 13.3.1.2, and 13.3.1.3. 
For the open-label period, observed SAPS Delusions domain score will be summarized using 
descriptive statistics at the open-label Baseline and Weeks 2, 4, 8, and 12. The change from 
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13.3.6 CGI-S Dementia-Related Psychosis 
For the double-blind period, observed CGI-S score will be summarized using descriptive 
statistics at the double-blind Baseline and Weeks 1, 2, 4, 6, 10, 14, 18, 22, and 26. The 
change from double-blind Baseline values will also be summarized at the double-blind Weeks 
1, 2, 4, 6, 10, 14, 18, 22, and 26. The change from double-blind Baseline in CGI-S score will 
be analyzed using the MMRM and ANCOVA models as described in Sections 13.3.1.1, 
13.3.1.2, and 13.3.1.3. 
For the open-label period, observed CGI-S score will be summarized using descriptive 
statistics at the open-label Baseline and Weeks 2, 4, 8, and 12. The change from open-label 
Baseline values will also be summarized at the open-label Weeks 2, 4, 8, and 12.  
13.3.7 Responder Analysis 
For the open-label period, the number and percentage of subjects in the Open-label Safety 
Analysis Set that met the following response criteria (≥30% reduction from open-label 
Baseline on SAPS-H+D Total Score and CGI-I score of 1 or 2, relative to open-label 
Baseline) will be provided for Week 2, Week 4, Week 8, and Week 12, and at both Weeks 8 
and 12.  
13.3.8 ZBI Score 
For the double-blind period, observed ZBI scores will be summarized using descriptive 
statistics at the double-blind Baseline and Weeks 6, 14, and 26. The change from 
double-blind Baseline values will also be summarized at the double-blind Weeks 6, 14, and 
26. The change from double-blind Baseline in ZBI score will be analyzed using the MMRM 
and ANCOVA models as described in Sections 13.3.1.1, 13.3.1.2, and 13.3.1.3. 
For the open-label period, observed ZBI score will be summarized using descriptive statistics 
at the open-label Baseline and Week 12. The change from open-label Baseline values will 
also be summarized at the open-label Week 12. 
13.3.9 KSS Score 
For the double-blind period, observed KSS scores will be summarized using descriptive 
statistics at double-blind Baseline and Weeks 6, 14, and 26. The change from double-blind 


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Baseline values will also be summarized at the double-blind Weeks 6, 14, and 26. The change 
from double-blind Baseline in KSS score will be analyzed using the MMRM and ANCOVA 
models as described in Sections 13.3.1.1, 13.3.1.2, and 13.3.1.3. 
For the open-label period, observed KSS scores will be summarized using descriptive 
statistics at open-label Baseline and open-label Week 12. The change from open-label 
Baseline values will also be summarized at the open-label Week 12.  
13.3.10 CGI-I Dementia-Related Psychosis 
For the double-blind period, observed CGI-I scores will be summarized using descriptive 
statistics at double-blind Weeks 1, 2, 4, 6, 10, 14, 18, 22, and 26. The CGI-I score will be 
analyzed using the MMRM and ANCOVA models as described in Sections 13.3.1.1, 13.3.1.2, 
and 13.3.1.3. For both the MMRM and ANCOVA models, the covariate double-blind 
Baseline score is the double-blind Baseline CGI-S score. 
For the open-label period, observed CGI-I scores will be summarized using descriptive 
statistics at open-label Weeks 2, 4, 8, and 12.   
13.3.11 EQ-5D VAS 
For the double-blind period, observed EQ-5D VAS scores will be summarized using 
descriptive statistics at double-blind Baseline and double-blind Weeks 6, 14, and 26. The 
change from double-blind Baseline values will also be summarized at the double-blind Weeks 
6, 14, and 26. The change from double-blind Baseline in QD-5D VAS score will be analyzed 
using the MMRM and ANCOVA models as described in Sections 13.3.1.1, 13.3.1.2, and 
13.3.1.3. 
For the open-label period, observed EQ-5D VAS scores will be summarized using descriptive 
statistics at open-label Baseline and Week 12. The change from open-label Baseline scores 
will also be summarized at the open-label Week 12.  
13.3.12 EQ-5D 5L Descriptive System 
For each EQ-5D-5L dimension the proportion of subjects reporting no, slight, moderate, 
severe, and extreme/unable to perform activity will be summarized descriptively at each 
timepoint. 


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For the double-blind period, EQ-5D-5L descriptive system will be summarized at 
double-blind Baseline and double-blind Weeks 6, 14, and 26. 
For the open-label period, EQ-5D-5L descriptive system will be summarized at open-label 
Baseline and open-label Week 12. 
13.3.13 Pareto Classification of Health Change 
Change from Baseline in EQ-5D 5L health state will be assessed with the Pareto 
classification of health change (PCHC) method. Using this methodology, at each 
post-Baseline visit, each EQ-5D health state will be classified into one of four categories, 
relative to the Baseline health state: 
• Improved = improved on at least one dimension and not worsened on any other 
dimension 
• Mixed = improved on at least one dimension and worsened on at least one other 
dimension 
• No change = no changes in any dimension 
• Worsened = deterioration on at least one dimension and no improvement on any other 
dimension 
For the double-blind period, the proportion of subjects in each PCHC category will be 
summarized descriptively at the double-blind Weeks 6, 14, and 26.  
For the open-label period, the proportion of subjects in each PCHC category will be 
summarized descriptively at the open-label Week 12.  
14 SAFETY ANALYSES 
The safety endpoints for this study are as follows: 
• Treatment-emergent adverse events (TEAEs) 
• Serious adverse events (SAEs) 
• Withdrawals due to adverse events (AEs) 
• Potentially clinically important changes in other safety assessments 
• Global Clinician Assessment of Suicidality (GCAS) score 


