Clinical trial NCT04292223
Conditions: Parkinson Disease Psychosis
Sponsor: ACADIA Pharmaceuticals Inc.
Start date: 2020-02-10; Completion date: 2022-04-26
Enrollment: 29 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
To assess the effect of pimavanserin on the activities of daily living in subjects with Parkinson's Disease Psychosis

Detailed description:
This study will be conducted as a 16-week, multi-center, single-arm, open-label study. Pimavanserin will be administered at a dose of 34 mg to approximately 50 subjects with PDP

Arms: arm 1: Pimavanserin 34 mg administered orally
Interventions: intervention 1: Pimavanserin
Intervention descriptions: intervention 1: Pimavanserin 34 mg (provided as 1×34 mg capsule), administered orally, once daily for 16 weeks

Protocol documents:
Prot_000.pdf: 
Official Title: A 16-Week Open-Label Study of the Effects of Treatment With 
Pimavanserin on Activities of Daily Living in Subjects With Parkinson’s Disease 
Psychosis 
NCT Numbers: NCT04292223 
Document Date: 20 May 2021 


 
 
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CLINICAL STUDY PROTOCOL  
AMENDMENT 1 
 
A 16-Week Open-Label Study of the Effects of Treatment With 
Pimavanserin on Activities of Daily Living in Subjects With Parkinson’s 
Disease Psychosis 
 
Protocol Number: ACP-103-063 
 
 
 
Original Protocol Date: 13 September 2019 
Protocol Amendment 1 Date: 20 May 2021 
 
 
Protocol Template Version: 1.0 
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. 


Study: ACP-103-063 
 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
 
Date: 20 May 2021 
 
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SPONSOR SIGNATURE PAGE 
Title: A 16-Week Open-Label Study of the Effects of Treatment With Pimavanserin on 
Activities of Daily Living in Subjects With Parkinson’s Disease Psychosis 
 
Acadia Global Head of Medical Affairs 
& Chief Medical Officer: 
 
 
 
 
 
 
 
See appended electronic signature page 
 
 
Signature 
Date 
 
 
 
Acadia Study Lead: 
 
 
 
 
See appended electronic signature page 
 
 
Signature 
Date 
 
 
 
 
 
 
 
 
 


Signature Page for ACP-103-063 Protocol Amendment 1
Signature Page for ACP-103-063 Protocol Amendment 1
Approve
Approve


Study: ACP-103-063 
 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
 
Date: 20 May 2021 
 
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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 Good Clinical Practices, as required by International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) Guideline E6 and as 
described in the United States (US) Code of Federal Regulations (CFR) 21 CFR parts 50, 54, 
56, 312, and according to applicable local requirements. 
Confidentiality Statement 
The confidential information in this document is provided to you as an 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. 
Investigator 
 
 
Signature 
 
Date 
 
 
 
Name (printed) 
 
 
 
 


Study: ACP-103-063 
 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
 
Date: 20 May 2021 
 
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PROTOCOL SYNOPSIS 
Protocol Number 
ACP-103-063 
EudraCT Number 
Not applicable 
Protocol Title 
A 16-Week Open-Label Study of the Effects of Treatment With 
Pimavanserin on Activities of Daily Living in Subjects With 
Parkinson’s Disease Psychosis  
Name of 
Investigational 
Product 
NUPLAZID (pimavanserin) 34 mg capsules 
Indication 
Parkinson’s Disease Psychosis 
Phase of 
Development 
4 
Sponsor 
Acadia Pharmaceuticals Inc. 
 
 
Primary Objective 
To assess the effect of pimavanserin on the 
activities of daily living (ADLs) in subjects 
with Parkinson’s disease psychosis (PDP) 
measuring the subject’s physical, 
psychological, social and role functions 
Primary Endpoint 
• Change from baseline (Week 0) to 
Week 16 on the modified Functional 
Status Questionnaire (mFSQ) total 
score  
Secondary Objectives 
To evaluate the efficacy and benefits of 
pimavanserin in subjects with PDP on 
activities of daily living 
To assess the clinician’s global impression of 
severity and improvement of 
hallucination/delusions 
Secondary Endpoints 
• Change from baseline to Week 16 on 
the Schwab and England ADL Scale 
(Caregiver and Patient Version) 
• Change from baseline to Week 16 on 
the Movement Disorders Society-
Unified Parkinson’s Disease Rating 
Scale (MDS-UPDRS) Parts I and II 
(Caregiver and Patient Version) 
• Week 16 Clinical Global Impression – 
Improvement (CGI-I) score for 
hallucinations and delusions  
• Change from Baseline to Week 16 on 
the Clinical Global Impression – 


Study: ACP-103-063 
 
Final Version: 1.0 
Clinical Study Protocol Amendment 1 
 
Date: 20 May 2021 
 
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Severity of Illness (CGI-S) score for 
hallucinations and delusions  
• Week 16 Patient Global Impression of 
Improvement (PGI-I) score for 
hallucinations and delusions  
Exploratory Objectives 
To assess the extent to which caregivers and 
families experience additional demands, 
responsibilities, and difficulties 
To explore the effects of pimavanserin in 
subjects with PDP on: 
• Functional capacity 
• Cognition 
• Depressive symptoms 
• Nighttime behavior 
• Caregiver burden 
Exploratory Endpoints 
• Change from Baseline to Week 16 on 
the Virtual Reality Functional Capacity 
Assessment Tool (VRFCAT) including 
total time to complete, total number of 
errors, and total number of forced 
progressions 
• Change from Baseline to Week 16 on 
the Caregiver Strain Index total score 
• Change from Baseline to Week 16 on 
the Neuropsychiatric Inventory-
Questionnaire (NPI-Q) Nighttime 
Behavior Domain Severity and 
Caregiver Distress 
• Change from Baseline to Week 16 on 
the Geriatric Depression Scale (GDS) 
(Short Form) 
• Change from Baseline to Week 16 on 
mFSQ score by subscale  
Safety Objective 
To assess the safety and tolerability of 
pimavanserin in adults with PDP 
Safety Endpoints 
The safety and tolerability of pimavanserin 
will be assessed using the following:  
• Treatment-emergent adverse events 
(TEAEs) 
• Columbia-Suicide Severity Rating 
Scales (C-SSRS) score 
• Potentially clinically important (PCI) 
findings on: 
• Physical examinations 
• Clinical laboratory tests 
• Vital signs 
• Electrocardiogram parameters 
Number of Study 
Sites 
Approximately 25 sites in the US will participate in this study. 


Study: ACP-103-063 
 
Final Version: 1.0 
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Date: 20 May 2021 
 
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Number of Subjects 
Planned 
Approximately 89 subjects with PDP will be screened and 53 subjects 
are expected to be enrolled, assuming a screen failure rate of 40%. 
Approximately 42 subjects are expected to complete the study, 
assuming a 20% drop-out rate. 
Test Product, Dose, 
and Administration 
Pimavanserin 34 mg (provided as 1×34 mg capsule), administered 
orally, once daily 
Study Design 
This study will be conducted as a 16-week, multi-center, single-arm, 
open-label study. Pimavanserin (ACP-103) will be administered at a 
dose of 34 mg to approximately 50 subjects with PDP.  
The study will have 3 periods: 
• Screening period (3-35 days) 
• Treatment period (16 weeks) 
• Safety follow-up period (30 [+4] days) 
The study will be conducted on an outpatient basis with visits 
performed at Screening, Baseline (Week 0), Week 2, Week 4, Week 8, 
Week 12, Week 16 (end of Treatment Period) and Follow-up (at least 
30 days and not to exceed 34 days after last dose of study drug). 
Screening Period (3-35 Days) 
During the screening period, subjects will be assessed for study 
eligibility and prohibited medications will be discontinued. 
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 and in 
consultation with the treating physician. 
Treatment Period (16 Weeks) 
The Baseline visit (Week 0) may occur as soon as screening 
procedures are completed and subject eligibility has been confirmed. 
Treatment with pimavanserin 34 mg once daily (QD) will begin on the 
morning of the day after the Baseline visit. Additional assessments will 
be conducted at Week 2, Week 4, Week 8, Week 12, Week 16 (end of 
treatment [EOT])/early termination [ET]). Subjects who are withdrawn 
will not be replaced. 
Safety Follow-up Period (30-34 Days) 
A follow-up safety assessment telephone call will be conducted at least 
30 days and no more than 34 days after the last dose of study drug. 
The schedule of assessments is provided in Table S–1. 


Study: ACP-103-063 
 
Final Version: 1.0 
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Date: 20 May 2021 
 
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Study Duration 
The duration of participation for individual study subjects will be up to 
26 weeks, consisting of the following 3 periods (Table S–1): 
• Screening period: 3-35 days 
• Treatment period: 16 weeks 
• Safety follow-up period: 30-34 days 
The study start date is defined as the date the first subject is enrolled, 
which is the baseline visit date for the first subject. 
The primary completion date is the last date that subject data was 
collected for the primary outcome measure. 
The study completion date is defined as the last date that subject data 
was collected, which includes the safety follow-up telephone call visit.  
Main 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. 
Inclusion Criteria: 
1. Male or female subjects at least 40 years of age  
2. Can understand the nature of the study and protocol 
requirements and provide written informed consent 
3. Is able to demonstrate the ability to complete subject-reported 
outcome measures on a handheld device, and can be reliably 
rated on assessment scales (in the opinion of the Investigator) 
4. Must be able to designate a caregiver or study partner who the 
subject agrees can provide reliable information on the subject’s 
well-being, and is willing to provide written informed consent 
and attend clinic visits with the subject 
5. Has a Schwab & England ADL Scale score of 40-80% 
(inclusive) at both Visit 1 (Screening) and Visit 2 (Baseline) as it 
relates to their PDP symptoms 
6. Has a Mini-Mental State Examination (MMSE) score ≥19 at 
Screening 
7. This criterion has been deleted; please consult the Summary of 
Changes for details. 
8. Has a diagnosis of idiopathic Parkinson’s disease (PD), 
according to the Movement Disorders Society criteria for the 
diagnosis of PD (Postuma et al. 2015), without any other known 
or suspected cause of parkinsonism. History of initial PD 
symptoms onset greater than 1 year prior to Screening. 


Study: ACP-103-063 
 
Final Version: 1.0 
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Date: 20 May 2021 
 
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9. Has psychotic symptoms that may impair function and are 
severe enough to warrant treatment with an antipsychotic agent 
10. Has a CGI-S score of ≥4 when assessing psychosis symptoms at 
Visit 1 (Screening) and Visit 2 (Baseline) 
11. If the subject is on anti-Parkinsonian medication, they must be 
on a stable regimen for 2 months prior to Baseline and not 
planning (at the time of the Baseline visit) to make a change in 
dose(s) 
12. This criterion has been deleted; please consult the Summary of 
Changes for details. 
13. Psychotic symptoms developed after the onset of symptoms of 
PD 
14. Psychotic symptoms present for at least 1 month overall (could 
be intermittent), with active psychotic symptoms in either of the 
last 2 weeks prior to screening 
15. Has clear sensorium at study entry (i.e., oriented to time, person, 
and place) in the opinion of the Investigator 
16. 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 TWO clinically 
acceptable methods of contraception   
Acceptable methods of contraception 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) 
Only one of the two clinically acceptable methods can be a 
hormonal method. 
Exclusion Criteria: 
1. Has atypical parkinsonism (Parkinson’s plus, multiple system 
atrophy [MSA], progressive supranuclear palsy [PSP]), or 
secondary parkinsonism variants such as tardive or medication 
induced parkinsonism 
2. Has undergone ablative procedures such as a pallidotomy, 
thalamotomy, or treatment with focused ultrasound, or has an 
implanted deep brain stimulator 
3. Is in hospice, is receiving end-of-life palliative care, or is 
bedridden or confined to a wheelchair  


Study: ACP-103-063 
 
Final Version: 1.0 
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Date: 20 May 2021 
 
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4. Has current evidence of an unstable neurological, 
cardiovascular, respiratory, gastrointestinal, renal, hepatic, 
hematologic, or other medical or psychiatric disorder, including 
cancer or malignancies that, in the judgment of the Investigator, 
would jeopardize the safe participation of the subject in the 
study or significantly interfere with the conduct or interpretation 
of the study 
5. Has a history of epilepsy 
6. Has atrial fibrillation unless adequately anticoagulated 
7. Has a history of myocardial infarction, unstable angina, acute 
coronary syndrome, or cerebrovascular accident within the last 
6 months prior to Screening 
8. Has any of the following: 
a. greater than New York Heart Association (NYHA) 
Class 2 congestive heart failure  
b. Grade 2 or greater angina pectoris (by Canadian 
Cardiovascular Society Angina Grading Scale)  
c. sustained ventricular tachycardia 
d. ventricular fibrillation 
e. torsades de pointes 
f. syncope due to an arrhythmia 
g. an implantable cardiac defibrillator 
9. Glycosylated hemoglobin (HbA1c) >8.5% at Screening 
10. This criterion has been deleted; please consult the Summary of 
Changes for details. 
11. Has a known history of a positive hepatitis B virus (HBV) or 
hepatitis C virus (HCV) test 
12. Has a history of human immunodeficiency virus (HIV) 
13. Has a history of neuroleptic malignant syndrome or serotonin 
syndrome 
14. Has a known personal or family history of long QT syndrome or 
family history of sudden cardiac death 
15. Has any of the following electrocardiogram (ECG) results at the 
Screening visit:  
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:  
iii. 
QTcF >425 ms, if QRS duration <120 ms 


Study: ACP-103-063 
 
Final Version: 1.0 
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iv. 
QTcF >450 ms, if QRS duration ≥120 ms 
If the mean corrected QT interval using Fridericia’s correction 
method (QTcF) value from the centrally read ECG done at 
Screening is prolonged due to an identifiable cause, and it is 
medically appropriate to address that cause, a repeat ECG may 
be performed during Screening at the discretion of the Medical 
Monitor.  
16. Has a heart rate as measured at Screening by the ECG machine 
<50 beats per minute. If bradycardia is secondary to iatrogenic 
or treatable causes and these causes are treated, a heart rate 
assessment can be repeated during the screening period.  
17. Has major surgery planned from the start of screening through 
the end of the follow-up period 
18. Requires treatment with a medication or other substance that is 
prohibited by the protocol 
19. Has a body mass index (BMI) <18.5 kg/m2 or >35 kg/m2 at 
Screening or Baseline or known unintentional clinically 
significant weight loss (i.e., ≥7%) over past 6 months 
20. The urine drug screen result at Visit 1 (Screening) indicates the 
presence of amphetamine/methamphetamine, barbiturates, 
cocaine, marijuana (tetrahydocannabinols [THC]), opiates, or 
phencyclidine (PCP). The use of benzodiazepines, marijuana 
(THC) or opiates on an as needed (PRN) basis, and when 
substance use disorder has been ruled out by the investigator in 
discussion with the medical monitor, does not necessarily 
exclude the subject from the study. 
21. Is suicidal at Screening or Baseline as defined below: 
a. According to the C-SSRS, he or she must not be actively 
suicidal at Visit 1 (Screening) or Visit 2 (Baseline) 
(including, an answer of “yes” to C-SSRS questions 4 or 
5 [current or over the last 6 months]) and must not have 
attempted suicide in the 1 year prior to Visit 1 
(Screening); OR 
b. The subject is actively suicidal in the Investigator’s 
judgment 
22. Has participated in or is participating in a clinical study of any 
investigational drug, device, or intervention, within 30 days or 
5 half-lives, whichever is longer, of Visit 2 (Baseline) 
23. Has previously been enrolled in any prior clinical study with 
pimavanserin  
24. Has previously or is currently taking pimavanserin 


Study: ACP-103-063 
 
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25. Has taken an antipsychotic medication less than 5 half-lives 
prior to Baseline 
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. Has a history of a significant psychotic disorder prior to or 
concomitantly with the onset of PD including, but not limited 
to, schizophrenia or bipolar disorder 
29. Had dementia prior to or concomitantly with the onset of motor 
symptoms of PD 
30. Has clinically significant laboratory abnormalities that in the 
judgment of the Investigator might jeopardize the safety of the 
subject 
31. Is judged by the Investigator or the Medical Monitor to be 
inappropriate for the study for any reason, including if the 
subject is judged to be a danger to self or others  
32. Positive COVID-19 polymerase chain reaction (PCR) or antigen 
result in the last 2 weeks prior to screening  
Sample Size 
Calculations  
 
This is an exploratory study and is not powered for statistical 
significance. Formal sample size calculations were not used to 
determine sample size. 
Statistical Methods 
Analysis Sets 
The Safety Analysis set will consist of all subjects who receive at least 
1 dose of study drug. 
The Full Analysis set will consist of all subjects who receive at least 
1 dose of study drug, and have both baseline and at least one post-
baseline value for the mFSQ total score. 
Primary Analysis 
The primary efficacy endpoint, change from baseline to Week 16 in the 
mFSQ total score, will be evaluated using a mixed-effects model for 
repeated measures (MMRM). The response variable is the change from 
Baseline to Weeks 4, 8, 12, and 16 and the fixed effects include visit 
(Weeks 4, 8, 12, and 16), corresponding Baseline score, and the 
Baseline score-by-visit interaction. 
Summary statistics for the mFSQ total score (observed and change 
from Baseline), least-squares (LS) means and the corresponding 95% 
confidence interval will be presented. 