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• Mini-Mental State Examination (MMSE) score 
• Extrapyramidal Symptom Rating Scale A (ESRS-A) score  
For the open-label period, safety data will be summarized for the Open-label Safety Analysis 
Set. The following summaries will be provided: 
1. all subjects combined;  
2. by randomization status (not randomized and randomized);  
3. by final dose level (20  and 34 mg) of open-label pimavanserin administered during 
the open-label period.  
For the double-blind period, safety data will be summarized for the Double-blind Safety 
Analysis Set. The following summaries will be provided: 
1. by treatment group (placebo and pimavanserin) 
2. by dose level (20 and 34 mg) of pimavanserin administered during the double-blind 
period for the pimavanserin group.  
14.1 Adverse Events  
All Adverse events (AEs) will be coded using MedDRA version 20.0 or newer. 
An AE (classified by preferred term) will be considered a treatment emergent AE (TEAE) if 
the onset date was on or after the date of first dose of open-label pimavanserin and up to 30 
days past the last dose of study drug. AEs reported on Day 1 based on open-label Baseline 
(pre-dose) findings (e.g. clinically significantly abnormal vital signs, laboratory test results, 
or electrocardiogram parameters) will not be considered as TEAEs. 
Each TEAE will be assigned to either the open-label or double-blind period based on the 
onset date. For randomized subjects, if the onset date was on or after the date of first dose of 
double-blind study drug, the TEAE will be assigned to the double-blind period. All other 
TEAE will be assigned to the open label period. 
The event counts and the number and percentage of subjects reporting TEAEs will be 
tabulated by SOC and preferred term; and, by SOC, preferred term, and maximum severity. If 
more than 1 AE occurs with the same preferred term for the same subject, the subject will be 
counted only once for that preferred term using the most severe occurrence for the 


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summarization by severity. In addition, the event counts and the number and percentage of 
subjects with TEAEs classified by the Investigators as related to the study drug, with most 
frequently reported TEAEs (preferred terms reported by ≥5% of subjects overall for the 
open-label period and ≥5% of subjects in either treatment group for the double-blind 
treatment period), with treatment emergent serious AEs, with fatal AEs (i.e. events that cause 
death), and with TEAEs leading to discontinuation of study drug will be summarized by SOC 
and preferred term. The display in these tables will be sorted alphabetically by SOC and then 
by descending subject frequency for the preferred terms using combined counts from both 
groups within each SOC. The event counts and the number and percentage of subjects with 
any TEAEs will also be tabulated by preferred term without SOCs. This table will be sorted 
by descending subject frequency using combined counts from all subjects. 
An AE listing by subject will display all events in the open-label period and in the 
double-blind period, including those which are not treatment-emergent, and will include the 
verbatim term in addition to the MedDRA SOC and preferred term. This listing will also 
include all relevant eCRF data associated with the event: e.g. study period, date of onset, date 
resolved, study dose level at AE onset, severity, frequency, outcome, relationship to study 
drug, action taken with study drug, and required therapy. When a date is presented, the study 
day associated with the date will also be displayed. If the onset date is prior to, or during, the 
open-label period, the study day will be calculated relative to the date of first dose of 
open-label pimavanserin; if the onset date is during the double-blind period, the study day 
will be calculated relative to the date of first dose of double-blind study drug. Separate 
listings will be presented for subjects with SAEs, subjects with AEs leading to 
discontinuation and subjects with fatal AEs (if any). In these listings, an indicator for 
treatment-emergent events will also be included. 
14.2 Clinical Laboratory Variables 
Clinical chemistry serum tests include the following: 
• Sodium (Na), potassium (K), chloride (Cl), phosphorus (P), calcium (Ca), carbon 
dioxide (CO2), blood urea nitrogen (BUN), creatinine (CR), uric acid 


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• Alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl 
transpeptidase (GGT), alkaline phosphatase (ALP), total bilirubin (TBIL), lactate 
dehydrogenase (LDH) 
• Magnesium (Mg) should only be performed at Visit 1 (Screening) 
• Vitamin B12 should only be performed at Visit 1 (Screening) 
• HbA1c should only be performed at Visit 1 (Screening), Visit 6, and Visit 17/ET 
• Glucose 
• Albumin (ALB), total protein 
• Prolactin 
• Thyroid stimulating hormone (TSH) and free T4 
o TSH should be performed only at Visit 1 (Screening) 
o Free T4 will be measured only if TSH is abnormal 
• Lipid Panel 
o Total cholesterol, high-density lipoprotein (HDL)-cholesterol, triglycerides, 
low-density lipoprotein(LDL)-cholesterol, cholesterol/HDL ratio, non-HDL 
cholesterol 
Hematology tests include the following: 
• Complete blood count (CBC) including: 
o White blood cell (WBC) count 
o Complete differential (relative and absolute) 
o Hematocrit (Hct), hemoglobin, red blood cells (RBC), platelets 
o Reticulocyte count 
Urinalysis tests include the following: 
• Color, clarity, blood, RBCs, WBCs, protein, glucose, ketones, specific gravity, pH, 
leukocyte esterase, nitrite, microscopic analysis 
All laboratory test results (including urine drug screen) are from a central laboratory and will 
be listed. The listings will include date and study day of collection. All units will be displayed 