Study: ACP-103-063 
 
Final Version: 1.0 
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Secondary Analyses 
Each of the secondary endpoints will be analyzed using the MMRM 
model similar to that described for the primary analysis. For CGI-I the 
baseline CGI-S score will be used as the covariate in the MMRM 
model. 
Safety Analyses 
Adverse events will be classified into standard terminology using the 
Medical Dictionary for Regulatory Activities (MedDRA). All adverse 
events (AEs) will be listed and TEAEs will be summarized by system 
organ class and preferred term. 
A TEAE is defined as an AE that occurs after the first dose of study 
drug and up to 30 days after the last dose of study drug. Summaries by 
maximum severity and by relationship to study drug as assessed by the 
investigator will also be provided. Serious TEAEs, fatal AEs, and 
TEAEs leading to discontinuation will also be summarized. 
The serum clinical chemistry, hematology, and urinalysis results at 
each time point will be summarized. Change from Baseline values will 
also be summarized. 
The number and percentage of subjects with PCI post-Baseline values 
will be summarized at each post-Baseline visit and overall 
post-Baseline for selected parameters. The PCI criteria will be 
specified in the statistical analysis plan. 
Vital signs, body weight, and BMI at Baseline and each post-Baseline 
visit will be summarized. Change from Baseline values will also be 
summarized. 
The results of the physical examinations at each visit will be tabulated. 
Electrocardiogram parameters at study visits will be summarized. 
Change from Baseline values will also be summarized. Categorical 
analyses will be conducted on the incidence of subjects with prolonged 
QTc intervals and changes in QTc intervals in accordance with ICH 
guidelines. 
For the C-SSRS, the number and percentage of subjects with suicidal 
ideation or suicidal behavior during the study will be tabulated. 
Date 
20 May 2021 
 


Study: ACP-103-063 
 
Final Version: 1.0 
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Date: 20 May 2021 
 
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Figure S–1 
Schematic of Study Design for ACP-103-063 
 
 
 
 
 
Abbreviations: EOT: end of trial; ET: early termination; QD: once daily
 
Open-Label Treatment Period 
16 weeks 
34 mg pimavanserin QD 
Follow-up Period 
30 days 
EOT/ET 
30-day follow-up 
(telephone call) 
Screening Period 
Up to 5 weeks 
Baseline 
Eligible subjects with 
Parkinson’s disease and 
psychotic symptoms 


Study: ACP-103-063 
 
Final Version: 1.0 
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Table S–1 
Schedule of Events and Assessments for ACP-103-063 
Period 
Screening 
Treatment 
        Baseline 
Safety  
Follow-up 
Visit Week 
-5 to 0 
0 
2 
4 
8 
12 
16/EOT 
20a 
Visit Number 
1 
2 
3 
4 
5 
6 
7/ETb 
8 
Visit window (days) 
 
 
±3 
±3 
±3 
±3 
±3 
+4 
Type of Visit 
clinic 
clinic 
clinic 
clinic 
clinic 
clinic 
clinic 
telephone 
Informed consent of subject 
X 
 
 
 
 
 
 
 
Informed consent of caregiver or study 
partner 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
Medical history and demographics 
X 
 
 
 
 
 
 
 
Weight, height, BMI 
X 
X 
 
 
 
 
X 
 
Physical examination 
X 
 
 
 
 
 
X 
 
12-lead ECGc 
X 
X 
 
X 
 
 
X 
 
Vital signsd 
X 
X 
X 
X 
X 
X 
X 
 
Clinical laboratory tests 
X 
X 
 
X 
 
 
X 
 
Urine drug screen 
X 
 
 
 
 
 
 
 
Pregnancy teste 
X 
X 
 
X 
X 
X 
X 
 
MMSE 
X 
 
 
 
 
 
 
 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
 
FSQ 
X 
X 
 
X 
X 
X 
X 
 
Schwab & England ADL Scale (Patient)  
X 
X 
X 
X 
X 
X 
X 
 
Schwab & England ADL Scale (Caregiver)  
X 
X 
X 
X 
X 
X 
X 
 
NPI domains A and B 
X 
X 
 
 
 
 
 
 
NPI-Q Nighttime Behavior Domain only 
 
X 
X 
X 
X 
X 
X 
 
MDS-UPDRS Parts I and II (Patient) 
X 
X 
X 
X 
X 
X 
X 
 
MDS-UPDRS Parts I and II (Caregiver) 
X 
X 
X 
X 
X 
X 
X 
 
 


Study: ACP-103-063 
 
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Table S–1 
Schedule of Events and Assessments for ACP-103-063 (Continued) 
Period 
Screening 
Treatment 
        Baseline 
Safety  
Follow-up 
Visit Week 
-5 to 0 
0 
2 
4 
8 
12 
16/EOT 
20a 
Visit Number 
1 
2 
3 
4 
5 
6 
7/ETb 
8 
Visit window (days) 
 
 
±3 
±3 
±3 
±3 
±3 
+4 
Type of Visit 
clinic 
clinic 
clinic 
clinic 
clinic 
clinic 
clinic 
telephone 
CGI-S specific to H&D 
X 
X 
X 
X 
X 
X 
X 
 
CGI-I specific to H&D 
 
 
X 
X 
X 
X 
X 
 
PGI-I specific to H&D 
 
 
X 
X 
X 
X 
X 
 
VRFCAT 
X 
X 
 
X 
 
 
X 
 
Caregiver Strain Index 
X 
X 
X 
X 
X 
X 
X 
 
Geriatric Depression Scale (Short Form) 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of adverse events 
 
X 
X 
X 
X 
X 
X 
X 
Dispense study drug 
 
X 
X 
X 
X 
X 
 
 
Study drug return 
 
 
X 
X 
X 
X 
X 
 
Study drug accountability 
 
 
X 
X 
X 
X 
X 
 
Abbreviations: ADL=activities of daily living; BMI=body mass index; CGI-I=clinical global impression – improvement; CGI-S=clinical global impression – severity; C-
SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; EOT=end of trial; ET=early termination; FSQ= functional status questionnaire; H&D=hallucinations 
and delusions; MMSE=mini-mental state examination; NPI=neuropsychiatric inventory; NPI-Q=neuropsychiatric inventory – questionnaire; PGI-I=patient global impression – 
improvement; MDS-UPDRS=Movement Disorders Society – Unified Parkinson’s Disease Rating Scale; VRFCAT=virtual reality functional capacity assessment tool 
a 
The safety follow-up telephone call visit is to occur 30 (+4) days after the last dose of study drug, nominally at Week 20 for completers and earlier for ET subjects. 
b 
A subject terminating early should at a minimum complete assessments of safety (vital signs, ECG, AEs, clinical laboratories, C-SSRS) and, if possible, complete all Week 16 
assessments. 
c 
The ECG may be repeated once at Screening in consultation with the Medical Monitor. ECGs can be performed any time before blood sampling or at least 30 minutes after 
blood sampling during clinic visits.  
d 
Vital signs (sitting or supine [>3 minutes] blood pressure, pulse rate, oral temperature, and respiratory rate) will be performed at Screening and each study visit. 
e 
Applicable only to women of childbearing potential. A serum pregnancy test is performed at Screening and a urine pregnancy test at Baseline and all subsequent visits (except 
Visit 3 at which neither serum nor urine pregnancy test is performed).


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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ............................................................................................... 2 
DECLARATION OF INVESTIGATOR ................................................................................... 4 
PROTOCOL SYNOPSIS ........................................................................................................... 5 
TABLE OF CONTENTS ......................................................................................................... 17 
LIST OF TABLES ................................................................................................................... 22 
LIST OF FIGURES ................................................................................................................. 22 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................. 23 
1 
INTRODUCTION ...................................................................................................... 25 
1.1 
Background Information ............................................................................................ 25 
1.2 
Investigational Product ............................................................................................... 25 
1.3 
Previous Clinical Experience ..................................................................................... 26 
1.3.1 
Parkinson’s Disease Psychosis Program .................................................................... 26 
1.4 
Study Rationale .......................................................................................................... 27 
1.5 
Benefit/Risk Assessment ............................................................................................ 28 
2 
STUDY OBJECTIVES AND ENDPOINTS .............................................................. 28 
2.1 
Primary Objective....................................................................................................... 28 
2.1.1 
Primary Endpoint ....................................................................................................... 28 
2.2 
Secondary Objectives ................................................................................................. 28 
2.2.1 
Secondary Endpoints .................................................................................................. 28 
2.3 
Exploratory Objectives ............................................................................................... 29 
2.3.1 
Exploratory Endpoints ................................................................................................ 29 
2.4 
Safety Objectives ........................................................................................................ 29 
2.4.1 
Safety Endpoints......................................................................................................... 30 
3 
STUDY DESCRIPTION ............................................................................................ 30 
3.1 
Overview of Study Design ......................................................................................... 30 
3.1.1 
Screening Period (3-35 Days) .................................................................................... 31 
3.1.2 
Treatment Period (16 Weeks) ..................................................................................... 31 
3.1.3 
Safety Follow-up Period (30 Days) ............................................................................ 31 
4 
SUBJECT ELIGIBILITY AND WITHDRAWAL CRITERIA .................................. 31 
4.1 
Inclusion Criteria ........................................................................................................ 31 
4.2 
Exclusion Criteria ....................................................................................................... 33 


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4.3 
Subject Withdrawal of Consent .................................................................................. 35 
4.4 
Subject or Study Discontinuation ............................................................................... 36 
4.4.1 
Handling of Subject Discontinuation During the Treatment Period .......................... 36 
4.5 
Subject Lost to Follow-up .......................................................................................... 37 
4.6 
Prior and Concomitant Therapy ................................................................................. 37 
4.6.1 
Prior Medication ......................................................................................................... 37 
4.6.2 
Concomitant Medication ............................................................................................ 37 
4.6.2.1 Permitted, Restricted, and Prohibited Medications .................................................... 37 
5 
INVESTIGATIONAL PRODUCT ............................................................................. 38 
5.1 
Investigational Product Description ........................................................................... 38 
5.1.1 
Formulation, Appearance, Packaging, and Labeling .................................................. 38 
5.1.2 
Product Storage and Stability ..................................................................................... 39 
5.1.3 
Dosing and Administration ......................................................................................... 39 
5.1.4 
Method of Assigning Subjects to Treatment Groups.................................................. 39 
5.1.5 
Blinding ...................................................................................................................... 39 
5.1.6 
Study Drug Compliance ............................................................................................. 39 
5.1.7 
Overdose ..................................................................................................................... 39 
5.2 
Investigational Product Accountability Procedures ................................................... 39 
6 
STUDY PROCEDURES ............................................................................................ 40 
6.1 
Screening Assessments ............................................................................................... 40 
6.1.1 
Mini-Mental State Examination ................................................................................. 40 
6.1.2 
Neuropsychiatric Inventory ........................................................................................ 40 
6.2 
Efficacy Assessments ................................................................................................. 41 
6.2.1 
Functional Status Questionnaire ................................................................................. 41 
6.2.2 
Schwab and England Activities of Daily Living Scale (Caregiver and Patient 
Version) ...................................................................................................................... 42 
6.2.3 
Movement Disorders Society – Unified Parkinson’s Disease Rating Scale Parts I and 
II (Caregiver and Patient Version) .............................................................................. 42 
6.2.4 
Clinical Global Impression – Improvement - Hallucinations and Delusions ............. 42 
6.2.5 
Clinical Global Impression – Severity - Hallucinations and Delusions ..................... 42 
6.2.6 
Patient Global Impression of Improvement - Hallucinations and Delusions ............. 43 
6.2.7 
Virtual Reality Functional Capacity Assessment Tool ............................................... 43 
6.2.8 
Caregiver Strain Index................................................................................................ 43 
6.2.9 
Neuropsychiatric Inventory – Questionnaire Nighttime Behavior Domain ............... 43 
6.2.10 Geriatric Depression Scale (Short Form) ................................................................... 43 
6.3 
Safety Assessments..................................................................................................... 44 


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6.3.1 
Columbia-Suicide Severity Rating Scale ................................................................... 44 
6.3.2 
Physical Examinations ............................................................................................... 44 
6.3.3 
Vital Signs .................................................................................................................. 44 
6.3.4 
Height, Weight, and Body Mass Index ....................................................................... 44 
6.3.5 
Electrocardiograms ..................................................................................................... 45 
6.3.6 
Laboratory Evaluations .............................................................................................. 45 
6.4 
Safety Follow-up ........................................................................................................ 48 
6.5 
Unscheduled Visits ..................................................................................................... 48 
7 
ADVERSE EVENTS ................................................................................................. 48 
7.1 
Specification of Safety Parameters............................................................................. 48 
7.1.1 
Definition of Adverse Event ....................................................................................... 48 
7.1.2 
Definition of Serious Adverse Event .......................................................................... 49 
7.2 
Classification of an Adverse Event ............................................................................ 51 
7.2.1 
Severity of Event ........................................................................................................ 51 
7.2.2 
Relationship to Study Drug ........................................................................................ 51 
7.2.2.1 Duration ...................................................................................................................... 51 
7.2.2.2 Frequency ................................................................................................................... 51 
7.2.2.3 Action Taken With Study Drug .................................................................................. 52 
7.2.2.4 Therapy ....................................................................................................................... 52 
7.2.2.5 Outcome ..................................................................................................................... 52 
7.2.2.6 Seriousness ................................................................................................................. 52 
7.2.3 
Definition of Unexpectedness .................................................................................... 52 
7.3 
Time Period and Frequency for Event Assessment and Follow-up ........................... 52 
7.4 
Reporting Procedures ................................................................................................. 53 
7.4.1 
Adverse Event Reporting ........................................................................................... 53 
7.4.2 
Serious Adverse Event Reporting............................................................................... 53 
7.4.3 
Reporting of Pregnancy .............................................................................................. 54 
7.4.3.1 Reporting Paternal Drug Exposure............................................................................. 54 
7.4.4 
Reporting of Overdose ............................................................................................... 54 
8 
CLINICAL MONITORING ....................................................................................... 55 
9 
STATISTICAL METHODS AND DATA ANALYSIS .............................................. 55 
9.1 
Statistical and Analytical Plans .................................................................................. 55 
9.2 
Statistical Hypotheses................................................................................................. 55 
9.3 
Sample Size Determination ........................................................................................ 55 
9.4 
Subject Populations for Analysis ................................................................................ 55 


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9.5 
Statistical Analyses ..................................................................................................... 55 
9.5.1 
Primary Analyses ........................................................................................................ 56 
9.5.2 
Secondary Analyses .................................................................................................... 56 
9.5.3 
Exploratory Analyses ................................................................................................. 56 
9.5.4 
Safety Analyses .......................................................................................................... 57 
9.5.4.1 Adverse Events ........................................................................................................... 57 
9.5.4.2 Other Safety Assessments .......................................................................................... 57 
9.5.4.3 Exposure to Study Drug ............................................................................................. 58 
9.5.4.4 Adherence and Retention Analyses ............................................................................ 58 
9.5.4.5 Demographics and Other Analyses ............................................................................ 59 
9.5.5 
Subgroup Analyses ..................................................................................................... 59 
9.6 
Interim Analyses ......................................................................................................... 59 
10 
STUDY MANAGEMENT AND DATA COLLECTION .......................................... 59 
10.1 
Data Collection and Management Responsibilities.................................................... 59 
10.2 
Source Documents ...................................................................................................... 59 
10.3 
Case Report Forms ..................................................................................................... 60 
10.4 
Confidentiality ............................................................................................................ 60 
10.5 
Study Records Retention ............................................................................................ 60 
10.6 
Protocol Exceptions and Deviations........................................................................... 60 
10.7 
Protocol Amendments ................................................................................................ 61 
11 
QUALITY MANAGEMENT .................................................................................... 61 
11.1 
Risk Management ....................................................................................................... 61 
11.2 
Quality Control and Quality Assurance...................................................................... 62 
12 
ETHICAL CONSIDERATIONS ................................................................................ 63 
12.1 
Ethical Standard ......................................................................................................... 63 
12.2 
Institutional Review Board/Ethics Committee ........................................................... 63 
12.3 
Informed Consent Process .......................................................................................... 63 
12.3.1 Consent and Other Informational Documents Provided to Subjects .......................... 64 
12.3.2 Consent Procedures and Documentation .................................................................... 64 
13 
PUBLICATION PLAN .............................................................................................. 64 
14 
CONFLICT OF INTEREST POLICY ....................................................................... 64 
14.1 
Finance, Insurance, and Indemnity............................................................................. 64 
15 
LITERATURE REFERENCES .................................................................................. 65 


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16 
APPENDICES ............................................................................................................ 68 
Appendix A Prohibited and Restricted Medications ............................................................. 68 
Appendix B Prohibited and Restricted Concomitant Medications: Inhibitors and 
Inducers of Cytochrome P450 Enzyme 3A4 .................................................... 72 
 


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LIST OF TABLES 
Table S–1 
Schedule of Events and Assessments for ACP-103-063 .................................. 15 
Table 6–1 
Safety Laboratory Evaluations......................................................................... 48 
 
LIST OF FIGURES 
Figure S–1 
Schematic of Study Design for ACP-103-063 ................................................. 14 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation/Term Definition 
5-HT 
5-hydroxytryptamine (serotonin) 
5-HT2A 
5-hydroxytryptamine (serotonin) 2A 
5-HT2C 
5-hydroxytryptamine (serotonin) 2C 
ADL 
Activities of Daily Living 
ADP 
Alzheimer’s disease psychosis 
AE(s) 
adverse event(s) 
BMI 
body mass index 
CGI-I 
Clinical Global Impression – Improvement 
CGI-S 
Clinical Global Impression – Severity 
CRF 
case report form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOT 
end of treatment 
ET 
early termination 
EU GDPR 
European Union General Data Protection Regulation 
FSQ 
Functional Status Questionnaire 
GCP 
Good Clinical Practice 
GDS 
Geriatric Depression Scale 
HbA1c 
glycosylated hemoglobin 
HDL 
high density lipoprotein 
ICF 
informed consent form 
ICH 
International Council for Harmonisation  
IRB 
institutional review board 
MDS-UPDRS 
Movement Disorders Society – Unified Parkinson’s Disease 
Rating Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
mFSQ 
modified Functional Status Questionnaire (the FSQ questionnaire 
results, without the work performance subscale and work 
situation question, used for statistical analysis in this study)  
MMRM 
mixed-effects model for repeated measures 
MMSE 
Mini-Mental State Examination 
NIA 
National Institute on Aging 


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Abbreviation/Term Definition 
NPI 
neuropsychiatric inventory 
NPI-Q 
neuropsychiatric inventory - questionnaire 
PCI 
potentially clinically important 
PCP 
phencyclidine 
PD 
Parkinson’s disease 
PDP 
Parkinson’s disease psychosis 
PGI-I 
patient global impression – improvement 
PR interval 
PR interval of ECG 
PRN 
as occasion requires; as needed 
QRS interval 
QRS interval of ECG 
QT 
QT interval 
QT interval 
QT interval for heart rate of ECG 
QTcB 
corrected QT interval using Bazett’s correction method 
QTcF 
corrected QT interval using Fridericia’s correction method 
SAP 
statistical analysis plan 
SAE(s) 
serious adverse event(s) 
TEAE(s) 
treatment emergent adverse event(s) 
THC 
tetrahydrocannabinols 
TSH 
thyroid stimulating hormone 
UPDRS 
Unified Parkinson Disease Rating Scale 
VRFCAT 
virtual reality functional capacity assessment tool 
 


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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 the International Council for Harmonisation (ICH) 
Good Clinical Practice (GCP) Guideline.  
1.1 
Background Information 
More than 10 million people worldwide have Parkinson’s disease (PD) (Parkinson’s Disease 
Foundation 2019). Parkinson’s disease is a synucleinopathy resulting in progressive 
neurodegeneration marked by motor dysfunction and non-motor symptoms including 
psychosis. More than 50% of patients with PD have psychosis at some time. Psychosis 
affects up to 75% of patients with Parkinson’s disease dementia, and symptoms are more 
intractable in this group. Such psychosis is expressed primarily as hallucinations and 
delusions, which can cause great distress for patients and their caregivers. These episodes 
present a major challenge for treatment and care, increase the likelihood of placement in 
nursing homes, and are associated with increased mortality (Aarsland et al. 2001; 
Starkstein et al. 2012). 
1.2 
Investigational Product 
Pimavanserin is an atypical antipsychotic that is present in the investigational product (IP) 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 
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 5-HT2C 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 have benefits with regard to overall tolerability relative to 
other antipsychotic agents. 


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1.3 
Previous Clinical Experience 
Pimavanserin is an atypical antipsychotic that is approved for the treatment of hallucinations 
and delusions associated with PDP (Mathis et al. 2017). Studies have also been conducted in 
Alzheimer’s disease agitation, Alzheimer’s disease psychosis (ADP) and depression in PD, 
and studies are ongoing in schizophrenia, major depressive disorder, and dementia related 
psychosis. The clinical program for PDP is reviewed below as the study population (elderly 
subjects) is most closely aligned with the intended study population of this protocol. A more 
complete discussion of these studies, other pimavanserin clinical studies, overall benefit/risk 
assessment, and the most current and accurate information on metabolism, pharmacokinetics, 
efficacy, and safety is available in the pimavanserin Investigator’s brochure (IB). 
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 
benefits were achieved without worsening of PD motor symptoms and without a number of 
other safety concerns associated with atypical antipsychotics. 
Pimavanserin is considered to be generally safe and well tolerated in patients with PDP. 
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 interval (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. 


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Additional information is provided in the pimavanserin IB and in the NUPLAZID® 
(pimavanserin) US package insert. 
1.4 
Study Rationale 
Onset and progression of disability are major factors in the diagnosis and management of PD 
(Shulman 2010; Shulman et al. 2008). The World Health Organization (WHO) defines 
disability as “any restriction or lack of ability to perform an activity within the range 
considered normal for a human being due to an impairment” (World Health Organization 
1980). In this context, “disability” is an umbrella term for the negative aspects of the 
interaction between an individual with a health condition and environmental and personal 
factors, in contrast to “functioning,” an umbrella term for the positive aspects of this 
interaction (World Health Organization 2001). Accurate assessment of disability is important 
given that the onset of functional limitations triggers changes in clinical management, 
including adjustment of medications or referral for deep brain stimulation (DBS) surgery. 
Neurological examination of PD-related impairments, including tremor, bradykinesia, gait, 
and cognitive function, does not provide adequate insight into the capacity for performance 
of daily activities because there is a broad range of compensatory strategies and support 
based on socioeconomic status. Patient insight into daily function also varies with PD 
patients tending to understate their level of disability (Shulman et al. 2006). Therefore, 
integrating data from multiple sources (examination, disability assessment, and patient and 
caregiver reports) is important. 
In a 6 week study evaluating pimavanserin in the treatment of PDP (Cummings et al. 2014), a 
decrease from baseline in the Unified Parkinson’s Disease Rating Scale (UPDRS) Parts II+III 
score was observed across both placebo and pimavanserin and the magnitude of the treatment 
difference (pimavanserin minus placebo) was 0.29 (95% confidence interval [CI], -2.14 to 
2.72). Since the upper limit of the 2-sided 95% CI for the treatment difference was ≤5, 
non-inferiority of pimavanserin 34 mg compared to placebo was concluded for the change 
from baseline to Day 43. This non-inferiority treatment difference suggests that there was no 
clinically meaningful difference in the activities of daily living and the motor examinations of 
the subjects taking pimavanserin 34 mg when compared with the subjects taking placebo. 
However, the post-baseline UPDRS was only measured once on Day 43, and this variable 
was considered a measure of safety and function rather than efficacy. These assessments were 
to be conducted in the “on” state. In addition it is known that the UPDRS measurements do 
not provide adequate insight into the capacity for performance of daily activities due to broad 
range of compensatory strategies (Shulman et al. 2006). 
Therefore an activities of daily living (ADL) study in patients with PDP is needed to evaluate 
pimavanserin in subjects with PDP using scales that measure disability, and patient and 


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caregiver reports. Open-label approaches are less complex which could be used to recruit 
more patients and to improve the value of trial results (Beyer-Westendorf et al. 2011). In a 
systematic review, it was noted that most ADL studies were performed over a minimum of 
3 months with many lasting for 12 months (Al Thomali et al. 2017). The rationale for the 
current study for 16 weeks is to allow adequate time for pimavanserin to demonstrate a 
measurable effect on ADL scales in patients experiencing PDP. 
The currently approved dose for the treatment of PDP of 34 mg per day is being utilized in 
this study. 
1.5 
Benefit/Risk Assessment 
In this open-label study, pimavanserin is being used in its approved indication, PDP. Hence, 
the benefit/risk for the patients is as would be expected from the approved prescribing 
information label for NUPLAZID (pimavanserin) (Acadia Pharmaceuticals Inc. 2020). There 
is no placebo group. The study will examine a range of symptoms in order to explore the 
correlation of the benefit on psychosis with functional improvement. 
2 STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objective 
• To assess the effect of pimavanserin on the activities of daily living (ADLs) in subjects 
with Parkinson’s disease psychosis (PDP) measuring the subject’s physical, 
psychological, social and role functions 
2.1.1 
Primary Endpoint 
• Change from baseline (Week 0) to Week 16 on the modified Functional Status 
Questionnaire (mFSQ) total score  
2.2 
Secondary Objectives 
• To evaluate the efficacy and benefits of pimavanserin in subjects with PDP on 
activities of daily living 
• To assess the clinician’s global impression of severity and improvement of 
hallucination/delusions 
2.2.1 
Secondary Endpoints 
• Change from baseline to Week 16 on the Schwab and England ADL Scale 
(Caregiver and Patient Version) 


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• Change from baseline to Week 16  on the Movement Disorders Society-Unified 
Parkinson’s Disease Rating Scale (MDS-UPDRS) Parts I and II (Caregiver and Patient 
Version) 
• Week 16 Clinical Global Impression – Improvement (CGI-I) score for hallucinations 
and delusions  
• Change from baseline to Week 16 on the Clinical Global Impression – Severity of 
Illness (CGI-S) score for hallucinations and delusions  
• Week 16 Patient Global Impression of Improvement (PGI-I) score for hallucinations 
and delusions 
2.3 
Exploratory Objectives 
• To assess the extent to which caregivers and families experience additional demands, 
responsibilities, and difficulties 
• To explore the effects of pimavanserin in subjects with PDP on: 
o Functional capacity 
o Cognition 
o Depressive symptoms 
o Nighttime behavior 
o Caregiver burden 
2.3.1 
Exploratory Endpoints 
• Change from baseline to Week 16 on the Virtual Reality Functional Capacity 
Assessment Tool (VRFCAT) including total time to complete, total number of errors, 
and total number of forced progressions  
• Change from baseline to Week 16 on the Caregiver Strain Index total score 
• Change from baseline to Week 16 on the Neuropsychiatric Inventory-Questionnaire 
(NPI-Q) Nighttime Behavior Domain Severity and Caregiver Distress  
• Change from baseline to Week 16 on the Geriatric Depression Scale (GDS) (Short 
Form) 
• Change from baseline to Week 16 on the mFSQ score by subscale 
2.4 
Safety Objectives 
• To assess the safety and tolerability of pimavanserin in adults with PDP 


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2.4.1 
Safety Endpoints 
The safety and tolerability of pimavanserin will be assessed using the following:  
• Treatment-emergent adverse events (TEAEs) 
• Columbia-Suicide Severity Rating Scales (C-SSRS) score 
• Potentially clinically important (PCI) findings on: 
o Physical examinations 
o Clinical laboratory tests 
o Vital signs 
o Electrocardiogram parameters 
3 STUDY DESCRIPTION 
3.1 
Overview of Study Design 
This study will be conducted as a 16-week, multi-center, single-arm, open-label study. 
Pimavanserin (ACP-103) will be administered at a dose of 34 mg to approximately 
50 subjects with PDP. Approximately 89 subjects with PDP will be screened and 53 subjects 
are expected to be enrolled, assuming a screen failure rate of 40%. Approximately 42 subjects 
are expected to complete the study, assuming a 20% drop-out rate.  Approximately 25 sites in 
the US will participate in this study. 
The duration of participation for individual study subjects will be up to 26 weeks, consisting 
of the following 3 periods (Figure S–1): 
• Screening period (3-35 days) 
• Treatment period (16 weeks) 
• Safety follow-up period (30-34 days). 
The study will be conducted on an outpatient basis with visits performed at Screening, 
Baseline (Week 0), Week 2, Week 4, Week 8, Week 12, Week 16 (end of Treatment Period) 
and Follow-up (at least 30 days and not to exceed 34 days after last dose of study drug). 
The study start date is defined as the date the first subject is enrolled, which is the baseline 
visit date for the first subject. The primary completion date is the last date that subject data 
was collected for the primary outcome measure. The study completion date is defined as the 
last date that subject data was collected, which includes the safety follow-up telephone call 
visit.  
Procedures for when a subject is lost to follow-up are provided in Section 4.5. 


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3.1.1 
Screening Period (3-35 Days) 
During the screening period, subjects will be assessed for study eligibility and prohibited 
medications will be discontinued if medically appropriate. Subject eligibility will be assessed 
by the site and the Sponsor through an eligibility review process. 
Investigators should not withdraw a subject’s prohibited medication for the purpose of 
enrolling them into the study. Medications should only be discontinued if it is deemed 
clinically appropriate to do so and in consultation with the treating physician. 
3.1.2 
Treatment Period (16 Weeks) 
The Baseline visit (Week 0) may occur as soon as screening procedures are completed and 
subject eligibility has been confirmed. Treatment with pimavanserin 34 mg once daily (QD) 
will begin on the morning of the day after the Baseline visit. Additional assessments will be 
conducted at Week 2, Week 4, Week 8, Week 12, Week 16 (end of treatment [EOT])/early 
termination [ET]). Subjects who are withdrawn will not be replaced. 
3.1.3 
Safety Follow-up Period (30 Days) 
A follow-up safety assessment telephone call will be conducted at least 30 days and no more 
than 34 days after the last dose of study drug. 
4 SUBJECT ELIGIBILITY AND WITHDRAWAL CRITERIA 
To be eligible for this study, subjects must meet all of the inclusion criteria and none of the 
exclusion criteria. 
4.1 
Inclusion Criteria 
A subject must meet all of the following inclusion criteria to be eligible for participation in 
the study: 
1. Male or female subjects at least 40 years of age  
2. Can understand the nature of the study and protocol requirements and provide written 
informed consent 
3. Is able to demonstrate the ability to complete subject-reported outcome measures on a 
handheld device, and can be reliably rated on assessment scales (in the opinion of the 
Investigator) 
4. Must be able to designate a caregiver or study partner who the subject agrees can 
provide reliable information on the subject’s well-being, and is willing to provide 
written informed consent, and to attend clinic visits with the subject 


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5. Has a Schwab & England ADL Scale score of 40-80% (inclusive) at both Visit 1 
(Screening) and Visit 2 (Baseline) as it relates to their PDP symptoms 
6. Has a Mini-Mental State Examination (MMSE) score ≥19 at Screening 
7. This criterion has been deleted; please consult the Summary of Changes for details. 
8. Has a diagnosis of idiopathic Parkinson’s disease (PD), according to the Movement 
Disorders Society criteria for the diagnosis of PD (Postuma et al. 2015), without any 
other known or suspected cause of parkinsonism. History of initial PD symptoms onset 
greater than 1 year prior to Screening 
9. Has psychotic symptoms that may impair function and are severe enough to warrant 
treatment with an antipsychotic agent 
10. Has a CGI-S score of ≥4 when assessing psychosis symptoms at Visit 1 (Screening) 
and Visit 2 (Baseline) 
11. If the subject is on anti-Parkinsonian medication, they must be on a stable regimen for 
2 months prior to Baseline and not planning (at the time of the Baseline visit) to make 
a change in dose(s) 
12. This criterion has been deleted; please consult the Summary of Changes for details. 
13. Psychotic symptoms developed after the onset of symptoms of PD  
14. Psychotic symptoms present for at least 1 month overall (could be intermittent), with 
active psychotic symptoms in either of the last 2 weeks prior to screening 
15. Has clear sensorium at study entry (i.e., oriented to time, person, and place) in the 
opinion of the Investigator 
16. 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 TWO clinically acceptable methods of 
contraception   
Acceptable methods of contraception 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) 
Only one of the two clinically acceptable methods can be a hormonal method. 


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4.2 
Exclusion Criteria 
A subject must meet none of the following exclusion criteria to be eligible for the study: 
1. Has atypical parkinsonism (Parkinson’s plus, multiple system atrophy [MSA], 
progressive supranuclear palsy [PSP]), or secondary parkinsonism variants such as 
tardive or medication induced parkinsonism 
2. Has undergone ablative procedures such as a pallidotomy, thalamotomy, or treatment 
with focused ultrasound, or has an implanted deep brain stimulator 
3. Is in hospice, is receiving end-of-life palliative care, or is bedridden or confined to a 
wheelchair  
4. Has current evidence of an unstable neurological, cardiovascular, respiratory, 
gastrointestinal, renal, hepatic, hematologic, or other medical or psychiatric disorder, 
including cancer or malignancies that, in the judgment of the Investigator, would 
jeopardize the safe participation of the subject in the study or significantly interfere 
with the conduct or interpretation of the study 
5. Has a history of epilepsy 
6. Has atrial fibrillation unless adequately anticoagulated 
7. Has a history of myocardial infarction, unstable angina, acute coronary syndrome, or 
cerebrovascular accident within the last 6 months prior to Screening 
8. Has any of the following: 
a. greater than New York Heart Association (NYHA) Class 2 congestive heart failure  
b. Grade 2 or greater angina pectoris (by Canadian Cardiovascular Society Angina 
Grading Scale)  
c. sustained ventricular tachycardia 
d. ventricular fibrillation 
e. torsades de pointes 
f. syncope due to an arrhythmia 
g. an implantable cardiac defibrillator 
9. Glycosylated hemoglobin (HbA1c) >8.5% at Screening 
10. This criterion has been deleted; please consult the Summary of Changes for details. 
11. Has a known history of a positive hepatitis B virus (HBV) or hepatitis C virus (HCV) 
test 
12. Has a history of human immunodeficiency virus (HIV) 


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13. Has a history of neuroleptic malignant syndrome or serotonin syndrome 
14. Has a known personal or family history of long QT syndrome or family history of 
sudden cardiac death 
15. Has any of the following electrocardiogram (ECG) results at the Screening visit:  
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:  
iii. 
QTcF >425 ms, if QRS duration <120 ms 
iv. 
QTcF >450 ms, if QRS duration ≥120 ms 
If the mean corrected QT interval using Fridericia’s correction method (QTcF) value 
from the centrally read ECG done at Screening is prolonged due to an identifiable 
cause, and it is medically appropriate to address that cause, a repeat ECG may be 
performed during Screening at the discretion of the Medical Monitor.  
16. Has a heart rate as measured at Screening by the ECG machine <50 beats per minute. 
If bradycardia is secondary to iatrogenic or treatable causes and these causes are 
treated, a heart rate assessment can be repeated during the screening period.  
17. Has major surgery planned from the start of screening through the end of the follow-up 
period 
18. Requires treatment with a medication or other substance that is prohibited by the 
protocol 
19. Has a body mass index (BMI) <18.5 kg/m2 or >35 kg/m2 at Screening or Baseline or 
known unintentional clinically significant weight loss (i.e., ≥7%) over past 6 months 
20. The urine drug screen result at Visit 1 (Screening) indicates the presence of 
amphetamine/methamphetamine, barbiturates, cocaine, marijuana 
(tetrahydrocannabinols [THC]), opiates, or phencyclidine (PCP). The use of 
benzodiazepines, marijuana (THC) or opiates on an as needed (PRN) basis, and when 
substance use disorder has been ruled out by the investigator in discussion with the 
medical monitor, does not necessarily exclude the subject from the study. 
21. Is suicidal at Screening or Baseline as defined below: 
a. According to the C-SSRS, he or she must not be actively suicidal at Visit 1 
(Screening) or Visit 2 (Baseline) (including, an answer of “yes” to C-SSRS 


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questions 4 or 5 [current or over the last 6 months]) and must not have 
attempted suicide in the 1 year prior to Visit 1 (Screening); OR 
b. The subject is actively suicidal in the Investigator’s judgment 
22. Has participated in or is participating in a clinical study of any investigational drug, 
device, or intervention, within 30 days or 5 half-lives, whichever is longer, of Visit 2 
(Baseline) 
23. Has previously been enrolled in any prior clinical study with pimavanserin  
24. Has previously or is currently taking pimavanserin 
25. Has taken an antipsychotic medication less than 5 half-lives prior to Baseline 
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. Has a history of a significant psychotic disorder prior to or concomitantly with the 
onset of PD including, but not limited to, schizophrenia or bipolar disorder 
29. Had dementia prior to or concomitantly with the onset of motor symptoms of PD 
30. Has clinically significant laboratory abnormalities that in the judgment of the 
Investigator might jeopardize the safety of the subject 
31. Is judged by the Investigator or the Medical Monitor to be inappropriate for the study 
for any reason, including if the subject is judged to be a danger to self or others 
32. Positive COVID-19 polymerase chain reaction (PCR) or antigen result in the last 
2 weeks prior to screening  
4.3 
Subject Withdrawal of Consent 
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. 
If the subject decides to withdraw consent from all components in the study, this must be 
documented and no additional assessments will be performed. If the subject wants to 
discontinue treatment and agrees to the evaluations specified at the EOT/ET visit and/or at 
safety follow-up (whichever is applicable), as outlined in Table S–1, the agreed assessments 
should be conducted. The subject’s reason for wanting to discontinue treatment and the 
agreement to continue with the applicable assessments for study termination must be 
documented. 


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4.4 
Subject or Study Discontinuation 
Subjects may be discontinued from the study for a number of reasons, including, but not 
limited to, those listed below: 
• Adverse event 
• Death 
• Lack of efficacy 
• Lost to follow-up (Section 4.5) 
• Non-compliance with study drug 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Study terminated by sponsor 
• Use of prohibited medication 
• Other (e.g., positive COVID-19 PCR or antigen test, loss of caregiver/study partner, 
inability to complete study procedures) 
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, ethical, or business 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. 
4.4.1 
Handling of Subject Discontinuation During the Treatment Period 
Unless the subject has withdrawn consent from all components of the study, every reasonable 
effort should be made to complete Visit 7/ET and the safety follow-up visit (as outlined in 
Table S–1) if a subject discontinues prematurely during the treatment period of the study. All 
information will be reported on the applicable pages of the electronic case report form 
(eCRF). 
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 


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be chronic or stable. For subjects who continue to be followed for safety, serious adverse 
events (SAEs) should continue to be reported as described in Section 7.4.2. All SAEs will 
continue to be followed until such events have resolved or the Investigator deems them to be 
chronic or stable. 
4.5 
Subject Lost to Follow-up 
A subject will be considered lost to follow-up if they fail to attend a scheduled visit 
(including the safety follow-up visit) and are unable to be contacted by the study site. Every 
reasonable effort should be made to contact the subject and will include a minimum of 
3 documented phone calls (each performed at different times of the day) and, if necessary, a 
certified letter to the subject’s last known mailing address or local equivalent methods. All 
contact attempts are to be documented in the source documents. 
4.6 
Prior and Concomitant Therapy 
All medications used from study screening until completion of the safety follow-up visit are 
to be recorded. 
4.6.1 
Prior Medication 
Prior medications is defined as any medication taken before the date of the first dose of study 
drug. 
4.6.2 
Concomitant Medication 
Concomitant medication is defined as any medication taken on or after the date of the first 
dose of study drug. 
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). 
The Investigator may prescribe appropriate medication to treat AEs. 
4.6.2.1 
Permitted, Restricted, and Prohibited Medications 
Prohibitions and restrictions for concomitant medications should be followed between the 
initial screening visit and Visit 7/EOT/ET as specified in Appendix A and Appendix B. These 
appendices do not constitute an exhaustive list and any questions regarding prohibited and 
restricted medications should be discussed with the Medical Monitor or designee. 
Use of medications that could interfere with study conduct or any questions regarding 
prohibited and restricted concomitant medications should be reviewed and/or discussed with 
the Medical Monitor or designee. 


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Medications that can prolong QT interval are prohibited (or restricted if approved by the 
Medical Monitor) as specified in Appendix A. 
Permitted concomitant medications should remain at a stable dose throughout the study.  
If a subject is on a medication restricted by the protocol, the medication should be adjusted 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) in 
consultation with the treating physician. 
Subjects who require current treatment with a prohibited medication will be withdrawn from 
the study. 
Subjects who have 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 who has taken a prohibited medication to continue in 
the trial will be made by the Sponsor/Medical Monitor, with medical input from the 
Investigator, and will be documented. If a subject is allowed to remain in the trial, 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 1×34 mg capsule). 
Capsules will be administered orally as a single dose once daily. 
5.1.1 
Formulation, Appearance, Packaging, and Labeling 
The Sponsor will supply pimavanserin 34 mg capsules. 
Commercial pimavanserin 34 mg capsules are opaque white and light green capsules with 
“PIMA” and “34” printed in black. Each pimavanserin capsule contains 40 mg of 
pimavanserin tartrate, which is equivalent to 34 mg of pimavanserin free base. 
 