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in Système International [SI] units. Out of range values will be flagged in the data listings 
(e.g. ‘L’ or ‘H’). 
14.2.1 Analysis for the Open-label Safety Analysis set 
Clinical laboratory tests are performed at Screening, Baseline and Week 12 visits during the 
open-label period. Clinical laboratory values for hematology, chemistry and urinalysis 
(specific gravity and pH) will be summarized using descriptive statistics at Baseline and 
Week 12 visits. The change from Baseline values will also be summarized at the Week 12 
visit.  
The overall minimum and maximum post-baseline observed and change from Baseline 
values during the open-label period will also be summarized. For hemoglobin, hematocrit and 
uric acid, the above summaries will be presented for each gender as well as for both genders 
combined. For urinalysis with categorical results, the number and percentage of subjects will 
be tabulated by category at Baseline and Week 12 visit, and the denominator is the number of 
subjects with non-missing values for the given parameter and visit. 
Laboratory values (except the ones that were only assessed at screening) will also be 
summarized in shift tables, to determine the number and percentage of subjects with values 
classified as below (low), within (normal), and above (high) normal ranges at Week 12 visit, 
overall post-baseline minimum and overall post-baseline maximum during the open-label 
period. For the Week 12 visit shift summary, the denominator is the number of subjects with 
non-missing values at Baseline and Week 12 visit for the given parameter. For the shift to the 
overall post-baseline minimum or maximum, the denominator is the number of subjects with 
non-missing baseline and at least 1 post-baseline value during the open-label period for the 
given parameter. For hemoglobin, hematocrit and uric acid, the shift summaries will be 
presented for each gender as well as for both genders combined. 
The number and percentage of subjects with potentially clinically important (PCI) laboratory 
values at Week 12 visit and overall post-baseline during the open-label period will be 
summarized for selected parameters. PCI criteria for hematology and chemistry are listed in 
Table 5 and PCI criteria for urinalysis are listed in Table 6. For the overall post-baseline 
summaries of PCI values, all post-baseline values during the open-label period will be 
considered, including unscheduled and out of window values. Subjects with multiple PCI 


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values for a given parameter will be counted only once for that parameter. For the by-visit 
summary, the numerator for the percentage is the number of subjects with a post-baseline 
PCI value for the given parameter and visit, and the denominator is the number of subjects 
with non-missing values for the given parameter and visit. For the overall post-baseline 
summary, the numerator for the percentage is the number of subjects with at least 1 
post-baseline PCI laboratory value during the open-label period for the given parameter, and 
the denominator is the number of subjects with at least 1 post-baseline laboratory value 
during the open-label period for the given parameter. For hemoglobin, hematocrit and uric 
acid, the count and percentage of subjects with PCI values will be presented for each sex as 
well as for both sexes combined. Subjects with any post-baseline PCI values will be 
presented in an additional listing. 
14.2.2 Analysis for the Double-blind Safety Analysis Set 
In addition to the open-label assessments at Screening, Baseline, and Week 12 visits, clinical 
laboratory tests are performed at Weeks 18, 26, and 38 visits during the double-blind period. 
Summaries for hematology, chemistry and urinalysis for the Double-Blind Safety Analysis 
Set will be similar to those described above for the Open-Label Safety Analysis Set and will 
include the following: 
• Observed values and change from open-label baseline by visit including both open-
label and double-blind visits; overall minimum and maximum for the open-label period; 
overall minimum and maximum for the double-blind period. 
• Observed values and change from double-blind baseline by visit for the double-blind 
period; overall minimum and maximum for the double-blind period. 
• Shifts from open-label baseline by visit including both open-label and double-blind 
visits; overall minimum and maximum for the open-label period; overall minimum and 
maximum for the double-blind period. 
• Shifts from double-blind baseline by visit for the double-blind period; overall minimum 
and maximum for the double-blind period. 


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• Incidence of PCI values by visit including both open-label and double-blind visits; 
open-label overall post-baseline; double-blind overall post-baseline, based on the OL 
baseline. 
• Incidence of PCI values by visit for the double-blind period; double-blind overall post-
baseline, based on the DB baseline. 
Urinalysis tests with categorical results will be summarized (number and percent of subjects 
in each category) by visit including both open-label and double-blind visits. 
 


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Table 5 Criteria for PCI Laboratory Values – Hematology and Chemistry 
 
Analyte 
Conventional 
Unit 
Low PCI 
Criteria 
High PCI 
Criteria 
SI Unit 
Low PCI 
Criteria 
High PCI 
Criteria 
Hematology (whole blood) 
Hemoglobin 
(male) 
g/dL 
<11 
>18 
g/L 
<110 
>180 
Hemoglobin 
(female) 
g/dL 
<10 
>17 
g/L 
<100 
>170 
Hematocrit 
(male) 
% 
<30 
>55 
L/L 
<0.3 
>0.55 
Hematocrit 
(female) 
% 
<30 
>50 
L/L 
<0.3 
>0.5 
Leukocyte 
(WBC Count) 
x 103/uL 
≤2.8 
≥15 
x 109/L 
≤2.8 
≥15 
Neutrophils 
x 103/uL 
≤1.5 
No upper limit 
x 109/L 
≤1.5 
No upper limit 
Platelet Count 
x 103/uL 
≤75 
≥700 
109/L 
≤75 
≥700 
Chemistry (serum or plasma) 
ALT (SGPT) 
U/L 
No lower 
limit  
≥3 X ULN 
U/L 
No lower 
limit  
≥3 X ULN 
AST (SGOT) 
U/L 
No lower 
limit  
≥3 X ULN 
U/L 
No lower 
limit  
≥3 X ULN 
Total 
Bilirubin 
mg/dL 
No lower 
limit 
≥1.5 ULN 
umol/L 
No lower 
limit 
≥1.5 ULN 
BUN 
mg/dL 
No lower 
limit 
≥30.0 
mmol/L 
No lower 
limit 
≥10.71 
Creatine 
Kinase (CK) 
U/L 
No lower 
limit 
≥3 ULN 
U/L 
No lower 
limit 
≥3 ULN 
Sodium 
mEq/L 
≤125 
≥155 
mmol/L 
≤125 
≥155 
Potassium 
mEq/L 
≤3.0 
≥5.5 
mmol/L 
≤3.0 
≥5.5 
Calcium, total 
mg/dL 
<8.0 
>11.0 
mmol/L 
<2.0 
>2.75 
LDH 
U/L 
No lower 
limit 
≥3 X ULN 
U/L 
No lower 
limit 
≥3 X ULN 
Alkaline 
Phosphatase 
U/L 
No lower 
limit 
≥3 X ULN 
U/L 
No lower 
limit 
≥3 X ULN 
Uric acid 
(male) 
mg/dL 
No lower 
limit 
≥10.5 
umol/L 
No lower 
limit 
≥624.75 
Uric acid 
(female) 
mg/dL 
No lower 
limit 
≥8.5 
umol/L 
No lower 
limit 
≥505.75 
Albumin 
g/dL 
≤2.6 
≥6.0 
g/L 
≤26 
≥60 
Total Protein 
g/dL 
≤5.0 
≥10.0 
g/L 
≤50 
≥100 
Chloride 
mEq/L 
≤85 
≥120 
mmol/L 
≤85 
≥120 
Glucose 
(random) 
mg/dL 
≤45.1 
≥200.0 
mmol/L 
≤2.48 
≥11 
Serum 
Creatinine 
mg/dL 
NA 
>1.5 ULN 
umol/L 
NA 
>1.5 ULN 
Triglycerides 
mg/dL 
NA 
>300 
mmol/L 
NA 
>3.39 
GGT 
U/L 
NA 
≥3 ULN 
U/L 
NA 
≥3 ULN 
NA = not applicable 


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Table 6 Criteria for PCI Laboratory Values - Urinalysis 
Urinalysis (qualitative dipstick) 
Low PCI Criteria 
High PCI Criteria 
Blood (occult blood) 
Not Applicable 
≥ Moderate  
Protein 
Not Applicable 
≥ 100 mg/dL  
Glucose 
Not Applicable 
≥ 500 mg/dL 
 
The pregnancy results (positive or negative) for female subjects will be presented in a listing. 
14.3 Vital Signs 
14.3.1 Analysis for the Open-label Safety Analysis Set 
Vital signs are assessed at Screening, Baseline, and Weeks 2, 4, 8, and 12 during the 
open-label period.  
Respiration rate, systolic blood pressure, diastolic blood pressure, and pulse rate, weight, 
height (only at Screening), and derived BMI will be summarized using descriptive statistics 
at Baseline and Weeks 2, 4, 8, and 12 during the open-label period. The change from Baseline 
values will also be summarized at the Weeks 2, 4, 8 and 12. 
Vital sign values will be considered PCI if they meet both the observed value criteria and the 
change from baseline criteria listed in Table 7. The number and percentage of subjects with 
PCI vital sign values at Weeks 2, 4, 8, and 12, and overall post-baseline during the open-label 
period will be summarized for selected parameters. For the overall post-Baseline summaries, 
all post-Baseline values during the open-label period will be considered, including 
unscheduled and out of window values. Subjects with multiple PCI values for a given 
parameter will be counted only once for that parameter. For the by-visit summary, the 
numerator for the percentage is the number of subjects with a post-baseline PCI vital sign 
value during the open-label period for the given parameter and visit, and the denominator is 
the number of subjects with non-missing values for the given parameter and visit. For the 
overall post-baseline summary, the numerator for the percentage is the number of subjects 
with at least 1 post-baseline PCI vital sign value during the open-label period for the given 
parameter, and the denominator is the number of subjects with at least 1 post-baseline vital 
sign value during the open-label period for the given parameter. Subjects with any 
post-baseline PCI values will be presented in an additional listing. 


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14.3.2 Analysis for the Double-blind Safety Analysis Set 
In addition to the open-label assessments at Screening, Baseline and Weeks 2, 4, 8, and 12, 
vital signs are assessed at Weeks 13, 14, 16, 18, 22, 26, 30, 34, and 38 during the 
double-blind period.  
Vital sign summaries for the Double-Blind Safety Analysis Set will be similar to those 
described above for the Open-Label Safety Analysis Set and will include the following: 
• Observed values and change from open-label baseline by visit including both 
open-label and double-blind visits; overall minimum and maximum for the open-label 
period; overall minimum and maximum for the double-blind period. 
• Observed values and change from double-blind baseline by visit for the double-blind 
period; overall minimum and maximum for the double-blind period. 
• Incidence of PCI values by visit including both open-label and double-blind visits; 
open-label overall post-baseline; double-blind overall post-baseline. 
• Incidence of PCI values by visit for the double-blind period; double-blind overall 
post-baseline. 


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Table 7 Criteria for PCI Vital Signs 
 
Vital Sign Parameter 
 
Unit 
Criteriaa 
Observed 
Value 
And/Or 
Change Relative to Baseline 
Systolic blood pressure 
(supine or sitting) 
mmHg 
≥180 
And 
Increase of ≥20 
≤90 
And 
Decrease of ≥20 
Diastolic blood pressure 
(supine or sitting) 
mmHg 
≥105 
And 
Increase of ≥15 
≤50 
And 
Decrease of ≥15 
Pulse (supine or sitting) 
bpm 
≥120 
And 
Increase of ≥15 
≤50 
And 
Decrease of ≥15 
Weight 
kg 
Not Applicable 
Increase of ≥7% 
Decrease of ≥7% 
aA post-baseline value is considered as a PCI value if it meets both criteria for observed value and change from 
 baseline.  
14.4 Electrocardiogram 
14.4.1 Analysis for the Open-label Safety Analysis Set 
All ECGs will be centrally read; the interpretation by the central cardiologist is considered 
the official interpretation. 12-lead electrocardiogram (ECG) assessments are performed at 
Screening, Baseline, Weeks 2 and 12 during the open-label period. 
ECG results (ventricular rate, PR, QRS, QT, and QTcF intervals) will be summarized using 
descriptive statistics at Baseline, Weeks 2 and 12 during the open-label period. The change 
from Baseline values will also be summarized at the Weeks 2 and 12.   
QTcF (msec) observed and change from Baseline values during the open-label period will 
also be classified into the following categories: 
• Observed: ≤450, 451 to 480, 481 to 500, and  >500 
• Change from Baseline: ≤10, 11 to 30, 31 to 60, and >60 
The number and percentage of subjects in each category will be summarized at each                                           
visit and for the overall post-baseline maximum during the open-label period. 
Electrocardiogram variable values will be considered PCI if they meet or exceed the upper 
limit values listed in Table 8. The number and percentage of subjects with PCI ECG values at 
Weeks 2 and 12, and overall post-baseline maximum during the open-label period will be 