 
 
 
Pimavanserin is manufactured under current Good Manufacturing Practices. 
During the treatment period, study drug will be distributed in a quantity sufficient to ensure 
the subject has an adequate supply of study drug between study visits. 


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5.1.2 
Product Storage and Stability 
Investigational product must be stored between 20°C and 25°C (68°F and 77°F) in a secure 
area with restricted access and according to local and national regulations. Excursions are 
permitted between 15°C and 30°C (59°F and 86°F) [See USP Controlled Room 
Temperature]. 
5.1.3 
Dosing and Administration 
Study drug will be dispensed to the subject to take home. Each daily dose consists of one 
capsule to be taken orally, once daily. The capsules may be taken with or without food. The 
first dose should be taken on the morning of the day after the Baseline visit.  
5.1.4 
Method of Assigning Subjects to Treatment Groups 
All subjects will be in the 34 mg pimavanserin treatment group. 
5.1.5 
Blinding 
This is an open-label study. 
5.1.6 
Study Drug Compliance 
If a subject misses one dose of study drug, he or she should not take an extra dose the next 
day. 
If a subject shows significant undercompliance (<80% compliance) between any two 
scheduled visits, the Medical Monitor should be notified to determine if the subject remains 
eligible for the study and whether the incident should be considered a protocol deviation. 
In the event that a subject is permanently unable to return study drug to the site (i.e., drug is 
lost, destroyed, or discarded), the subject/caregiver testimony is to be used in determining 
compliance. 
5.1.7 
Overdose 
An overdose is a deliberate or inadvertent administration of a treatment at a dose higher than 
the maximum recommended dose per protocol. It must be reported, irrespective of outcome, 
even if toxic effects were not observed (Section 7.4.4). All events of overdose are to be 
captured 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 regulatory authority and the 
Sponsor that the study drug is being handled appropriately. Subjects should be instructed to 
return all packaging and unused study drug to the Investigator at regularly scheduled clinic 


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visits and ET visits. Any study drug supplied is for use in this study only and should not be 
used for any other purpose. 
At appropriate intervals during the study, study drug reconciliation will be performed by the 
Sponsor (or designee) 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 the 
Sponsor. Any remaining unused study drug and all used and unused packaging will be sent 
back to the Sponsor’s designee for destruction.  
6 STUDY PROCEDURES 
Study specific procedures are detailed below. All assessments will be completed according to 
the schedule described in Table S–1. Every effort should be made to complete the required 
procedures and evaluations at the designated visits and times. 
All references to performing assessments, procedures, and evaluations at the clinic, both in 
Table S-1 and in other parts of this protocol, should be understood as including the option of 
performing these at the subject’s home in the presence of a member of the clinical site staff 
and the subject’s caregiver. 
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. Only subtraction of serial 7s will be used in this 
study; spelling the word ‘world’ backwards option should not be used. The MMSE is being 
used in this study to screen for cognitive impairment. 
6.1.2 
Neuropsychiatric Inventory 
The NPI was developed to assess psychopathology in dementia patients (Cummings et al. 
1994). The original NPI evaluated 10 neuropsychiatric disturbances common in dementia: 
delusions, hallucinations, agitation, dysphoria, anxiety, apathy, irritability, euphoria, 
disinhibition, and aberrant motor behavior. Two other domains, nighttime behavior 
disturbances and appetite and eating abnormalities, were subsequently added to the NPI 
(Cummings 1997). 


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At Screening (Visit 1) and Baseline (Visit 2), the degree of the patient’s neuropsychiatric 
symptoms will be evaluated using two of the domains of the Neuropsychiatric Inventory 
(NPI), Domain A (Delusions) and Domain B (Hallucinations). 
6.2 
Efficacy Assessments 
All scales should be conducted in the “on” state.  
6.2.1 
Functional Status Questionnaire 
The Functional Status Questionnaire is a self-administered questionnaire that provides an 
assessment in ambulatory patients of physical, psychological, social, and role function 
(Jette et al. 1986). It comprises 34 core items that produce 6 summary scale scores:  
• Basic activities of daily living (eating, dressing, bathing, moving in and out of bed or 
chair, walking indoors e.g., in the home)  
• Intermediate activities of daily living (walking several blocks; walking one block or 
climbing one flight of stairs; house cleaning, yard work, or home maintenance; doing 
errands e.g., grocery shopping; driving a car or using public transportation; doing 
vigorous activities e.g., running, lifting heavy objects, participating in strenuous 
sports) 
• Psychological function and mental health (been a very nervous person; felt calm and 
peaceful; felt downhearted and blue; been a happy person; felt so down in the dumps 
that nothing could cheer you up) 
• Social/role function 
o Work performance (done as much work as others in similar jobs, worked 
for short periods or taking frequent rests because of your health, worked 
your regular number of hours, done your job as carefully and accurately as 
others with similar jobs, worked at your usual job but with some changes 
because of your health, feared losing your job because of your health) 
o Social activity (had difficulty visiting with relatives and friends, had 
difficulty participating in community activities [e.g., religious services, 
social activities, volunteer work], had difficulty taking care of other people 
[e.g., family members]) 
o Quality of interaction (isolated yourself from people around you, acted 
affectionate toward others, acted irritable toward those around you, made 
unreasonable demands on family and friends, gotten along well with other 
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It also includes 6 single-item scores (work situation; days per month in bed due to illness or 
injury; days per month when illness injury reduced activities normally performed for half a 
day or more; satisfaction with sexual relationships; satisfaction with own health; frequency of 
social interaction). 
6.2.2 
Schwab and England Activities of Daily Living Scale (Caregiver and Patient 
Version) 
The Schwab & England ADL Scale is widely used in PD. It is rated by physicians, patients, 
or staff using a 0% to 100% scale with 10% intervals, where 100% is “Completely 
independent. Unaware of difficulty” and 0% is “Vegetative functions...Bedridden” 
(Schwab and England 1969; McRae et al. 2000). 
6.2.3 Movement Disorders Society – Unified Parkinson’s Disease Rating Scale Parts I 
and II (Caregiver and Patient Version) 
The MDS-UPDRS is a comprehensive battery of motor and behavioral indices derived from 
the Columbia Scale (Fahn et al. 1987). The MDS-UPDRS Parts I and II will be used to assess 
Non-Motor Aspects of Experiences in Daily Living (nM-EDL) (Part I) and Motor Aspects of 
Experience of Daily Living (M-EDL) (Part II) and consist of 13 items each (Goetz et al. 
2008). 
Part I has two components: Part IA concerns a number of behaviors that are assessed by the 
Investigator with all pertinent information from patients and caregivers, and Part IB is 
completed by the patient with or without the aid of the caregiver, but independently of the 
Investigator. These sections can, however, be reviewed by the rater to ensure that all 
questions are answered clearly, and the rater can help explain any perceived ambiguities. 
Part II is designed to be a self-administered questionnaire like Part IB, but can be reviewed 
by the Investigator to ensure completeness and clarity.  
6.2.4 
Clinical Global Impression – Improvement - Hallucinations and Delusions 
The CGI-I is a clinician-rated, 7-point scale that is designed to rate the improvement in the 
subject’s symptoms at the time of assessment, relative to the symptoms at Baseline 
(Guy 1976). Severity ratings should be based on the behavioral domains of clinical concern, 
namely hallucinations and delusions. 
6.2.5 
Clinical Global Impression – Severity - Hallucinations and Delusions 
The CGI–S scale is a clinician-rated, 7-point scale that is designed to rate the severity of the 
subject’s neuropsychiatric symptoms at the time of assessment using the Investigator’s 
judgment and past experience with subjects who have the same disorder (Guy 1976). 


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Severity ratings should be based on the behavioral domains of clinical concern, namely 
hallucinations and delusions. 
6.2.6 
Patient Global Impression of Improvement - Hallucinations and Delusions 
The PGI-I is a global index used to rate the response of a condition to a therapy. It is a 
simple, direct, easy to use scale that is intuitively understandable to subjects and clinicians. 
The PGI-I asks the patient to rate their symptoms now, as compared with how it was at 
Baseline before beginning treatment, ranging from 1=very much better to 7=very much 
worse. Severity ratings should be based on the behavioral domains of clinical concern, 
namely hallucinations and delusions. 
6.2.7 
Virtual Reality Functional Capacity Assessment Tool  
The VRFCAT is a tablet-based assessment that simulates key instrumental activities of daily 
living (iADLs) in a realistic and interactive virtual environment. With demonstrated 
sensitivity to basic functional capacity deficits, the VRFCAT was developed to improve 
clinical trials by detecting functionally meaningful improvements in patients’ everyday lives 
(Ruse et al. 2014). The brief (VRFCAT shortened-list) version will be utilized for this study.  
6.2.8 
Caregiver Strain Index 
The Caregiver Strain Index (CSI) is a tool that can be used to quickly identify families with 
potential caregiving concerns. It is a 13-question tool that measures strain related to care 
provision. There is at least one item for each of the following major domains: Employment, 
Financial, Physical, Social and Time. Positive responses to seven or more items on the index 
indicate a greater level of strain. This instrument can be used to assess individuals of any age 
who have assumed the role of caregiver for an older adult (Robinson 1983; Pearlin et al. 
1990).  
6.2.9 
Neuropsychiatric Inventory – Questionnaire Nighttime Behavior Domain 
The NPI-Q was developed and cross-validated with the standard NPI to provide a brief 
assessment of neuropsychiatric symptomatology (Kaufer et al. 2000). The NPI-Q is a 
self-administered questionnaire completed by informants about patients for whom they care. 
Of the 12 domains in the full questionnaire, only the Nighttime Behavior domain will be 
completed by informants in this study. 
6.2.10 
Geriatric Depression Scale (Short Form) 
The Geriatric Depression Scale (GDS) (Short Form) may be used with healthy, medically ill 
and mild to moderately cognitively impaired older adults. It has been extensively used in 
community, acute care, and long-term care settings. The GDS was found to have a 92% 
sensitivity and an 89% specificity when evaluated against diagnostic criteria. The validity and 


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reliability of the tool have been supported through both clinical practice and research. In a 
validation study comparing the Long and Short Forms of the GDS for self-rating of 
symptoms of depression, both were successful in differentiating depressed from non-
depressed adults with a high correlation (r = 0.84, p <0.001) (Sheikh and Yesavage 1986; 
Yesavage et al. 1983; Stanford/VA/NIA Aging Clinical Resource Center, 2019). 
6.3 
Safety Assessments  
6.3.1 
Columbia-Suicide Severity Rating Scale 
The C-SSRS monitors changes in suicidal thinking and behavior over time, in order to 
determine risk (Posner et al. 2011). The following four constructs are measured: the severity 
of ideation, the intensity of ideation, behavior, and lethality. 
The C-SSRS will be used to assess suicidal ideations and behaviors. The Baseline/Screening 
version will be administered at Visit 1 (Screening), and the “Since Last Visit” version will be 
administered at all other designated visits. The C-SSRS results for each subject should be 
reviewed by the Investigator at each visit. If at any time the C-SSRS results for a given 
subject reveal potential suicidality, then the Investigator should assess the clinical 
significance of such results. If a clinically significant risk of suicidality is identified for a 
subject, then the Investigator should discontinue the subject and implement appropriate 
treatment (Section 4.4). 
This assessment is to be completed at all clinic visits. 
6.3.2 
Physical Examinations 
A physical examination including neurological exam (cranial nerves, motor, sensory, reflexes, 
gait, and coordination) will be conducted. 
6.3.3 
Vital Signs 
Vital signs will include body temperature, resting respiration rate, sitting or supine systolic 
and diastolic blood pressure, and pulse rate. Blood pressure should be measured after the 
subject has been sitting or supine for ≥3 minutes. 
6.3.4 
Height, Weight, and Body Mass Index 
Height and weight will be measured and reported. 
Body mass index will be calculated using the following formula: 
Weight (kg) / [height (m)]2. 


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6.3.5 
Electrocardiograms 
All 12-lead ECGs will be complete, standardized recordings. All ECGs will be centrally read; 
the interpretation by the central cardiologist is considered the official interpretation. Each 
ECG will be recorded continuously for 5 minutes. 
The five minutes of ECG data will be converted into a Summary ECG (simulated 10-second 
ECG) for each subject. The summary ECG is created by first calculating a median beat for 
each lead based on all normal, good-quality beats in the lead, using standard methods and 
then linked together with an intervening RR interval equal to the average for the entire 
record. The full ECG will be evaluated algorithmically and over-read by a cardiologist. The 
over-reading cardiologist will review the entire 5-minute recording for arrhythmias and, if 
present, will add them to the interpretation of the summary ECG 
The following conditions apply: 
• If the QTcF value from the ECG done at Screening is prolonged due to an identifiable 
cause, and it is medically appropriate to address that cause, a repeat ECG may be 
performed during Screening at the discretion of the Medical Monitor. In this case, the 
repeat ECG 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. 
The subject must rest in a supine position for at least 3 minutes before the ECG is obtained. 
ECG tracings (paper or electronic) will be reviewed and interpreted by a qualified clinician. 
ECG tracings and results (ventricular rate, PR, QRS, QT, QTcF and QTcB intervals) will be 
included and summarized in the subject's study records. 
6.3.6 
Laboratory Evaluations 
Clinical laboratory sample collection (including HbA1c at Screening only) is encouraged, but 
not required to be completed under fasting conditions. 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), 
magnesium (Mg), carbon dioxide (CO2), blood urea nitrogen (BUN), creatinine 
(CR), uric acid 
 Mg should only be performed at Visit 1 (Screening) 


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o Alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), total 
bilirubin (TBIL), lactate dehydrogenase (LDH) 
o Vitamin B12 
 Vitamin B12 should only be performed at Visit 1 (Screening) 
o Glycosylated hemoglobin (HbA1c) 
 HbA1c should only be performed at Visit 1 (Screening) 
o Glucose 
o Albumin (ALB), total protein 
o Thyroid stimulating hormone (TSH) and free T4, if TSH is out of range 
 TSH/free T4 should only be performed at Visit 1 (Screening) 
o Creatine kinase (CK)/creatine phosphokinase (CPK) 
o Lipid panel 
 Total cholesterol, high-density lipoprotein (HDL)-cholesterol, triglycerides, 
low-density lipoprotein (LDL)-cholesterol, cholesterol/HDL ratio, non-HDL 
cholesterol 
• 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 Baseline and all subsequent visits 
(except Visit 3) up to and including EOT (Table 6–1) for women of child-bearing 
potential 
 If urine cannot be obtained in women of childbearing potential, a serum 
pregnancy test should be done in its place 
• 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 


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• Urinalysis 
o Blood, RBCs, WBCs, protein, glucose, ketones, specific gravity, pH 
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 Urine toxicity screen will test for controlled substances at screening. The 
following controlled substances may be tested with a urine toxicity screen 
according to the schedule presented in Table 6–1: amphetamine, barbiturates, 
benzodiazepines, cocaine, methadone, morphine/opiates, methamphetamine, 
marijuana (THC), phencyclidine (PCP), ecstasy (3,4-methylenedioxy-
methamphetamine [MDMA]). Negative drug screens are required for study 
eligibility. 
o Subjects who test positive and have a valid prescription for a controlled substance 
may be retested if they agree to abstain from the medication for the length of their 
participation in the study. The repeat test, and any other tests, must be negative for 
them to participate in the study. 
Laboratory evaluations will be completed according to the schedule presented in Table 6–1 
and procedures detailed in the study laboratory manual. 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 
Tests 
Visit 1 (Screening) 
CHEM, CBC, UA, urine toxicity screen, serum pregnancy test  
Visit 2 (Baseline) 
CHEM, CBC, UA, urine pregnancy test 
Visit 4 (4 weeks) 
CHEM, CBC, UA, urine pregnancy test 
Visit 5 (8 weeks) 
Urine pregnancy test 
Visit 6 (12 weeks) 
Urine pregnancy test 
Visit 7 (ET/EOT)  
CHEM, CBC, UA, urine pregnancy test  
Abbreviations: CBC=complete blood count; CHEM=clinical chemistry serum tests; EOT=end of treatment; 
ET=early termination; UA=urinalysis 
6.4 
Safety Follow-up 
A 30-day safety follow-up telephone contact is to be completed for subjects who complete 
the treatment period of the study as well as those who discontinue prematurely from the 
study. Subjects should have the following completed at least 30 days after last dose of study 
drug: 
• Assessment of concomitant medications/treatments 
• Assessment of AEs 
6.5 
Unscheduled Visits 
Unscheduled visits may occur as determined by the Investigator and may include any safety 
evaluations deemed by the Investigator to be clinically indicated. The following safety 
assessments will typically be performed; however, these are not required and other 
assessments besides the following may be performed as needed: assessment of AEs, 
assessment of concomitant medications/treatments, measurement of vital signs, and 
suicidality assessment. 
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 in a patient or clinical study 
participant, temporally associated with the use of study drug, whether or not considered 
related to study drug”. 
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 


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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. 
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 
Baseline. 
• Overdose of 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 
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, which, had it occurred in a more severe form, might 
have caused death. 
Definition of Hospitalization 
Hospitalization is defined by the Sponsor 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 product 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 


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• Recurrent: More than one discrete episode with the same severity 
7.2.2.3 
Action Taken With Study Drug 
• Dose not changed: No change in study drug 
• Drug interrupted: Study drug temporarily stopped 
• Drug withdrawn: Study drug discontinued permanently 
• Not applicable 
• Unknown 
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 due to an 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 
Adverse events will be recorded from the time informed consent is obtained through the 
safety follow-up period. All AEs must be either resolved or stable at the end of the safety 
follow-up period. If ongoing at the end of the safety follow-up period, the subject should be 
referred for appropriate treatment. 


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In the event that a subject discontinues and has an ongoing AE at the time of discontinuation 
(Section 4.4.1) or 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. 
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, 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. 
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 the Sponsor or designee to the regulatory authorities is a regulatory 
requirement. Each regulatory authority has established a timetable for reporting SAEs based 
upon established criteria. 
Serious AEs must be reported within 24 hours of discovery to the Sponsor or its designee; use 
the appropriate form for initial and/or follow-up reporting. 
At a minimum, events identified by the Sponsor 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), as per applicable regulations. These will be provided by 
the Sponsor after their assessment. It is the Investigator’s responsibility to provide these 
expedited reports, and any new and significant information, to the responsible IRB. 


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When an SAE occurs, Investigators will review all documentation related to the event and 
will complete the paper SAE form (for initial and/or follow-up information) and fax or email 
(within 24 hours of discovery) to the contact information provided on the SAE form. 
Subjects will be followed through the safety follow-up period for 30 days after last dose of 
study drug for any SAEs and/or other reportable information until such events have resolved 
or the Investigator, in conjunction with the Sponsor, 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 informed consent form 
(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. 
Serious AEs occurring greater than 30 days after last dose of study drug should be reported if 
in the judgment of the Investigator there is “a reasonable possibility” that the event may have 
been caused by the product. 
SAEs should also be reported to the institutional review board/ethics committee (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 within 
24 hours of discovery to the Sponsor or its designee. Any female subject who becomes 
pregnant during the study will be followed through the pregnancy outcome. 
Any AEs that are the consequence of pregnancy and which meet the criteria for serious 
should also be reported via the SAE form. 
7.4.3.1 
Reporting Paternal Drug Exposure 
Paternal drug exposure is defined as a father’s exposure to a medicinal product before or 
during his partner’s pregnancy. Any paternal drug exposure cases must be reported to the 
Sponsor within 24 hours of discovery via the Pregnancy form. Any AEs that are the 
consequence of paternal drug exposure and which meet the criteria for serious must also be 
reported to the Sponsor within 24 hours of discovery via the SAE form. 
7.4.4 
Reporting of Overdose 
An overdose is a deliberate or inadvertent administration of a treatment at a dose higher than 
the maximum recommended dose per protocol. It must be reported to the Sponsor or 
designee on the Overdose form within 24 hours of discovery. In addition, all events of 
overdose are to be captured as protocol deviations. 


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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. 
9 STATISTICAL METHODS AND DATA ANALYSIS 
9.1 
Statistical and Analytical Plans 
Statistical methods will be documented in detail in a statistical analysis plan (SAP) to be 
approved by the Sponsor prior to database lock. 
9.2 
Statistical Hypotheses 
No formal testing of efficacy or safety hypotheses is planned. Efficacy and safety outcomes 
will be summarized descriptively. 
9.3 
Sample Size Determination 
This is an exploratory study and is not powered for statistical significance. Formal sample 
size calculations were not used to determine sample size. 
9.4 
Subject Populations for Analysis 
The Safety Analysis Set will consist of all subjects who have taken at least 1 dose of study 
drug. The Safety Analysis Set will be used for all safety analyses. 
The Full Analysis Set will consist of all randomized subjects who have taken at least 1 dose 
of study drug and have both a Baseline value and at least 1 post-Baseline value for the mFSQ 
total score. The Full Analysis Set will be used for all efficacy analyses. 
9.5 
Statistical Analyses 
All safety and efficacy measures will be summarized using descriptive statistics. 
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). 


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All efficacy analyses will be based on the Full Analysis Set. All confidence intervals will be 
2-sided 95% CIs, unless stated otherwise. 
Baseline is defined to be the last non-missing value prior to the first dose of study drug. 
9.5.1 
Primary Analyses 
The primary efficacy endpoint, change from baseline to Week 16 in the mFSQ total score, 
will be evaluated using a mixed-effects model for repeated measures (MMRM). The response 
variable is the change from Baseline to Weeks 4, 8, 12, and 16 and the fixed effects include 
visit (Weeks 4, 8, 12, and 16), corresponding Baseline score, and the Baseline score-by-visit 
interaction. The mFSQ total score will be calculated as the unweighted mean of the subscale 
scores (Basic ADL, Intermediate ADL, Psychological Function, Social Activity and Quality 
of Social Interaction). The Work Performance subscale will be excluded, given the age and 
non-employment status of the intended patient population.   
Summary statistics for the mFSQ total score (observed and change from Baseline), least-
squares (LS) means and the corresponding 95% CI will be presented. 
9.5.2 
Secondary Analyses 
The change from Baseline to Week 16 in the secondary endpoints measured at scheduled 
visits, including Schwab & England ADL Scale (Patient and Caregiver), MDS-UPDRS Part I 
(Patient and Caregiver), and MDS-UPDRS Part II (Patient and Caregiver) will be 
summarized using an MMRM model similar to that described for the primary analysis, 
except that the Baseline value of the endpoint being analyzed will be included in the model 
instead of the Baseline mFSQ total score. 
For CGI-I the response variable is the observed score at Week 16 and the MMRM will 
include fixed effects for visit (Week 2, 4, 8, 12, and 16), Baseline CGI-S score, and Baseline 
CGI-S score-by-visit interaction. 
For PGI-I the response variable is the observed score at Week 16 and the MMRM model will 
include a fixed effect for visit (Week 2, 4, 8, 12, and 16). 
9.5.3 
Exploratory Analyses 
The change from Baseline to Week 16 in the exploratory endpoints measured at scheduled 
visits, including individual mFSQ subscales, Caregiver Strain Index total score, NPI-Q 
Nighttime Behavior domain severity and caregiver distress, Geriatric Depression Scale (Short 
Form), and the VRFCAT (total time to complete, total number of errors, and total number of 
forced progressions), will be summarized using an MMRM model similar to that described 
for the primary analysis, except that 1) the Baseline value of the endpoint being analyzed will 
be included in the model instead of the Baseline mFSQ total score; and 2) VRFCAT is not 


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assessed at Weeks 2, 8, and 12, thus the model will only include Weeks 4 and 16. Additional 
exploratory analyses may be conducted on the VRFCAT data to adjust for deficits of 
cognition. 
In addition to the Week 16 timepoint, each of the primary, secondary, and exploratory 
endpoints will also be assessed at all other timepoints (Weeks 2, 4, 8, and 12) using the 
MMRM models described in Sections 9.5.1, 9.5.2, and 9.5.3. These additional timepoints will 
be considered exploratory. 
9.5.4 
Safety Analyses 
Safety results will be summarized using descriptive statistics using the Safety Analysis Set. 
9.5.4.1 
Adverse Events 
All AEs will be classified into standard terminology using the Medical Dictionary for 
Regulatory Activities (MedDRA). All AEs will be listed.  
A TEAE is defined as an AE that started after the first administration of study drug and no 
later than the last administration of study drug plus 30 days. All TEAEs, TEAEs leading to 
discontinuation, TEAEs related to study drug, TEAEs by maximum severity, fatal TEAEs, 
serious TEAEs, and serious TEAEs related to study drug will all be summarized by system 
organ class and preferred term. 
9.5.4.2 
Other Safety Assessments 
In addition to the AE reporting described in Section 7.4, the overall safety and tolerability of 
study drug will be assessed throughout the study by evaluating the following safety variables: 
• Measurements or rating scores and change from Baseline values at scheduled 
timepoints for: 
o Clinical laboratory test results (including hematology, serum chemistry, 
and urinalysis with continuous results) 
o Vital sign measurements 
o Height, weight, and BMI 
o 12-lead ECG parameters 
• Subject counts and percentages for: 
o Abnormal physical examination findings 
o Urinalysis with categorical results 


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o Categorical analysis for QTc prolongation in accordance with ICH E14 
Guidance Document 
• Subject counts and percentages for potentially clinically significant (criteria will be 
specified in the SAP) findings on: 
o Clinical laboratory test results (to include hematology, serum chemistry, 
and urinalysis) 
o Vital sign measurements 
o 12-lead ECG parameters 
• Subject counts and percentages with suicidal ideation or suicidal behavior during the 
study as assessed by the C-SSRS 
Descriptive statistics for continuous results from clinical laboratory tests, vital signs, ECG, 
height, body weight, and BMI, including changes from Baseline, will be tabulated by 
timepoint. 
For categorical variables, excluding C-SSRS, the frequency distribution (i.e., number and 
percentage of subjects for each category) will be summarized by timepoint. 
For C-SSRS assessment, descriptive statistics for the incidence of subjects with suicidal 
ideation, suicidal behavior, or suicidality (either ideation or behavior) during the study will be 
tabulated. 
The number and percentage of subjects with PCI post-Baseline values will be summarized at 
each post-Baseline visit and overall post Baseline for selected parameters. The PCI criteria 
will be specified in the statistical analysis plan. 
9.5.4.3 
Exposure to Study Drug 
For each subject, the duration of exposure to study drug will be calculated as the number of 
days from first dose date to last dose date inclusive. Descriptive statistics will be tabulated. A 
categorical summary will also be provided using categories defined in the SAP. 
9.5.4.4 
Adherence and Retention Analyses 
The number and percentage of subjects in each analysis set, and the number and percentage 
of subjects who completed the study or withdrew early will be summarized descriptively. A 
tabulation of the corresponding reasons for early withdrawal from the study will also be 
provided. 


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9.5.4.5 
Demographics and Other Analyses 
Subject demographics and other characteristics, including medical and disease history, will be 
summarized using descriptive statistics. 
In addition, the use of concomitant medications will be summarized by therapeutic class 
using subject counts and percentages. Concomitant medications will include all medications 
taken between the first dose date and the last dose date of study drug, inclusive. Concomitant 
medications will be summarized by anatomical therapeutic chemical (ATC) Level 3 
classification and World Health Organization (WHO) Drug Dictionary preferred term. 
9.5.5 
Subgroup Analyses 
Selected subgroup analyses may be performed. Additional details will be provided in the 
SAP. 
9.6 
Interim Analyses 
An efficacy analysis may be performed when 50% of subjects have completed the study or 
terminated early. Additional analyses may be performed as necessary throughout the course 
of the study. 
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 authorities. 
The Investigator and institution must permit authorized representatives of the Sponsor or 
designees (including monitors and auditors), regulatory authorities (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). This data will be entered into a validated electronic data 
capture (EDC) database by trained site personnel and/or transferred electronically into EDC, 
as applicable. The source documentation may consist of source notes captured by site 
personnel as well as laboratory reports, ECG reports, and electronic source data. 


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10.3 Case Report Forms 
Subject data required by this protocol are to be recorded in an EDC system on eCRFs and/or 
transferred electronically and securely for data review. 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 omission or discrepancy will require explanation. All 
information on eCRFs must be traceable to source documentation (unless the eCRF is 
considered the source) at the site. 
10.4 Confidentiality 
The Investigator must ensure that each subject’s anonymity is maintained as described below. 
On the eCRFs or other documents submitted to the Sponsor or designees, subjects must be 
identified by a subject identification number only. Subject identifiers uniquely identify 
subjects within the study and do not identify any person specifically. Documents that are not 
for submission to the Sponsor or designees (e.g., signed ICFs, medical records submitted 
with SAE reporting) should be kept in strict confidence by the Investigator in compliance 
with Federal regulations or other applicable laws or ICH guidance on GCP. Data collection 
and handling should comply with the European Union General Data Protection Regulation 
(EU GDPR), where applicable. Acadia has assigned a Data Protection Officer (DPO) as per 
the EU GDPR. 
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. 


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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 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 6.4). 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. 
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 authorities, 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 QUALITY MANAGEMENT 
11.1 Risk Management 
The Sponsor utilizes the ICH E6 (GCP) Revision 2 risk management approach that includes 
methods to assure and control the quality of the trial proportionate to the risks inherent in the 
trial and the importance of the information collected. The intent is that all aspects of this trial 
are operationally feasible and that any unnecessary complexity, procedures, and data 
collection are avoided. The Sponsor’s risk management approach includes the following 
activities:  
• Critical Process and Data Identification: during protocol development, risks of 
processes and data that are critical to ensure human subject protection and the 
reliability of trial results are identified and assessed. 
• Risk Identification: risks to critical trial processes, governing systems, investigational 
product, trial design, data collection, and recording are identified. 
• Risk Evaluation: identified risks are evaluated by considering the following factors: (a) 
likelihood of occurrence, (b) impact on human subject protection and data integrity, 
and (c) detectability of errors. 


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• Risk Control: risks that can be reduced (e.g., mitigating) or can be accepted are 
differentiated. Risk mitigation activities are incorporated in protocol design and 
implementation, study plans, training, processes, and other documents governing the 
oversight and execution of study activities. Where possible, predefined quality 
tolerance limits are to be defined to identify systematic issues that can impact subject 
safety or data integrity and deviations from the predefined quality tolerance limits will 
trigger an evaluation and possibly an action. Contingency plans are developed for 
issues with a high risk factor that cannot be avoided. 
• Periodic risk review, communication, and escalation of risk management activities 
during trial execution and risk outcome reporting in the clinical study report (CSR). 
11.2 Quality Control and Quality Assurance 
The Sponsor or designees and regulatory authority 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 authority 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. 


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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 (e.g., Serious Breach reporting, 
urgent safety measures, and EU GDPR). 
The study will be performed in accordance with current US 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 and their 
study partner/caregiver prior to any screening procedures, including discontinuation of 
prohibited medications.  
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. 


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The consent form must be revised if new information becomes available during the study that 
may be relevant to the subject’s willingness to continue participation. Any revision must be 
submitted to the appropriate IRB/EC for review and approval in advance of use. 
12.3.1 
Consent and Other Informational Documents Provided to Subjects 
The subject must be given a copy of the signed informed consent and the original 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 after adequate explanation of the aims, methods, anticipated benefits, and potential 
hazards of the study. The subject 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 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. 
Records related to a study subject’s participation will be maintained and processed according 
to local laws, and where applicable, the European Union General Data Protection Regulation 
(EU GDPR). The consent and study information documentation will include statements 
describing local and regional requirements concerning data privacy, and who to contact for 
questions. 
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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15 LITERATURE REFERENCES 
Aarsland D, Ballard C, Larsen JP, McKeith I. A comparative study of psychiatric symptoms 
in dementia with Lewy bodies and Parkinson’s disease with and without dementia. Int J 
Geriatr Psychiatry. 2001;16:528–536. 
Acadia Pharmaceuticals Inc. NUPLAZID® [package insert]. San Diego, CA, November 
2020. 
Al Thomali ME, Juni MH, Rosliza AM, Hayati KS, Gaggad A. A systematic review on 
intervention programs to improve activity of daily living status and health related quality of 
life. Int J Pub Hlth Clin Sci. e-ISSN:2289-7577. 2017;4(5):38-61. 
Beyer-Westendorf J, Büller H. External and internal validity of open label or double‐blind 
trials in oral anticoagulation: better, worse or just different? J Thromb Haemostasis. 
2011;9(11):2153-2158.  
Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The 
Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. 
Neurology. 1994;44(12):2308-2314. 
Cummings JL. The Neuropsychiatric Inventory: assessing psychopathology in dementia 
patients. Neurology. 1997;48:S10-S16. 
Cummings J, Isaacson S, Mills R, et al. Pimavanserin for patients with Parkinson's disease 
psychosis: a randomised, placebo-controlled phase 3 trial. Lancet. 2014;383(9916):533–540. 
Fahn S, Elton RL, Members of the UPDRS Development Committee. In: Fahn S, Marsden 
CD, Calne DB, Lieberman A. Recent developments in Parkinson's disease. Unified 
Parkinson's Disease Rating Scale. Macmillan Health Care Information. 1987;153–163,293-
304. 
Folstein MF, Folstein SE, McHugh PR. “Mini-Mental state”: A practical method for grading 
the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12(3):189-198. 
Goetz CG, Tilley, BC, Shaftman SR, et al. Movement Disorder Society- sponsored revision 
of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS): scale presentation and 
clinimetric testing results. Movement Disorders. 2008;23(15): 2129-2170. 
Guy, W. Clinical Global Impression. In: ECDEU Assessment Manual for 
Psychopharmacology, Revised (DHEW Publ No. ADM 76-338). National Institute of Mental 
Health: Rockville, MD. 1976:218-222. 
Jette AM, Davies AR, Cleary PD, et al. The functional status questionnaire: reliability and 
validity when used in primary care. J Gen Intern Med. 1986;1:143-149. 


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Kaufer DI, Cummings JL, Ketchel P, et al. Validation of the NPI-Q, a brief clinical form of 
the neuropsychiatric inventory. J Neuropsych Clin Neurosci. 2000;12:233-239. 
Mathis MV, Muoio BM, Andreason P, et al. The US Food and Drug Administration’s 
perspective on the new antipsychotic pimavanserin. J Clin Psychiatry. 2017;78(6):e668-e673.  
McRae C, Diem G, Vo A, O’Brien C, Seeberger L. Schwab and England: standardization of 
administration. Mov Disord. 2000;15(2):335-359. 
Mehta MA, Manes FF, Magnolfi G, Sahakian BJ, Robbins TW. Impaired set-shifting and 
dissociable effects on tests of spatial working memory following the dopamine D2 receptor 
antagonist sulpiride in human volunteers. Psychopharmacology (Berl). 2004;176(3-4):331-
342. 
Parkinson’s Disease Foundation. Statistics on Parkinson’s. 
https://www.parkinson.org/Understanding-Parkinsons/Statistics. Accessed August 14, 2019. 
Pearlin L, Mullan J, Semple S, Skaff M. Caregiving and the stress process: an overview of 
concepts and their measures. The Gerontologist. 1990;30:583-594. 
Peretti CS, Danion JM, Kauffmann-Muller F, Grangé D, Patat A, Rosenzweig P. Effects of 
haloperidol and amisulpride on motor and cognitive skill learning in healthy volunteers. 
Psychopharmacology (Berl). 1997;131(4):329-338. 
Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry. 2011;168(12):1266-1277. 
Postuma RB, Berg D, Stern M, et al. MDS Clinical Diagnostic Criteria for Parkinson’s 
Disease. Mov Disord. 2015;30(12):1591-1601. 
Robinson BC. Validation of a caregiver strain index. J Gerontol. 1983;38(3):344-348. 
Ruse SA, Davis VG, Atkins AS, et al. Development of a virtual reality assessment of 
everyday living skills. J Vis Exp. 2014;86:e51405 
Saeedi H, Remington G, Christensen BK. Impact of haloperidol, a dopamine D2 antagonist, 
on cognition and mood. Schizophr Res. 2006;85(1-3):222-231. 
Schwab RS, England AC. Projection technique for evaluating surgery in Parkinson’s disease. 
In: Billingham, F.H. and Donaldson, M.C., Eds., Third symposium on Parkinson’s disease. 
Churchill Livingstone, Edinburgh. 1969:152-157. 
Sheikh JI, Yesavage JA. Geriatric Depression Scale (GDS). Recent evidence and 
development of a shorter version. In: T.L. Brink (Ed.). Clinical Gerontology: A Guide to 
Assessment and Intervention. NY: The Haworth Press, Inc. 1986; 165-173.  


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Shulman LM. Understanding disability in Parkinson’s disease. Mov Disord. 
2010;25(1):S131-S135. 
Shulman L, Gruber-Baldini A, Anderson K, et al. The evolution of disability in Parkinson 
disease. Mov Disord. 2008;23:790-796.  
Shulman L, Pretzer-Aboff I, Anderson K, et al. Subjective report versus objective 
measurement of activities of daily living in Parkinson’s disease. Mov Disord. 2006;21:794-
799. 
Starkstein SE, Brockman S, Hayhow BD. Psychiatric syndromes in Parkinson’s disease. Curr 
Opin Psychiatry. 2012;25:468–472. 
The Stanford/VA/NIA Aging Clinical Resource Center (ACRC) website. Information on the 
GDS. http://www.stanford.edu/~yesavage/GDS.html. Accessed August 30, 2019. 
Vanover KE, Weiner DM, Makhay M, et al. Pharmacological and behavioral profile of N-(4-
fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl) 
carbamide (2R,3R)-dihydroxybutanedioate (2:1) (ACP-103), a novel 5-
hydroxytryptamine(2A) receptor inverse agonist. J Pharmacol Exp Ther. 2006;317(2):910-
918. 
Wang PS, Schneeweiss S, Avorn J, et al. Risk of death in elderly users of conventional vs. 
atypical antipsychotic medications. N Engl J Med. 2005;353(22):2335-2341. 
World Health Organization. International classification of impairments, disabilities, and 
handicaps: a manual of classification relating to the consequences of disease. Geneva, 
Switzerland. World Health Organization. 1980. 
World Health Organization. International classification of functioning, disability and health: 
ICF. Geneva, Switzerland. World Health Organization. 2001. 
Yesavage JA, Brink TL, Rose TL, et al. Development and validation of a geriatric depression 
screening scale: A preliminary report. Journal of Psychiatric Research. 1983;17:37-49. 
 