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summarized for selected parameters.  For the by-visit summary, the numerator for the 
percentage is the number of subjects with a post-baseline PCI ECG value during the 
open-label period for the given parameter and visit, and the denominator is the number of 
subjects with non-missing values during the open-label period for the given parameter and 
visit. For the overall post-Baseline summary, the numerator for the percentage is the number 
of subjects with at least 1 post-baseline PCI ECG value during the open-label period for the 
given parameter, and the denominator is the number of subjects with at least 1 post-baseline 
ECG value during the open-label period for the given parameter. Subjects with any 
post-baseline PCI values will be presented in an additional listing. 
Overall ECG interpretation at Baseline, Weeks 2 and 12 and overall post-baseline worst 
interpretation during the open-label period will be summarized descriptively. Within each 
summary time frame a subject is counted only once in the category with the worst 
interpretation (“abnormal, clinically significant” is worse than “abnormal, not clinically 
significant” is worse than “normal”). For overall post-Baseline worst interpretation, all 
post-baseline interpretations during the open-label period will be considered, including 
unscheduled and out-of-window interpretations. For the by-visit summary, the denominator 
for the percentage is the number of subjects with non-missing interpretations during the 
open-label period at the given visit. For the overall post-Baseline summary the denominator 
is the number of subjects with at least one post-baseline interpretation during the open-label 
period.  
Overall ECG interpretation results will also be summarized in shift tables, to determine the 
number and percentage of subjects with results classified as normal and abnormal at Weeks 2 
and 12, and overall post-Baseline worst interpretation during the open-label period. For the 
by-visit shift summary, the denominator is the total number of subjects with non-missing 
results at Baseline and the given visit during the open-label period. For the overall 
post-Baseline summary the denominator is the number of subjects with a non-missing 
Baseline and at least one post-baseline result during the open-label period. 
14.4.2 Analysis for the Double-blind Safety Analysis Set 
In additional to the open-label assessments at Screening, Baseline and Weeks 2 and 12, ECG 
assessments are performed at Weeks 18, 26, and 38 during the double-blind period. 


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ECG summaries for the Double-Blind Safety Analysis Set will be similar to those described 
above for the Open-Label Safety Analysis Set and will include the following: 
• Observed values and change from open-label baseline by visit including both 
open-label and double-blind visits. 
• Observed values and change from double-blind baseline by visit for the double-blind 
period. 
• Categorical analysis of QTcF Observed Values and Change from open-label Baseline by 
Visit including both open-label and double-blind visits; overall maximum for the 
open-label period; overall maximum for the double-blind period. 
• Categorical analysis of QTcF Observed Values and Change from double-blind Baseline 
by Visit for the double-blind period; overall maximum for the double-blind period. 
• Incidence of PCI values by visit including both open-label and double-blind visits; 
open-label overall post-baseline; double-blind overall post-baseline. 
• Incidence of PCI values by visit for the double-blind period; double-blind overall 
post-baseline. 
• Overall interpretation by visit including both open-label and double-blind visits; overall 
worst interpretation for the open-label period; overall worst interpretation for the 
double-blind period. 
• Overall interpretation shift from open-label baseline by visit including both open-label 
and double-blind visits; overall worst interpretation for the open-label period; overall 
worst interpretation for the double-blind period. 
• Overall interpretation shift from double-blind baseline by visit for the double-blind 
period; overall worst interpretation for the double-blind period. 


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Table 8 Criteria for PCI ECG Values 
ECG Parameter 
Unit 
High PCI Criteria 
QRS Interval 
msec 
≥120 
PR Interval 
msec 
≥220 
QTcF 
msec 
>500 
QTcF: change from baseline 
msec 
>60 
 
14.5 Physical and Neurological Examinations 
14.5.1 Analysis for the Open-label Safety Analysis Set 
Physical examinations and neurological examinations (cranial nerves, motor, sensory, 
reflexes, gait, and coordination), are performed at Screening, Baseline, and Week 12 during 
the open-label period. 
Physical and neurological examination results (normal, abnormal, and not done) will be 
summarized in a frequency table by body/neurological system at Baseline and Week 12. 
14.5.2 Analysis for the Double-blind Safety Analysis Set 
In addition to the open-label assessments at Screening, Baseline and Week 12, physical 
examinations and neurological examinations (cranial nerves, motor, sensory, reflexes, gait, 
and coordination), are performed at Weeks 22 and 38 during the double-blind period. 
Summaries for the Double-blind Safety Analysis Set will include both the open-label and 
double-blind periods.  
Physical and neurological examination results (normal, abnormal, and not done) during the 
open-label and double-blind periods will be summarized in a frequency table by 
body/neurological system. 
14.6 Global Clinician Assessment of Suicidality 
14.6.1 Analysis for the Open-label Safety Analysis Set 
Global Clinician Assessment of Suicidality (GCAS) scores are measured at Screening, 
Baseline, and Weeks 2, 4, 8, and 12 visits during the open-label period. The number and 
percentage of subjects for each GCAS rating (0-4) will be tabulated by visit. The number and 