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16 APPENDICES 
Appendix A Prohibited and Restricted Medications 
Subjects taking prohibited medications at study entry will not be eligible for the study. 
Subjects who require current treatment with a prohibited medication will be withdrawn from 
the study. 
Subjects who 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 continue in the trial will be made by the 
Sponsor/Medical Monitor 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. 
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. 
Medication Class 
Medicationa 
Prohibition/restrictions 
Adenosine receptor 
antagonists 
PROHIBITED 
• istradefylline 
• Must be washed out at least 5 half-lives prior to 
Baseline 
Antipsychotics other 
than pimavanserin  
PROHIBITED 
All in class 
• Must be washed out 1 month or 5 half-lives 
(whichever is longer) prior to Baseline 
• Prohibited throughout the study until completion of 
the EOT visit 
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 must be 
washed out and discontinued at least 2 weeks or 
5 half-lives (whichever is longer) prior to Baseline 
UNRESTRICTED 
• peripherally acting 
anticholinergics 
• topical diphenhydramine 
Oxybutynin and other anticholinergics may be used if 
dose unchanged for at least 4 weeks prior to Baseline 
and dose is expected to remain unchanged throughout 
the study until completion of the EOT visit. 


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Medication Class 
Medicationa 
Prohibition/restrictions 
Anticonvulsant and 
mood stabilizers 
PROHIBITED 
• carbamazepine 
• lamotrigine 
• lithium 
• phenytoin 
• Must be washed out 5 half-lives prior to Baseline 
• Prohibited throughout the study until completion of 
the EOT visit 
RESTRICTED 
• valproate 
Valproate may be used if dose unchanged for at least 
4 weeks prior to Baseline and dose is expected to 
remain unchanged until completion of the EOT visit. 
Antidepressants 
PROHIBITED 
• mirtazapine 
• nefazadone 
• fluvoxamine 
• mianserin 
• trazodone 
• amitriptyline 
• nortriptyline 
• imipramine 
• trimipramine 
• desipramine 
• clomipramine 
• esketamine 
• ketamine 
• Prohibited throughout the study until completion of 
the EOT visit 
• 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 is expected to remain unchanged until 
completion of the EOT 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 Baseline and throughout the study until 
completion of the EOT visit 


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Medication Class 
Medicationa 
Prohibition/restrictions 
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 Baseline and throughout the study until 
completion of the EOT visit 
RESTRICTED 
• zaleplon 
• ramelteon 
May not be used within approximately 12 hours prior to 
an assessment (including assessments on handheld 
device and in clinic), 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 Baseline and throughout the study until 
completion of the EOT visit (see Section 6.3.6 for 
procedures related to a positive amphetamine test at 
study entry) 
Non-stimulant 
ADHD medications 
PROHIBITED 
• atomoxetine 
Prohibited at Baseline and throughout the study until 
completion of the EOT visit 
Serotonin 
antagonists  
PROHIBITED 
• cyproheptadine 
• Prohibited throughout the study until completion of 
the EOT visit 
• 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 
Prohibited at Baseline and throughout the study until 
completion of the EOT visit 


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Medication Class 
Medicationa 
Prohibition/restrictions 
• propafenone 
• quinidine 
• sotalol, d-sotalol 
Opioids 
PROHIBITED 
• methadone 
Prohibited at Baseline and throughout the study until 
completion of the EOT visit 
Antimicrobials, 
antifungals, and 
antimalarials 
PROHIBITED 
• clarithromycin 
• erythromycin 
• levofloxacin 
• moxifloxacin 
• pentamidine 
• roxithromycin 
Prohibited at Baseline and throughout the study until 
completion of the EOT visit 
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 
a 
Medications within each class include but are not limited to the examples listed in this table. 


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Appendix B 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.  
Subjects who require current treatment with a prohibited medication will be withdrawn from 
the study. 
Subjects who 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 continue in the study will be made by the 
Sponsor/Medical Monitor with medical input from the Investigator, and will be documented. 
If allowed to remain in the study, this will be reported as a major protocol deviation and not a 
waiver. 
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 are allowed but should be 
used with caution. 
STRONG 
INHIBITORS 
grapefruit juicea 
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®) 
MODERATE 
INHIBITORS 
grapefruit juicea 
amprenavir (Agenerase®) 
aprepitant (Emend®) 
atazanavir (Reyataz®) 
ciprofloxacin (Cipro®) 
darunavir/ritonavir 
(Prezista®/Ritonavir) 
diltiazem 
erythromycin (Erythrocin® 
Lactobionate) 
fluconazole (Diflucan®) 
fosamprenavir (Lexiva®) 
imatinib (Gleevec®) 


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posaconazole (Noxafil®) 
quinupristin (Synercid®) 
ritonavir (Norvir®, part of Viekira 
Pak™) 
saquinavir (Invirase®) 
telaprevir (Incivek®) 
telithromycin (Ketek®) 
voriconazole (Vfend®) 
verapamil (Calan®) 
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). 

SAP_001.pdf: 
Official Title: A 16-Week Open-Label Study of the Effects of Treatment With 
Pimavanserin on Activities of Daily Living in Subjects With Parkinson’s Disease 
Psychosis 
NCT Numbers: NCT04292223 
Document Date: 28 Mar 2022 
 


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STATISTICAL ANALYSIS PLAN 
 
Protocol No.: 
ACP-103-063 
Protocol Title: 
A 16-Week Open-Label Study of the Effects of 
Treatment With Pimavanserin on Activities of Daily 
Living in Subjects With Parkinson’s Disease Psychosis 
Drug: 
Pimavanserin 
Sponsor:  
Acadia Pharmaceuticals Inc. 
 
Version No. and Date 
Version 1.0, 28 March 2022 
 
 
 
 
 
 
 
 
 


Protocol ACP-103-063 
Version 1.0 
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SIGNATURE/APPROVAL PAGE 
AUTHOR 
_________________________________________________________________________ 
 
Date 
Director, Biostatistics 
Acadia Pharmaceuticals Inc. 
APPROVERS 
____________ 
_________________________________________________________________________ 
 
Date 
Executive Director, Biostatistics 
Acadia Pharmaceuticals Inc. 
_________________________________________________________________________ 
                                                                                Date 
Vice President, Medical Affairs 
Acadia Pharmaceuticals Inc. 
See appended electronic signature page 


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TABLE OF CONTENTS 
TABLE OF CONTENTS ........................................................................................................... 4 
LIST OF TABLES ..................................................................................................................... 7 
LIST OF FIGURES ................................................................................................................... 7 
ABBREVIATIONS .................................................................................................................... 8 
1 INTRODUCTION ............................................................................................................. 10 
2 OBJECTIVES AND ENDPOINTS ................................................................................... 10 
2.1 
Primary Objective .......................................................................................................... 10 
2.1.1 
Primary Endpoint ....................................................................................................... 10 
2.2 
Secondary Objectives .................................................................................................... 10 
2.2.1 
Secondary Endpoints ................................................................................................. 10 
2.3 
Exploratory Objectives .................................................................................................. 11 
2.3.1 
Exploratory Endpoints ............................................................................................... 11 
2.4 
Safety Objectives ........................................................................................................... 11 
2.4.1 
Safety Endpoints ........................................................................................................ 11 
3 STUDY DESIGN ............................................................................................................... 12 
3.1 
General Study Design .................................................................................................... 12 
3.2 
Schedule of Assessments ............................................................................................... 14 
3.3 
Randomization ............................................................................................................... 14 
3.4 
Blinding ......................................................................................................................... 14 
3.5 
Determination of Sample Size ....................................................................................... 14 
3.6 
Coronavirus Disease 2019 ............................................................................................. 14 
4 ANALYSIS SETS .............................................................................................................. 14 
4.1 
Safety Analysis Set ........................................................................................................ 14 
4.2 
Full Analysis Set ............................................................................................................ 14 
5 DATA HANDLING CONVENTIONS .............................................................................. 15 
5.1 
General Data Reporting Conventions ............................................................................ 15 
5.2 
Derived Efficacy Variables ............................................................................................ 16 
5.2.1 
Mini-Mental State Examination ................................................................................ 16 
5.2.2 
NPI Domains A and B ............................................................................................... 16 
5.2.3 
NPI-Q Nighttime Behavior Domain .......................................................................... 17 


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5.2.4 
Modified Functional Status Questionnaire ................................................................ 17 
5.2.5 
Schwab and England ADL Scale (Patient and Caregiver Versions) .......................... 20 
5.2.6 
MDS-UPDRS Parts I and II (Patient and Caregiver Version) ................................... 20 
5.2.7 
CGI-S for Hallucinations and Delusions ................................................................... 21 
5.2.8 
CGI-I for Hallucinations and Delusions .................................................................... 21 
5.2.9 
PGI-I for Hallucinations and Delusions .................................................................... 21 
5.2.10 
Virtual Reality Functional Capacity Assessment Tool .............................................. 21 
5.2.11 
Caregiver Strain Index ............................................................................................... 23 
5.2.12 
Geriatric Depression Scale (Short Form) .................................................................. 23 
5.3 
Analysis Visit Windows ................................................................................................. 24 
5.3.1 
Unscheduled Assessments ......................................................................................... 24 
5.3.2 
Multiple Measurements within Visit Windows ......................................................... 24 
5.3.3 
Data Listings .............................................................................................................. 25 
5.4 
Data Handling Conventions........................................................................................... 25 
5.4.1 
Missing or Incomplete Date for Last Dose of Study Drug ........................................ 25 
5.4.2 
Missing or Incomplete Dates for Concomitant or Post-Treatment Medications ....... 25 
5.4.3 
Missing or Incomplete Dates for Adverse Events ..................................................... 26 
5.4.4 
Missing Severity Assessment for Adverse Events ..................................................... 26 
5.4.5 
Missing Relationship to Study Drug for Adverse Events .......................................... 26 
5.4.6 
Character Values of Clinical Laboratory Variables.................................................... 26 
6 SUBJECT DISPOSITION ................................................................................................. 26 
7 PROTOCOL DEVIATIONS .............................................................................................. 27 
8 DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS .......................... 27 
8.1 
Baseline Disease Characteristics ................................................................................... 28 
8.2 
Neuropsychiatric Inventory ........................................................................................... 28 
9 MEDICAL HISTORY ....................................................................................................... 28 
10 PRIOR, CONCOMITANT, AND POST-TREATMENT MEDICATION ......................... 28 
11 EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE ................................... 29 
11.1 Exposure to Treatment ................................................................................................... 29 
11.2 Measurement of Treatment Compliance ........................................................................ 29 
12 EFFICACY ANALYSES ................................................................................................... 30 
12.1 Primary Efficacy Endpoint ............................................................................................ 30 
12.2 Secondary Efficacy Endpoints ....................................................................................... 30 


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12.3 Exploratory Efficacy Endpoints .................................................................................... 30 
12.4 Handling of Missing Data .............................................................................................. 31 
12.5 Multiple Comparisons/Multiplicity ............................................................................... 31 
12.6 Examination of Subgroups ............................................................................................ 31 
12.7 Analysis of Efficacy Endpoints ..................................................................................... 31 
12.8 Mixed Model Repeated Measures (MMRM) ................................................................ 31 
13 SAFETY ANALYSES ....................................................................................................... 32 
13.1 Adverse Events .............................................................................................................. 32 
13.2 Other Safety Analyses ................................................................................................... 34 
13.2.1 
Clinical Laboratory Variables .................................................................................... 34 
13.2.2 
Chemistry ................................................................................................................... 34 
13.2.3 
Hematology ............................................................................................................... 34 
13.2.4 
Urinalysis ................................................................................................................... 35 
13.2.5 
Methods of Analysis for Clinical Laboratory Variables ............................................ 35 
13.2.6 
Vital Signs and Height, Weight, and BMI ................................................................. 38 
13.2.7 
Electrocardiogram (ECG) .......................................................................................... 39 
13.2.8 
Physical Examinations ............................................................................................... 41 
13.2.9 
C-SSRS ...................................................................................................................... 41 
14 CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES ........ 42 
15 INTERIM ANALYSIS ....................................................................................................... 42 
16 DATA MONITORING/REVIEW COMMITTEE ............................................................. 42 
17 COMPUTER METHODS ................................................................................................. 42 
18 CHANGES TO ANALYSES SPECIFIED IN PROTOCOL ............................................. 42 
19 REFERENCES .................................................................................................................. 42 
20 APPENDICES ................................................................................................................... 44 
20.1 Summary of Version Changes ....................................................................................... 44 
20.2 Schedule of Events and Assessments for ACP-103-063 ............................................... 45 
 


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LIST OF TABLES 
Table 1 
VRFCAT Mini Scenarios and Objectives ........................................................ 22 
Table 2 
Analysis Visit Windows ................................................................................... 24 
Table 3 
Criteria for Potentially Clinically Important Laboratory Values – 
Hematology and Chemistry ............................................................................. 37 
Table 4 
Criteria for Potentially Clinically Important Laboratory Values - 
Urinalysis ......................................................................................................... 38 
Table 5 
Criteria for Potentially Clinically Important Vital Signs ................................. 39 
Table 6 
Criteria for Potentially Clinically Important ECG Values ............................... 40 
 
LIST OF FIGURES 
Figure 1 Schematic of Study Design for ACP-103-063 .......................................................... 13 
 


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ABBREVIATIONS 
ADL 
Activities of Daily Living 
AE(s) 
adverse event(s) 
ATC 
Anatomical Therapeutic Chemical 
BMI 
body mass index 
CGI-I 
Clinical Global Impression – Improvement 
CGI-S 
Clinical Global Impression – Severity 
CI 
confidence interval 
COVID-19 
Coronavirus disease 2019 
CSI 
Caregiver Strain Index 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DMP 
Data Management Plan 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOT 
End-of-Treatment 
ET 
Early Termination 
GDS 
Geriatric Depression Scale  
MDS-UPDRS 
Movement Disorders Society-Unified Parkinson’s Disease Rating Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
mFSQ 
modified Functional Status Questionnaire 
MMRM 
mixed-effect model repeated measures 
MMSE 
Mini-Mental State Examination 
msec 
milliseconds 
NPI 
Neuropsychiatric Inventory 
NPI-Q 
Neuropsychiatric Inventory-Questionnaire 
PCI 
potentially clinically important 
PDP 
Parkinson’s disease psychosis 
PGI-I 
Patient Global Impression - Improvement 
QTcB 
QT interval corrected for heart rate using Bazett’s formula 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
SAE(s) 
serious adverse event(s) 
SAP 
statistical analysis plan 
SD 
standard deviation 
SE 
standard error  
SOC 
system organ class 


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TEAE(s)   
treatment-emergent adverse event(s) 
VRFCAT 
Virtual Reality Functional Capacity Assessment Tool 


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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 the protocol Amendment 1.0 
dated 20 May 2021 and the electronic case report form (eCRF). This SAP will be approved 
prior to database lock. Specifications for tables, figures, and listings are contained in separate 
documents (ACP-103-063 Table Shells, ACP-103-063 Figure Shells, and ACP-103-063 
Listing Shells, respectively). 
2 OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objective 
The primary objective of this study is to assess the effect of pimavanserin on the activities of 
daily living (ADLs) in subjects with Parkinson’s disease psychosis (PDP) measuring the 
subject’s physical, psychological, social and role functions. 
2.1.1 
Primary Endpoint 
Change from baseline (Week 0) to Week 16 on the modified Functional Status Questionnaire 
(mFSQ) total score. 
2.2 
Secondary Objectives 
•  To evaluate the efficacy and benefits of pimavanserin in subjects with 
PDP on activities of daily living 
• To assess the clinician’s global impression of severity and 
improvement of hallucination/delusions 
2.2.1 
Secondary Endpoints 
• Change from baseline to Week 16 on the Schwab and England ADL Scale 
(Caregiver and Patient Version) 
• Change from baseline to Week 16 on the Movement Disorders Society-Unified 
Parkinson’s Disease Rating Scale (MDS-UPDRS) Parts I and II (Caregiver and 
Patient Version) 
• Week 16 Clinical Global Impression – Improvement (CGI-I) score for 
hallucinations and delusions 
• Change from baseline to Week 16 on the Clinical Global Impression – 
Severity of Illness (CGI-S) score for hallucinations and delusions 


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• Week 16 Patient Global Impression of Improvement (PGI-I) score for 
hallucinations and delusions 
2.3 
 Exploratory Objectives 
• To assess the extent to which caregivers and families experience additional 
demands, responsibilities, and difficulties 
• To explore the effects of pimavanserin in subjects with PDP on: 
o Functional capacity 
o Cognition 
o Depressive symptoms 
o Nighttime behavior  
o Caregiver burden 
2.3.1 
Exploratory Endpoints 
•  Change from baseline to Week 16 on the Virtual Reality Functional Capacity 
Assessment Tool (VRFCAT) including total time to complete, total number of 
errors, and total number of forced progressions 
• Change from baseline to Week 16 on the Caregiver Strain Index (CSI) total score 
• Change from baseline to Week 16 on the Neuropsychiatric Inventory-
Questionnaire (NPI-Q) Nighttime Behavior Domain Severity and Caregiver 
Distress 
• Change from baseline to Week 16 on the Geriatric Depression Scale (GDS) 
(Short Form) 
• Change from baseline to Week 16 on the mFSQ score by subscale 
2.4 
Safety Objectives 
• To assess the safety and tolerability of pimavanserin in adults with PDP 
2.4.1 
Safety Endpoints 
The safety and tolerability of pimavanserin will be assessed using the following: 
• Treatment-emergent adverse events (TEAEs) 
• Columbia-Suicide Severity Rating Scales (C-SSRS) score 
• Potentially clinically important (PCI) findings on: 
o Physical examinations 


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o Clinical laboratory tests 
o Vital signs 
o Electrocardiogram parameters 
3 STUDY DESIGN 
3.1 
General Study Design 
This study will be conducted as a 16-week, multi-center, single-arm, open-label study. 
Pimavanserin (ACP-103) will be administered at a dose of 34 mg to approximately 
53 subjects with PDP. Approximately 42 subjects are expected to complete the study, 
assuming a 20% drop-out rate. Approximately 25 sites in the US will participate in this 
study. 
The duration of participation for individual study subjects will be up to 26 weeks, consisting 
of the following 3 periods: 
• Screening period (3-35 days) 
• Treatment period (16 weeks) 
• Safety follow-up period (30-34 days) 
The study will be conducted on an outpatient basis with visits performed at Screening, 
Baseline (Week 0), Week 2, Week 4, Week 8, Week 12, Week 16 (end of Treatment 
Period) and Follow-up (at least 30 days and not to exceed 34 days after last dose of 
study drug). The first dose of study drug (pimavanserin) should be taken on the 
morning of the day after the Baseline visit. 
The study start date is defined as the date the first subject is enrolled, which is the 
baseline visit date for the first subject. The primary completion date is the last date that 
subject data was collected for the primary outcome measure. The study completion date  
is defined as the last date that subject data was collected, which includes the safety 
follow-up telephone call visit.   
Figure 1 illustrates the study design. 
 


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Figure 1 Schematic of Study Design for ACP-103-063 
 
Abbreviations: EOT: end of trial; ET: early termination; QD: once daily 
 
  
 
30-day follow-up 
(telephone call) 
Baseline 
EOT/ET 
34 mg pimavanserin QD 
Eligible subjects with 
Parkinson’s disease and 
psychotic symptoms 
Follow-up Period 
30 days 
Open-Label Treatment Period 
16 weeks 
Screening Period        
Up to 5 weeks 


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3.2 
Schedule of Assessments 
The schedule of events and assessments for the study is presented in the Appendix (Schedule 
of Events and Assessments). 
3.3 
Randomization 
This is a single-arm study; therefore, randomization is not applicable. 
3.4 
Blinding 
This is an open-label study; therefore, blinding is not applicable. 
3.5 
Determination of Sample Size 
This is an exploratory study and is not powered for statistical significance. Formal sample 
size calculations were not used to determine sample size. 
3.6 
Coronavirus Disease 2019 
In March 2020, the emerging coronavirus disease 2019 (COVID-19) pandemic resulted in the 
implementation of urgent safety measures designed to ensure subject safety (FDA 2020). 
Mechanisms to record information on the potential impact of the COVID-19 pandemic on 
data itself, as well as data collection and integrity, were implemented (as detailed in 
Appendix B of the Data Management Plan [DMP]). The impact of COVID-19 on the 
statistical analysis is discussed in each of the relevant sections of this SAP. 
Because of possible restrictions due to COVID-19, all references to performing assessments, 
procedures, and evaluations at the clinic should be understood as including the options of 
performing these at the subject’s home in the presence of a member of the clinical site staff 
and the subject’s caregiver.  
4 ANALYSIS SETS 
4.1 
Safety Analysis Set 
The Safety Analysis Set will consist of all subjects who have taken at least 1 dose of study 
drug. Safety analyses will be based on the Safety Analysis Set. 
4.2 
Full Analysis Set 
The Full Analysis Set will consist of all subjects who receive at least 1 dose of study drug, 
and have both baseline and at least one post-baseline value for the mFSQ total score. Efficacy 
analyses will be based on the Full Analysis Set. 


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5 DATA HANDLING CONVENTIONS 
All data collected in the study will be listed. 
5.1 
General Data Reporting Conventions 
For continuous variables, the following summary statistics will be provided: number of 
subjects, mean, standard error (SE) of the mean, standard deviation (SD), minimum, 
maximum, and median. Unless specified otherwise, means, medians, and confidence 
intervals (CIs) will be presented to one more decimal place than the raw data, and the SDs 
and SEs will be presented to 2 more decimal places than the raw data. In general, the 
maximum number of decimal places is 4 and values will be truncated to 4 decimal places in 
situations where there are more than 4 decimal places. Wherever possible data will be 
decimal aligned. 
For categorical variables, summaries will include the number and percentage of subjects in 
each category; the number of subjects and the percentage of subjects with missing data will 
be summarized for demographic and baseline characteristics (if applicable). Categories with 
zero counts will not have zero percentages displayed. Percentages will be presented to 
1 decimal place. For demographic (except for Childbearing Potential) and baseline 
summaries (except for NPI-Q distress), percentages will be calculated by using the total 
number of subjects as the denominator. 
Unless specified otherwise, all statistical tests will be 2-sided hypothesis tests performed at 
the significance level of 0.05 for main effects. All CIs will be 2-sided, 95% CIs, p-values will 
generally be presented to 4 decimal places, and p-values less than 0.0001 will be presented as 
<0.0001 
Values that are collected with “<” or “>” signs will generally be analyzed as the numerical 
value without the sign in tables and figures. In listings, these data will be reported as 
collected with the sign. 
Duration in months will be calculated as (number of days/365.25)*12 and will be rounded to 
1 digit after the decimal point (tenths) for presentation purposes. 
Duration in years will be calculated as number of days/365.25 and will be rounded to 1 digit 
after the decimal point (tenths) for presentation purposes. 
Baseline is defined as the last non-missing value prior to the first dose of study drug. All 
change from baseline endpoints are calculated as the value of the corresponding post-baseline 
visit minus the value at baseline.  


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5.2 
Derived Efficacy Variables 
In general, all assessment scale total scores and subscores will be derived within the analysis 
datasets (with the exception of the VRFCAT variables, which are derived by the VRFCAT 
software). In the event that total scores and/or subscores are also collected on the eCRF, the 
derived values will be used for all analyses. Both the raw and derived scores will be 
presented in data listings. 
5.2.1 
Mini-Mental State Examination 
The Mini-Mental State Examination (MMSE) is assessed only at the Screening visit. The 
MMSE is being used in this study to screen for cognitive impairment. 
The MMSE is a 30-item questionnaire that includes simple questions and problems in the 
following areas: time and place of testing, repeating lists of words, arithmetic, language use 
and comprehension, and copying or drawing.  
Each of the 30 items is scored as 0 for an incorrect response, and 1 for a correct response. 
The MMSE total score will be derived as the sum of the 30 item scores; thus, the total score 
has a potential range of 0 to 30. Lower scores indicate more severe cognitive impairment. 
The total score will be set to missing if there are one or more missing items. 
5.2.2 
NPI Domains A and B 
 At Screening (Visit 1) and Baseline (Visit 2), the degree of the patient’s neuropsychiatric 
symptoms will be evaluated using two of the domains of the Neuropsychiatric Inventory 
(NPI), Domain A (Delusions) and Domain B (Hallucinations). For each domain, three 
separate ratings are collected, Frequency, Severity and Distress, and are scored as follows: 
• Frequency of the symptom: 0=no symptom, 1=occasionally, 2=often, 3=frequently, 
4=very frequently 
• Severity of the symptom: 0=no symptom, 1=mild, 2=moderate, 3=severe 
• Distress (how it affects the caregiver): 0=no distress, 1=minimal, 2=mild, 
3=moderate, 4=severe, 5=extreme or very severe 
The individual domain scores are calculated as the frequency score × severity score. The NPI 
psychosis score is derived as the sum of the domain A and domain B scores. If either A or B 
domain scores are missing then the psychosis total score will be missing. 
Missing NPI scores (frequency, severity, and distress) will not be imputed. However, each of 
the individual domains contains a screening question that is used to elicit whether the 


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symptom is present or absent. If the answer to the screening question is “No” then the 
derived domain score will be set to 0. 
5.2.3 
NPI-Q Nighttime Behavior Domain 
The NPI-Q is a self-administered questionnaire completed by informants about patients for 
whom they care. In this study, the informant is typically the caregiver. There are 12 domains 
in the full questionnaire; however, only the Nighttime Behavior domain will be completed by 
informants in this study. Two separate ratings are collected, Severity and Distress, and are 
scored as follows: 
• Severity of the symptom (how it affects the subject): 0=no symptom, 1=mild, 
2=moderate, 3=severe 
• Distress (how it affects the informant): 0=not distressing at all, 1=minimal, 2=mild, 
3=moderate, 4=severe, 5=extreme or very severe 
If the informant reports that nighttime behaviors are not present, the Severity score will be set 
to 0, and the Distress score will remain a missing value. Otherwise, missing Severity and 
Distress scores will not be imputed. 
5.2.4 
Modified Functional Status Questionnaire 
The Functional Status Questionnaire (FSQ) is a self-administered questionnaire that 
provides an assessment in ambulatory patients of physical, psychological, social, and role 
function (Jette et al. 1986). It comprises 34 core items that produce 6 summary scale scores: 
basic activities of daily living (ADL), intermediate activities of daily living, psychological 
function and mental health, work performance, social activity, and quality of interaction. 
In addition, it also includes 6 single-item scores: work situation; days per month in bed due 
to illness or injury; days per month when illness injury reduced activities normally 
performed for half a day or more; satisfaction with sexual relationships; satisfaction with 
own health; and frequency of social interaction. 
Basic ADL consists of the following items: 
1. Taking care of yourself, that is, eating, dressing or bathing 
2. Moving in or out of a bed or chair 
3. Walking indoors, such as around your home 
Intermediate ADL consists of the following items: 
1. Walking several blocks 


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2. Walking one block or climbing one flight of stairs 
3. Doing work around the house, such as cleaning, light yard work, home maintenance 
4. Doing errands such as grocery shopping 
5. Driving a car or using public transportation 
6. Doing vigorous activities such as running, lifting heavy objects or participating in 
strenuous sports 
Social Activity consists of the following items: 
1. Had difficulty visiting with relatives or friends 
2. Had difficulty participating in community activities, such as religious services, social 
activities, or volunteer work 
3. Had difficulty taking care of other people such as family members 
Each of the Basic ADL, Intermediate ADL, and Social Activity items are scored as follows: 
0=usually did not do for other reasons; 1=usually did not do because of health; 2=much 
difficulty; 3=some difficulty; 4=usually did with no difficulty. 
Psychological Function consists of the following items: 
1. Have you been a very nervous person 
2. Have you felt calm and peaceful 
3. Have you felt downhearted and blue 
4. Were  you a happy person 
5. Did you feel so down in the dumps that nothing could cheer you up 
Quality of Interaction consists of the following items: 
1. Isolated yourself from people around you 
2. Acted affectionate toward others 
3. Acted irritable toward those around you 
4. Made unreasonable demands on your family and friends 
5. Gotten along well with other people 
The Psychological Function and Quality of Interaction items are scored as follows: 1=all of 
the time; 2=most of the time; 3=a good bit of the time; 4=some of the time; 5=a little of the 
time; 6=none of the time. 


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Work Performance (for those employed during the preceding month) consists of the 
following items: 
1. Done as much as others in similar jobs 
2. Worked for short periods of time or taken frequent rests because of your health 
3. Worked your regular number of hours 
4. Done your job as carefully and accurately as others with similar jobs 
5. Worked at your usual job but with some changes because of your health 
6. Feared losing your job because of your health 
The Work Performance items are scored as follows: 1=all of the time; 2=most of the time; 
3=some of the time; 4=none of the time. 
The modified FSQ (mFSQ) score will be calculated as the unweighted mean of the 
following subscale scores: Basic ADL, Intermediate ADL, Psychological Function, Social 
Activity, and Quality of Social Interaction. The Work performance subscale is excluded 
due to the age and non-employment status of the intended patient population. Prior to 
deriving the mFSQ total score, the following items scores are reversed: items 2 and 4 of 
the Psychological Function, and items 2 and 5 of the Quality of Interaction. 
Subscale scores (SS, or transformed scale scores) are calculated according to this formula 
[Erratum 1986]: 
SS = (100/k) × (Sum of individual item scores – n)/n 
Where,  
n = number of questions in the subscale for which non-missing, valid information 
is available 
k = maximum minus minimum valid response score 
Activities that are not attempted because of non-health-related reasons are scored as 0 and 
will be excluded from average calculations [Tedesco et al. 1990]. Therefore, the maximum 
minus minimum valid response score for the Basic ADL, Intermediate ADL, and Social 
Activity will have a value of 3. 
The mFSQ score will be calculated as (Basic ADL SS + Intermediate ADL SS + 
Psychological Function SS + Social Activity SS + Quality of Social Interaction SS)/5. 


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If any of the 5 subscale scores are missing then neither the mFSQ nor the subscale will 
be imputed. 
5.2.5 
Schwab and England ADL Scale (Patient and Caregiver Versions) 
The Schwab and England ADL scale is an assessment of an individual’s ability in activities of 
daily living, rated in 10% increments where 100%=completely independent, and 
0%=vegetative. The scale will be completed independently by both the subject and the 
caregiver. Missing scores will not be imputed. 
5.2.6 
MDS-UPDRS Parts I and II (Patient and Caregiver Version) 
The MDS-UPDRS is a comprehensive battery of motor and behavioral indices. The 
MDS-UPDRS Parts I and II will be used to assess non-motor aspects of experiences of daily 
living (Part I) and motor aspects of experiences of daily living (Part II).  
5.2.6.1 
MDS-UPDRS Part I 
Part I of the MDS-UPDRS assesses the non-motor aspects of experiences of daily living. Part 
I consists of 13 items: cognitive impairment, hallucinations and psychosis, depressed mood, 
anxious mood, apathy, features of dopamine dysregulation syndrome, sleep problems, 
daytime sleepiness, pain and other sensations, urinary problems, constipation problems, light 
headedness on standing, and fatigue. The first 6 items are assessed by the investigator (with 
input from patients or caregivers), and the last 7 items are completed by the patient with or 
without the aid of a caregiver. 
Each item is scored on a 5-point Likert scale: 0=normal, 1=slight, 2=mild, 3=moderate, 
4=severe. 
The total score will be derived as the sum of the 13 individual items from Part I. If 1 or 
2 items are missing, the total score will be imputed as the mean of the non-missing items 
multiplied by 13 and rounded to the nearest integer. If more than 2 items are missing, the 
total score will be set to missing. 
5.2.6.2 
MDS-UPDRS Part II 
Part II of the MDS-UPDRS concerns the motor aspects of experiences of daily living. Part II 
consists of 13 items: speech, saliva and drooling, chewing and swallowing, eating tasks, 
dressing, hygiene, handwriting, doing hobbies and other activities, turning in bed, tremor, 
getting out of bed (or a car or a deep chair), walking and balance, and freezing. All 13 items 
are completed by the patient with or without the aid of a caregiver. 


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Each item is scored on a 5-point Likert scale: 0=normal, 1=slight, 2=mild, 3=moderate, 
4=severe. 
The total score will be derived as the sum of the 13 individual items from Part II. If 1 or 
2 items are missing, the total score will be imputed as the mean of the non-missing items 
multiplied by 13 and rounded to the nearest integer. If more than 2 items are missing, the 
total score will be set to missing. 
5.2.7 
CGI-S for Hallucinations and Delusions 
The CGI-S is a single-item, 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 Investigator’s 
judgment and past experience with subjects who have the same disorder. The 7-point scores 
are: 1=normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 
5=markedly ill; 6=severely ill; 7=among the most extremely ill patients. Higher scores denote 
more severe symptoms of hallucinations and delusions. Missing CGI-S scores will not be 
imputed. 
5.2.8 
CGI-I for Hallucinations and Delusions 
The CGI-I is a clinician-rated, 7-point scale that is designed to rate the total improvement in 
the subject’s hallucinations and delusions at the time of the assessment, relative to the 
symptoms at Baseline. The 7-point 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. Higher scores denote more severe symptoms of hallucinations and delusions. Missing 
CGI-I scores will not be imputed. 
5.2.9 
PGI-I for Hallucinations and Delusions 
The PGI-I is a single-item, global index used to rate the patient’s impression of response of a 
condition to a therapy. The PGI-I asks the patient to rate their symptoms (of hallucinations 
and delusions) now, as compared with how it was at Baseline before beginning treatment, 
according to a 7-point scale. The 7-point 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 PGI-I scores will not be imputed. 
5.2.10 Virtual Reality Functional Capacity Assessment Tool 
The Virtual Reality Functional Capacity Assessment Tool (VRFCAT) is a tablet-based 
assessment of functional capacity that simulates key instrumental activities of daily living in 
a realistic and interactive virtual environment. It will be used to explore the effects of 
pimavanserin on  functional capacity and cognition. VRFCAT tablets will be provided by 


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VeraSci. The specific VRFCAT software utilized in this study are Pathway version 1.16.15 
and software build 20200206.1 
Study participants are asked to complete 12 objectives associated with multiple components 
of a shopping trip, including searching the pantry, making a shopping list, taking the correct 
bus to the store, shopping, paying for purchases, and getting home (see Table 1). Two 
different versions of the 4 mini scenarios are utilized in this study. Each version has a unique 
recipe, unique bus fares, and unique amounts of money in the wallet. 
Table 1 
VRFCAT Mini Scenarios and Objectives 
Mini Scenario 
Objective 
Description 
Apartment 
1 
Pick-up the recipe on the counter 
2 
Search for ingredients  
3 
Cross off ingredients and pick up bus schedule 
4 
Pick up wallet 
5 
Exit the apartment 
Bus to Store 
6 
Board the bus to grocery store 
Store 
7 
Pay for the bus 
8 
Select food aisle 
9 
Shop for groceries 
10 
Pay for groceries 
Bus to Apartment 
11 
Board the bus for home 
12 
Pay for the bus 
 
For each objective, participants who are unable to complete the objective within a pre-
specified time period or who make too many errors are automatically progressed (i.e., forced 
progression) to the next objective.  
For each objective the VRFCAT derives the following quantities: 
1) Adjusted time (msec): Time to complete an objective, corrected for time of forced 
inactivity when an error occurs (as well as other factors). For example, if a subject 
makes an error, an error message is given during which the subject is not able to 


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proceed. The time required for the error message to display is removed from the 
adjusted time.  
2) Forced progression: Progressions are scored using a binary value, such that 
1 indicates the subject was progressed to the next objective at least once in a given 
testing period because the current objective was not completed in a timely manner.  
3) Error count: total number of errors for a given objective. 
The total adjusted time, total forced progressions, and total errors are then calculated as the 
sum of the adjusted time, forced progression, and error count, respectively, across all 
12 objectives. Adjusted times will be converted from msec to seconds for purposes of 
analysis. 
The VRFCAT software then takes the total adjusted time, total errors, and total forced 
progression scores and transforms them into T-scores according to the following algorithm: 
1) calculate Z-score using age and sex corrected mean and standard deviation values 
from Verasci’s proprietary normative data, i.e. 
Z-score=  -1 × (raw value – normative_mean) ÷ normative standard deviation  
2) calculate T-score as (Z-score×10) + 50 
Missing scores will not be imputed for any of the VRFCAT variables. 
5.2.11 Caregiver Strain Index 
The Caregiver Strain Index (CSI) is a 13-item questionnaire that measures strain related to 
care provision, and can be used to quickly identify families with potential caregiving 
concerns. There is at least one item for each of the following major domains: employment, 
financial, physical, social and time. Positive responses to seven or more items indicate a 
greater level of strain. Each item is scored zero (answered no) or one (answered yes). The 
total score is the sum score of the 13 items, resulting in a minimum possible score of 0 (no 
strain) and a maximum possible score of 13 (maximum possible strain). A score of 7 or 
higher indicates a high level of stress. 
If 1 or 2 items are missing, the total score will be imputed as the mean of the non-missing 
items multiplied by 13 and rounded to the nearest integer. If more than 2 items are missing, 
the total score will be set to missing. 
5.2.12 Geriatric Depression Scale (Short Form) 
The Geriatric Depression Scale (GDS) (Short Form) is a brief 15-item questionnaire in which 
participants are asked to respond by answering yes or no in reference to how they felt over 


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the past week. For items 1, 5, 7, 11, and 13 a “no” response is scored as 1, and a “yes” 
response as 0. For items 2, 3, 4, 6, 8, 9, 10, 12, 14, and 15 a “yes” response is scored as 1, and 
a “no” response is scored as 0.  
The GDS total score will be calculated as the sum of the 15 item scores. A total score of ≥5 
suggests depression.  
If 1 or 2 items are missing, the total score will be imputed as the mean of the non-missing 
items multiplied by 15 and rounded to the nearest integer. If more than 2 items are missing, 
the total score will be set to missing. 
5.3 
Analysis Visit Windows  
Baseline is defined as the last non-missing value, including results from repeated and 
unscheduled measurements, prior to the first dosing of study drug. The first dose date is 
defined as the date of the first dose of study drug. Efficacy and safety assessments will be 
summarized by analysis visit as presented in Table 2 below, excluding Follow-up. 
Table 2 
Analysis Visit Windows 
Analysis Visit Name 
Target Study Day1 
Study Day Interval 
Baseline  
1 
≤1 
Week 2 
15 
2 - 21 
Week 4 
29 
22 – 43 
Week 8 
57 
44 – 71 
Week 12 
85 
72 - 99 
Week 16 
113 
100 – 127 
Follow-up 
141 
128  to maximum 
1 
If the assessment date ≥ first dose date, study day = assessment date - first dose date + 1, otherwise 
study day = assessment date – first dose date. Study day 1 is the day of first dose. 
5.3.1 
Unscheduled Assessments 
Both scheduled and unscheduled assessments, including early termination visits, will be 
considered for planned timepoint summaries, unless noted otherwise. All assessments will be 
presented in data listings. 
5.3.2 
Multiple Measurements within Visit Windows 
If more than one assessment falls within a given window then the assessment closest to the 
target study day will be selected for the by-visit summaries. If two assessments are 
equidistant from the target day then the chronologically last assessment will be used for 
summary. Exceptions may be made for incomplete assessments, in which case, more 
complete assessments may be given priority. If multiple measurements occur on the same day 