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percentage of subjects reporting any post-Baseline GCAS score of 3 or 4 during the 
open-label period will also be tabulated. 
14.6.2 Analysis for the Double-blind Safety Analysis Set 
In addition to the open-label assessments at Screening, Baseline and Weeks 2, 4, 8, and 12 
during the open-label period, CGAS is assessed at Weeks 13, 14, 16, 18, 20, 22, 24, 26, 30, 
34, 38 during the double-blind period. Summaries for the Double-blind Safety Analysis Set 
will include both the open-label and double-blind periods.  
The number and percentage of subjects for each GCAS rating (0-4) will be tabulated by visit. 
The number and percentage of subjects reporting any post-Baseline GCAS score of 3 or 4 
during the open-label period and during the double-blind period will also be tabulated .  
14.7 Mini-Mental State Examination  
14.7.1 Analysis for the Open-label Safety Analysis Set 
Mini-Mental State Examination (MMSE) scores are measured at Screening, Baseline, and 
Weeks 2, 4, 8, and 12 during the open-label period.  
Observed MMSE scores will be summarized using descriptive statistics at Baseline, Weeks 2, 
4, 8, and 12. The change from Baseline scores at Weeks 2, 4, 8, and 12 values will also be 
summarized.   
14.7.2 Analysis for the Double-blind Safety Analysis Set 
In addition to the open-label assessments at Screening, Baseline and Weeks 2, 4, 8, and 12, 
MMSE scores are measured at Weeks 13, 14, 16, 18, 22, 26, 30, 34, and 38 during the 
double-blind period. Summaries for the Double-blind Safety Analysis Set will include both the 
open-label and double-blind study periods. 
Observed MMSE values and change from open-label baseline will be summarized by visit for 
both open-label and double-blind visits. 
Observed MMSE values and change from double-blind baseline will be summarized by visit 
for the double-blind visits. In addition, treatment comparisons will be made between the 
placebo group and the pimavanserin group (20 mg and 34 mg combined) for change from 


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double-blind baseline using the MMRM and an ANCOVA model respectively described in 
Sections 13.3.1.1 and 13.3.1.2. 
14.8 Extrapyramidal Symptom Rating Scale - Abbreviated 
14.8.1 Analysis for the Open-label Safety Analysis Set 
Extrapyramidal Symptom Rating Scale - Abbreviated (ESRS-A) scores are measured at 
Baseline and Week 12 during the open-label period. 
Observed ESRS-A total scores and the four individual global CGI-S scores will be 
summarized using descriptive statistics at Baseline and Week 12. The change from Baseline 
values will also be summarized at Week 12.   
14.8.2 Analysis for the Double-blind Safety Analysis Set 
In addition to the open-label assessments at Baseline and Week 12, ESRS-A scores are 
measured at Weeks 13, 14, 16, 18, 22, 26, 30, 34, and 38 during the double-blind period. 
Summaries for the Double-blind Safety Analysis Set will include both the open-label and 
double-blind study periods. 
ESRS-A total scores and the four individual global CGI-S scores, along with change from 
open-label baseline, will be summarized by visit for both open-label and double-blind visits.  
ESRS-A total scores and the four individual global CGI-S scores, along with change from 
double-blind baseline, will be summarized by visit for the double-blind visits.  
15 CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
The PK endpoints for this study are as follows: 
• Plasma concentration of pimavanserin and AC-279 
• Pimavanserin PK parameters using a population PK approach 
Pimavanserin and AC-279 plasma concentration data collected in the double-blind period 
will not be available to the Sponsor until the unblinding of the clinical database at the end of 
the study. 
If data allow, population PK and PK/PD analyses may be performed to further characterize 
the PK profile and exposure response relationship of pimavanserin and AC-279 using 


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measures of safety, and efficacy parameters. The results of population PK and PK/PD 
modeling will be presented in a separate report. 
Concentrations that are below the limit of quantitation (LLOQ) will be displayed as “LLOQ” 
in the data listings and imputed as 0 for computing summary statistics. 
15.1 Analysis for the Open-label Pharmacokinetic Analysis Set 
Pharmacokinetic samples are collected at Baseline, and Weeks 8 and 12 during the open-label 
period, and also at any early termination visit or the visit immediately following any SAE or 
an AE leading to discontinuation in the open-label period. 
Plasma concentrations for pimavanserin and AC-279 will be summarized by visit using 
descriptive statistics for the Open-label Pharmacokinetic Analysis Set.  
15.2 Analysis for the Double-blind Pharmacokinetic Analysis Set 
In addition to the open-label assessments at Baseline, and Weeks 8 and 12 during the 
open-label period, pharmacokinetic samples are collected at double-blind Weeks 13, 22, and 
38 of the double-blind period, and also at any early termination visit or the visit immediately 
following any SAE or an AE leading to discontinuation in the double-blind period. 
Summaries for the Double-blind Pharmacokinetic Analysis Set will include both the 
open-label and double-blind study periods. 
Plasma concentrations for pimavanserin and AC-279 will be summarized by visit using 
descriptive statistics for both open-label and double-blind visits. 
16 UNBLINDED INTERIM EFFICACY ANALYSIS 
The database cutoff date for the interim analysis is defined as the date that the adjudication of 
the 38th relapse event is complete (complete is defined as when the data has been entered by 
the responsible reviewer, source data verified by the independent adjudication committee 
project manager, and entry restricted to further modification). Double-blind discontinuations 
that occur on or before the database cutoff date will be adjudicated and included in the 
interim analysis. The ITT Analysis Set for the interim analysis will include all subjects 
randomized on or before the database cutoff date. 
 


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The interim analysis will be based on the interim analysis dataset, created from the interim 
analysis data extract. Data occurring after the database cutoff date will not be included in the 
interim analysis dataset; however, data that occurs [e.g., from a visit] on or before the 
database cutoff date but are entered into the clinical database in the period between the 
database cutoff date and the date of the interim analysis data extract would be included in the 
interim analysis datasets. The final database will be locked after all data are included at study 
termination. If the study is stopped at the interim analysis, sensitivity analyses investigating 
the impact of overrun events (See Section 16.2.2) will be based on datasets created from the 
final database. If the study is not stopped at the interim analysis, the primary analysis of the 
primary and key secondary efficacy endpoints will be based on the final database using all 
data collected up until the study discontinuation date. 
16.1 Primary Efficacy Endpoint 
An interim analysis evaluating efficacy based on the primary efficacy endpoint will be 
conducted by an independent statistical group (ISG) when at least 38 adjudicated relapse 
events determined by the IAC have been accrued. The ISG is not affiliated with the Sponsor 
or the DSMB.  The ISG statistician will disseminate the unblinded interim results at the 
closed session of the DSMB meeting. In order to protect the blinding and the integrity of this 
study, the actual computational output will be securely stored by the ISG and retained until 
the study is unblinded after the final database lock.  
Table 9 displays the O’Brien-Fleming stopping boundary information for the group 
sequential design having one interim analysis if it is conducted with exactly 38 relapse events 
and a final analysis to be conducted with exactly 75 relapse events.  
Table 9 O’Brien-Fleming Stopping Boundary Information 
 
Stopping Boundary: P-value Scale 
Stage 
Relapse Events 
Proportion 
 1-sided 
2-sided  
Interim 
38 
0.5067 
0.0027 
0.0054 
Final 
75 
1.0000 
0.0239 
0.0479 
 
In the event that not exactly 38 relapse events have accrued at the interim analysis, the 
O’Brien-Fleming stopping boundary will be recalculated based on the actual number of 


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relapse events accrued at the interim analysis. The decision to stop or continue the study will 
be made based on this recalculated boundary. More specifically, let 𝑍𝑍1 be the Wald test 
statistics evaluated at the time of interim analysis and let 𝑍𝑍2 be the Wald test statistics at the 
time of the final analysis. The test statistics are constructed such that a negative value favors 
the study drug. Let 𝑛𝑛 be the number of relapse events observed at interim time and 𝑁𝑁 be the 
total number of events and  𝑡𝑡=
𝑛𝑛
𝑁𝑁  be the information fraction for the interim analysis. At the 
trial design stage, the plan is to take 𝑛𝑛= 38, 𝑁𝑁= 75  and  𝑡𝑡=
38
75 which implies that the 
correlation between 𝑍𝑍1 and 𝑍𝑍2 is √𝑡𝑡 . Let c be a constant such that  
𝑃𝑃൬𝑍𝑍1 < 𝑐𝑐
√𝑡𝑡൰+ 𝑃𝑃൬𝑍𝑍1 ≥𝑐𝑐
√𝑡𝑡, 𝑍𝑍2 < 𝑐𝑐൰= 0.025. 
The one-sided P-value scale boundary for the interim analysis is 𝑝𝑝1
(1) = Φ ቀ
𝑐𝑐
√𝑡𝑡ቁ and the 
one-sided P-value scale boundary for final analysis is 𝑝𝑝2
(1) = Φ(𝑐𝑐), where Φ(∙) is the 
standard normal cumulative distribution function. 
At the trial implementation stage, the observed number of relapse events might be different 
from the planned one. Denote the actual observed number of events at the interim by 𝑛𝑛∗ and 
let 𝑡𝑡∗=
𝑛𝑛∗
75  be the observed information fraction at the time of interim analysis. 
 Let 𝑐𝑐∗ be the constant satisfying the following equation 
𝑃𝑃൬𝑍𝑍1 < 𝑐𝑐∗
√𝑡𝑡∗൰+ 𝑃𝑃൬𝑍𝑍1 ≥𝑐𝑐∗
√𝑡𝑡∗, 𝑍𝑍2 < 𝑐𝑐∗൰= 0.025, 
where the updated correlation between 𝑍𝑍1  and 𝑍𝑍2 is √𝑡𝑡∗. Then the updated one-sided P-value 
scale boundaries for the interim and final analyses are given by 𝑝𝑝1
(1)∗= Φ ቀ
𝑐𝑐∗
√𝑡𝑡∗ቁ and 
𝑝𝑝2
(1)∗= Φ(𝑐𝑐∗). 
At the interim analysis, if the observed one-sided p-value from the Cox regression analysis is 
less than the corresponding lower stopping boundary p-value 𝑝𝑝1
(1)∗, then the null hypothesis 
will be rejected with the conclusion that the study demonstrates superiority of pimavanserin 
compared to placebo. Conversely, if the observed one-sided p-value is greater than or equal 
to the lower stopping boundary p-value, the null hypothesis will not be rejected and the study 


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recruitment will continue until 75 adjudicated relapse events have been accrued for the final 
analysis. At the final stage, if the observed p-value is less than the corresponding lower 
stopping boundary p-value  𝑝𝑝2
(1)∗, then the null hypothesis will be rejected with the 
conclusion that the study demonstrates superiority of pimavanserin compared to placebo. In 
the event that not exactly 75 relapse events have accrued at the final analysis, the 
O’Brien-Fleming stopping boundary will be recalculated based on the actual number of 
relapse events accrued at the interim and final analyses and the information fraction. This 
recalculated boundary will be used to determine superiority of pimavanserin compared to 
placebo. More specifically, let 
𝛼𝛼1 = Φ ቀ
𝑐𝑐∗
√𝑡𝑡∗ቁ denote the actual type I error spent at the interim analysis time. Let  𝑁𝑁෩ be the 
observed number of relapse events at the final analysis and  𝑡𝑡̃ =
𝑛𝑛∗
𝑁𝑁෩. The one-sided P-value 
scale boundary for the final analysis is given by Φ(𝑐𝑐̃) where the  𝑐𝑐̃ satisfies the following 
equation 
𝛼𝛼1 + 𝑃𝑃൬𝑍𝑍1 ≥𝑐𝑐∗
√𝑡𝑡∗,   𝑍𝑍2 < 𝑐𝑐̃൰= 0.025, 
and where the correlation between 𝑍𝑍1 and 𝑍𝑍2 is √𝑡𝑡̃.  
16.2 Key Secondary Efficacy Endpoint 
Testing of the key secondary endpoint will be conducted at most once either at the interim 
analysis or the final analysis provided that the primary endpoint reaches statistical 
significance. The test statistics are constructed such that a negative value favors the study 
drug. 
An O’Brien-Fleming stopping boundary will also be used for the key secondary endpoint. Let 
𝑌𝑌1 and 𝑌𝑌2 be the Wald statistics for testing the key secondary efficacy endpoint at the interim 
and final analysis. The one-sided P-value scale boundary for the key secondary efficacy 
endpoint at the interim analysis is given by  
𝑝𝑝1
(2)∗= 𝛼𝛼1, 
i.e. the same type I error spent at the interim analysis for the primary efficacy endpoint. 


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At the time of the final analysis, the one-sided P-value scale boundary is 𝑝𝑝2
(2)∗= Φ(𝑑𝑑) where 
𝑑𝑑 satisfies the following equation 
𝛼𝛼1 + 𝑃𝑃൬𝑌𝑌1 ≥𝑐𝑐∗
√𝑡𝑡∗ , 𝑌𝑌2 < 𝑑𝑑൰= 0.025, 
and where the correlation between 𝑌𝑌1 and 𝑌𝑌2 is given by ට
𝑚𝑚
𝑀𝑀  and  𝑚𝑚 is the observed number 
of discontinuation events from the double-blind period at the time of interim analysis and 𝑀𝑀 
is the total number of discontinuation events at the final analysis. 
16.2.1 Overrunning of Relapse Events at Interim Analysis 
If the decision to stop the study for efficacy at the interim analysis is triggered, an overrun in 
termination events may occur if double-blind termination events occur after the database 
cutoff date for the interim analysis. For the primary efficacy endpoint defined by adjudicated 
relapse events, the overrun includes events that occur between the database cutoff date and 
the study discontinuation date. These events will be adjudicated by the Independent 
Adjudication Committee and will be included in the sensitivity analysis. Early terminations 
and relapse events that occur after the study discontinuation date will not be adjudicated and 
thus will not be included in this sensitivity analysis. Sensitivity analysis of overrun events 
described in Section 13.1.2 will be considered supportive.   
16.2.2 Analysis Following a Sequential Test 
To account for the fact that a sequential design is used, the stage-wise ordering of the sample 
space will be used to compute an adjusted estimate for the hazard ratio, 95% confidence 
interval, and p-value following rejection of the null hypothesis at the final analysis, if the 
study was not stopped early at the interim analysis (Tsiatis, et. al., 1984). 
17 DATA AND SAFETY MONITORING BOARD 
An independent Data and Safety Monitoring Board (DSMB) will review interim safety data 
including data on AEs and SAEs. The DSMB will be independent of the Sponsor and the 
Investigators and will be empowered to recommend stopping the study due to safety 
concerns. In addition, the DSMB will review the results of the pre-planned unblinded interim 


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analyses conducted by the ISG. The roles and responsibilities of DSMB members and ISG 
and planned frequency of meetings are detailed in the DSMB Charter.  
The ISG will produce unblinded interim statistical outputs and provide these outputs to 
DSMB members using a secure method. The Sponsor and the Investigators will remain 
blinded until the official unblinding of the database at the end of the study. The outputs 
presented to DSMB members by the independent statistician will be consistent with what is 
described in the DSMB Charter.  
18 INDEPENDENT ADJUDICATION COMMITTEE 
An Independent Adjudication Committee (IAC) will perform validation of protocol-defined 
relapse events. The validation is based on review of predefined clinical data related to: 1) a 
relapse (identified by the Investigator) occurring before the study discontinuation date and 2) 
all early termination events which occur in the double-blind period before the study 
discontinuation date. Early termination and relapse events that occur in the double-blind 
period after the study discontinuation date will not be adjudicated. 
The events will be reviewed by the IAC in a blinded manner. 
Predefined clinical data consist of copies of source documents collected and delivered by the 
investigational sites.  The IAC will work in accordance with written guidelines included in 
the IAC Charter describing in detail the composition, tasks, responsibilities and work 
processes of the committee. Only events determined to be relapse events by the IAC will be 
used in the primary efficacy analysis (Section 13.1). 
19 COMPUTER METHODS 
Statistical analyses will be performed using Version 9.4 (or newer) of SAS® (SAS® Institute, 
Inc., Cary, North Carolina) on a suitably qualified and validated environment.  
Validation and quality control of the tables, listings, and figures containing the results of the 
statistical analyses will follow appropriate standard operating procedures. 
20 CHANGES TO ANALYSES SPECIFIED IN PROTOCOL 
There are no planned deviations from the specified analyses in Protocol Amendment 1, dated  
16 August, 2018. 


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21 REFERENCES 
1. Lin, DY, Wei LJ. The robust inference for the proportional hazards model. Journal of the 
American Statistical Association 1989;84:1074-1078. 
2. Rubin DB. Inference and missing data. Biometrika 1976;63:581:592. 
3. Tsiatis AA, Rosner GL, Mehta CR. Exact confidence interval following a group sequential test. 
Biometrics 1984;40:797-803. 
4. ICH Guidance for Industry: E14 Clinical Evaluation of QT/QTc Interval Prolongation and 
Proarrhythmic Potential for Non-Antiarrhythmic Drugs, 2005.  
5. Lu K, et.al. Comparison Between Two Controlled Multiple Imputation Methods for Sensitivity 
Analyses of Time-to-Event Data With Possibly Information Censoring. Statistics in 
Biopharmaceutical Research. 2015; 7, 199-213. 
 


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22 APPENDICES 
Appendix 1 Summary of Version Changes   
Version No: 
Document History 
Description of Update 
Author(s) 
Version Date