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at the same time (or the time is not available), the average of the measurements will be taken. 
Details are provided in a separate programming specifications document. 
For safety summaries where the most extreme post-baseline values should be selected, e.g. 
overall post-baseline minimum and overall post-baseline maximum, all non-missing 
post-Baseline values should be considered, regardless of whether the value is selected for the 
by-visit summaries.  
When replicate ECGs are collect at a given timepoint (typically, in triplicate), the average of 
the replicate values (i.e., PR interval, QRS duration, QT interval, QTcB interval, QTcF 
interval, and RR interval) will be considered as one assessment for the analyses. 
5.3.3 
Data Listings 
All results will be presented in data listings, and the values selected for analysis will be 
marked. 
5.4 
Data Handling Conventions 
5.4.1 
Missing or Incomplete Date for Last Dose of Study Drug 
In the 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 missing last dose date of study drug 
will be imputed using the last expected dosing date which is defined as the minimum of the 
non-missing drug return date of the last dispensed drug kits, the last drug dispensed date plus 
the number of days that the dosing would continue per protocol or the end-of-treatment/early 
termination visit (EOT/ET) date, whichever occurs earlier. For the incomplete last dose date 
of the study drug, the imputation will be compared against the last expected dosing date 
defined as above. Detailed algorithms will be documented in a separate programming 
specifications document. The missing or incomplete dates will be displayed in the data 
listings as reported on the eCRF rather than the imputed dates. 
For data summarizations before final database lock, if a subject is still ongoing, then the 
subject’s last dose date will be imputed using the database cutoff date.  
5.4.2 
Missing or Incomplete Dates for Concomitant or Post-Treatment 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 programming specifications 


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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 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 13.1 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. 
5.4.4 
Missing Severity Assessment for Adverse Events 
If the severity is missing for a treatment-emergent AE, 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 presented in data listings. 
5.4.5 
Missing Relationship to Study Drug for Adverse Events 
If the relationship to study drug is missing for a treatment-emergent AE, 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. 
5.4.6 
Character Values of Clinical Laboratory Variables  
If the reported value of a clinical laboratory variable cannot be used in a summary due to, for 
example, a character string reported for a numeric variable, an appropriately determined 
coded value will be used in the summary. 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 of sites that screened at least 1 subject, number of sites that enrolled at least 
1 subject, number of subjects screened, and number of unique subjects screened will be 
summarized. In addition, the number of subjects enrolled at each site will also be tabulated.  
For enrolled subjects, the number and percentage of subjects in the analysis sets will be 
summarized. A listing will be provided displaying all subjects excluded from the analysis sets 
(if any), and will include reason(s) for exclusion.  


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For subjects who participate in the screening phase and are screen failures, their 
demographics information (including age, sex, ethnicity, and primary race), screen failure 
reasons (the specific inclusion/exclusion criterion [or criteria] not met or other reason), 
informed consent information, and protocol version will be provided in a listing. 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 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.    
Early terminations of subjects due to COVID-19 related reasons will be captured in the 
eCRFs and tabulated. The number and percentage of subjects who completed the study or 
discontinued (all discontinued and by discontinuation reason) will also be summarized for the 
Safety and Full Analysis sets.  
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 will be detailed in the study Protocol Deviation Management Plan. Protocol 
deviations will also be assessed with respect to relationship to COVID-19. 
For Safety subjects, a summary of the number and percentage of subjects with major protocol 
deviations for each deviation category will be presented by relationship to COVID-19 
(overall, COVID-19 related, and non-COVID-19 related). A listing of all protocol deviations 
will also be provided by relationship to COVID-19 (overall, COVID-19 related, and 
non-COVID-19 related).  
8 DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
Demographics and baseline characteristics will be summarized for the Safety and Full 
Analysis sets using descriptive statistics. 
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, body mass index (BMI), childbearing potential, subject/caregiver living situation, and 
caregiver relationship. 
The reported age reflects a subject’s age at the informed consent date. Age and BMI will be 
presented as both continuous and categorical variables. Age categories will be presented as 


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<65, 65 to 74, 75 to 84, and ≥85 years old. BMI categories (kg/m2) will be presented as <25, 
25 to 30, and >30. Race will be categorized as White vs. Non-White. 
8.1 
Baseline Disease Characteristics 
Disease characteristics at Baseline will be summarized for the Safety and Full Analysis sets 
using descriptive statistics. MMSE total score, CGI-S, NPI-Q nighttime behavior (severity 
and distress), MDS-UPDRS Part I total score, and MDS-UPDRS Part II total score, will be 
presented as continuous variables. CGI-S and NPI-Q will also be presented as categorical 
variables using discrete categories. The number and percentage of subjects reporting suicidal 
ideation (within the past 6 months) and suicidal behavior (within the past 12 months) and 
lifetime, and suicidal ideation or behavior since the Screening visit, will be tabulated. 
8.2 
Neuropsychiatric Inventory 
Baseline NPI will summarized for the Safety and Full Analysis sets using descriptive 
statistics. The delusions total score, hallucinations total score, and psychosis total score will 
be presented as continuous variables. In addition, for each of the delusions and hallucinations 
domains the frequency, severity, and distress scores will be presented as categorical variables. 
9 MEDICAL HISTORY 
Medical and surgical history data will be coded using Medical Dictionary for Regulatory 
Activities (MedDRA) version 23.0 or newer. The subject incidence will be summarized for 
each system organ class (SOC) and preferred term for the Safety Analysis Set and Full 
Analysis Set. 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 at Screening will be provided. 
10 PRIOR, CONCOMITANT, AND POST-TREATMENT MEDICATION 
Medications will be coded using WHO Drug Dictionary (WHODRUG-Global-B3) March 
2019 or later. Relationship to COVID-19 will be assessed by the investigator as specified in 
the DMP, Appendix B. 
For medications, the number and percentage of subjects taking each drug class (ATC Level 3) 
and medication preferred term will be tabulated. A subject will be counted only once per drug 
class or per medication preferred term for the summary. Prior, concomitant, and 


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post-treatment medications will be summarized separately using the Safety Analysis Set. 
Concomitant medications will also be summarized by relationship to COVID-19.  
Listings of the prior, concomitant, and post-treatment medications will also be provided. 
Prior medication is defined as any medication with a start and stop date prior to the date of 
the first dose of study drug.  
Concomitant medication is defined as any medication with a start date prior to the date of the 
first dose of study drug and continuing after the first dose of study drug, or with a start date 
between the dates of the first and last doses of study drug, inclusive.  
Post-treatment medication is defined as any medication with a start date after the last dose of 
study drug.  
11 EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE 
Summaries of exposure and compliance to study drug will be provided for the Safety 
Analysis Set using descriptive statistics. 
11.1 Exposure to Treatment 
Pimavanserin dose levels are expressed as free base. 
Duration of pimavanserin exposure (days) for each subject is calculated as follows: 
Duration of exposure = last dose date – first dose date + 1 
The number and percentage of subjects in each of the following categories will be displayed: 
≤2 weeks (1 to 14 days), ≤4 weeks (1 to 28 days), ≤8 weeks (1 to 56 days), ≤12 weeks (1 to 
84 days), and ≤16 weeks (1 to 112 days). An additional category may be added depending on 
the length of maximum exposure. 
11.2 Measurement of Treatment Compliance 
Treatment compliance is defined as the total number of tablets actually taken by a subject 
divided by the number of tablets expected to be taken while on treatment, then multiplied by 
100. The total number of tablets actually taken is calculated by the total number of tablets 
dispensed minus the number of tablets returned. The number of tablets expected to be taken 
is calculated as the duration of exposure multiplied by 2 (the planned number of tablets taken 
per day). If one or more kits are not returned, the tablets expected to be taken will be 
imputed; the details will be provided in the analysis dataset specification document.  


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Treatment compliance will be summarized descriptively as both continuous and categorical 
variables. 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%. 
12 EFFICACY ANALYSES 
All efficacy analyses will be performed using the Full Analysis Set. Descriptive summaries of 
all efficacy endpoints will be provided. No hypothesis testing is planned. 
12.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from Baseline to Week 16 in the mFSQ total 
score. 
12.2 Secondary Efficacy Endpoints 
The secondary efficacy endpoints are the following: 
• Change from Baseline to Week 16 on the Schwab and England ADL Scale (Caregiver 
and Patient version) 
• Change from Baseline to Week 16 on the MDS-UPDRS Parts I total score and 
MDS-UPDRS Part II total score (Caregiver and Patient version) 
• Change from Baseline to Week 16 on the CGI-S score for hallucinations and 
delusions 
• Week 16 CGI-I score for hallucinations and delusions 
• Week 16 PGI-I score for hallucinations and delusions 
12.3 Exploratory Efficacy Endpoints 
The exploratory efficacy endpoints are the following: 
• Change from Baseline to Week 16 on the VRFCAT including adjusted total time 
T-score, total number of errors T-score, and total number of forced progressions 
T-score 
• Change from baseline to Week 16 on the CSI total score 
• Change from Baseline to Week 16 on the NPI-Q Nighttime Behavior Domain 
Severity and Caregiver Distress scores 
• Change from Baseline to Week 16 on the GDS (Short Form) 
• Change from Baseline to Week 16 mFSQ score by subscale 


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• Change from Baseline to Week 16 for each item in MDS-UPDRS Part II 
12.4 Handling of Missing Data 
Scores that are missing, after any imputation of individual missing items as described in 
Section 5.2, will not be imputed. MMRM analyses will be used as the statistical approach for 
handling of missing data. Model parameters are simultaneously estimated using restricted 
maximum likelihood estimation. The MMRM method is unbiased in the estimation of 
treatment effect under the missing at random assumption and can be thought of as attempting 
to estimate the treatment effect that could have been observed if all subjects had continued on 
study for the full study duration. 
12.5 Multiple Comparisons/Multiplicity 
Multiplicity adjustments will not be made as this is an exploratory study and no hypothesis 
testing is planned.  
12.6 Examination of Subgroups 
Selected subgroup analyses may be performed.   
12.7 Analysis of Efficacy Endpoints 
Descriptive statistics for all exploratory efficacy endpoints listed in Section 12.3 will be 
tabulated at scheduled timepoints (excluding Screening).  In addition, descriptive statistics 
may be provided for various subscales and individual scale items. 
12.8 Mixed Model Repeated Measures (MMRM) 
The MMRM method with restricted maximum likelihood estimation (REML) will be used 
for selected efficacy endpoints. The dependent variable will be the change from Baseline. 
The independent variables in the model will include effects for visit, Baseline score, and 
Baseline score-by-visit-interaction. An unstructured covariance matrix will be used to model 
the within patient errors, and the Kenward-Roger approximation will be used to adjust the 
denominator degrees of freedom.  
In the event that the model fails to converge using the unstructured covariance matrix, then 
only descriptive statistics will be presented. 
Summary statistics (observed and change from Baseline, LS means with corresponding 
two-sided 95% confidence intervals (CIs), and p-values will be presented at each 
post-Baseline visit for the Full Analysis Set. The primary comparison is based on the LS 
mean change from Baseline to Week 16.  


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LS mean ± SE from the MMRM model over time for the change from Baseline values will be 
displayed in line plots for the Full Analysis Set.   
The above MMRM model will be used for each of the primary, secondary, and exploratory 
endpoints. CGI-I score will be analyzed using a similar MMRM model with effects for visit, 
Baseline CGI-S score, and Baseline CGI-S score-by-visit interaction. PGI-I score will be 
analyzed using an MMRM model with an effect for visit.  
NPI-Q Caregiver and Distress scores will be summarized in shift tables to determine the 
number and percentage of subjects with Severity scores classified as none, mild, moderate, or 
severe relative to the same classification at the Baseline visit; and the number and percentage 
of subjects with Distress scores classified as not distressing at all, minimal, mild, moderate, 
severe, and extreme or very severe relative to the same classification at the Baseline visit.  
For the by-visit shift summary, the denominator is the number of subjects with non-missing 
values at Baseline and the given visit for the given parameter.  
For each of the continuous efficacy endpoints (except for CGI-I and PGI-I) the null 
hypothesis is that the change from baseline to a certain time-point is equal to 0. The 
corresponding alternative hypothesis is that the change from baseline to a certain endpoint is 
not equal to 0. 
For the CGI-I and PGI-I endpoints the null hypothesis is that the score at a certain time-point 
is equal to 4 (no change); the corresponding alternative hypothesis is that the score at a 
certain time-point is not equal to 4. 
For each of the continuous efficacy endpoints (except for CGI-I and PGI-I), in addition to 
MMRM, a paired t-test using a last observation carried forward imputation method will be 
performed at each post-baseline visit. For CGI-I and PGI-I, a one sample t-test (against a 
value of 4, indicating no change) will be performed instead of the paired t-test. 
Additional exploratory analyses may be conducted on VRFCAT data to adjust for deficits in 
cognition. 
13 SAFETY ANALYSES 
All safety analyses will be performed using the actual treatment for the Safety Analysis Set 
using descriptive statistics.   
13.1 Adverse Events  
All adverse events (AEs) will be coded using MedDRA version 23.0 or higher. 


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An AE (classified by preferred term) will be considered a treatment-emergent AE (TEAE) if 
it started after the first dose of study drug and no later than the last study drug dose date + 30. 
AEs reported on Day 1 based on Baseline (pre-dose) findings (e.g., laboratory test results or 
ECG parameters) will not be considered as TEAEs.   
For the following summaries, the event counts and the number and percentage of subjects 
reporting TEAEs will be tabulated:  
• TEAEs by SOC and preferred term (PT) 
• Most frequently reported TEAEs by SOC and PT 
• TEAEs by PT 
• TEAEs by maximum severity, SOC, and PT 
− 
if more than 1 AE occurs with the same PT for the same subject, the subject 
will be counted only once for that PT using the most severe occurrence 
• TEAEs related to study drug by SOC and PT 
• Treatment-emergent serious adverse events (TESAEs) by SOC and PT 
• TEAEs leading to study drug discontinuation or study termination by SOC and PT 
• AEs with fatal outcome by SOC and PT 
• TEAEs with fatal outcome (that occurred within 30 days of last dose) by SOC and PT 
The relationship of selected AEs to COVID-19 will be assessed as detailed in the DMP, 
Appendix B. COVID-19 related TEAEs will be tabulated separately. 
For tabulations that include SOC and PT the display will be sorted alphabetically by SOC and 
then by descending subject frequency for the PTs within each SOC. SOCs will not be 
included in the TEAEs by PT tabulation. This display will be sorted by descending subject 
frequency. 
An AE listing by subject will display all events, including those which are not treatment-
emergent, and will include the verbatim term in addition to the MedDRA SOC and PT. This 
listing will also include all relevant eCRF data associated with the event: e.g. date of onset, 
date resolved, date of the first and last dose of study drug, 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. Separate listings will 
be presented for subjects with SAEs, subjects with TEAEs leading to study drug 
discontinuation or study termination, subjects who died (if any), and COVID-19 related AEs. 
In these listings, an indicator for TEAEs will also be included. 


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13.2 Other Safety Analyses 
13.2.1 Clinical Laboratory Variables 
Clinical laboratory tests are performed at Screening, Baseline, Week 4, and Week 16/ET 
visits. All laboratory test results are from a central laboratory.  All units will be displayed in 
Système International [SI] units. 
13.2.2 Chemistry 
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 
• Alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl 
transpeptidase (GGT), alkaline phosphatase (ALP), total bilirubin (TBIL), lactate 
dehydrogenase (LDH) 
• Glucose 
• Albumin (ALB), total protein 
• Creatine kinase (CK)/creatine phosphokinase (CPK) 
• Lipid panel 
– total cholesterol, high-density lipoprotein (HDL)-cholesterol, triglycerides, 
LDL-cholesterol, cholesterol/HDL ratio, ratio, non-HDL-cholesterol 
• Magnesium (Mg), Vitamin B12, glycosalated hemoglobin (HbA1c), thyroid 
stimulating hormone (TSH) and free T4 (if TSH is out of range) 
– these tests should only be performed at Screening 
• Serum pregnancy test 
– performed only at Screening for women of childbearing potential 
13.2.3 Hematology 
Hematology tests include the following: 
• Complete blood count (CBC) including: 
− 
White blood cell (WBC) count, complete differential (relative and 
absolute),hematocrit (Hct), hemoglobin (Hgb), red blood cells (RBC), 
platelets, reticulocyte count  


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13.2.4 Urinalysis 
Urinalysis tests include the following: 
• Blood, RBCs, WBCs, leukocyte esterase, protein, glucose, ketones, specific gravity, 
pH 
• A urine pregnancy test will be performed for all women of childbearing potential at 
Baseline and at each scheduled post-baseline visit (except Week 2) 
• A urine toxicity screen will test for controlled substances at screening (and 
Baseline for those subjects enrolled under the original Protocol), and may include 
the following: amphetamine, barbiturates, benzodiazepines, cocaine, methadone, 
morphine/opiates, methamphetamine, marijuana (THC), phencyclidine (PCP), 
ecstasy (3,4-methylenedioxy- methamphetamine [MDMA]). Negative drug 
screens are required for study eligibility. 
13.2.5 Methods of Analysis for Clinical Laboratory Variables 
13.2.5.1 
Observed Values and Change from Baseline 
Clinical laboratory values reported as continuous values for hematology, chemistry and 
urinalysis will be summarized using descriptive statistics at Baseline and post-Baseline visits. 
The change from Baseline values will also be summarized at post-Baseline visits.  
The overall post-Baseline minimum, maximum, and last post-Baseline observed and change 
from Baseline values will also be summarized (for continuous values only).  
For hemoglobin, hematocrit and uric acid, by-visit as well as overall post-Baseline minimum, 
maximum, and last post-Baseline 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 each scheduled post-Baseline visit. For the categorical 
urinalysis by-visit summary, the denominator is the number of subjects with non-missing 
values for the given parameter and visit.  
13.2.5.2 
Shift Tables 
Laboratory values will be summarized in shift tables to determine the number and percentage 
of subjects with values classified as below (low), within (normal), or above (high) normal 
ranges at each scheduled post-Baseline visit relative to the same classification at the Baseline 
visit.  For the by-visit shift summary, the denominator is the number of subjects with 
non-missing values at Baseline and the given visit for the given parameter.  
The shifts from Baseline to overall post-Baseline minimum and maximum will also be 


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presented. The denominator is the number of subjects with non-missing Baseline and at least 
1 post-Baseline value for the given parameter.  
13.2.5.3 
Potentially Clinically Important (PCI) Laboratory Values 
The number and percentage of subjects with PCI laboratory values at scheduled 
post-Baseline visits Week 4 and Week 8 and overall post-Baseline will be summarized by 
Baseline status (all or within normal range) for selected parameters. PCI criteria are listed in 
Table 3 and 
.  Subjects with multiple PCI values for a given parameter will be counted 
only once for that parameter.  All post-Baseline values will be considered, including 
unscheduled and out-of-window values, for the overall post-Baseline visit. 
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 value for the given parameter, and the denominator is the number of 
subjects with at least 1 post-Baseline value for the given parameter. For hemoglobin, 
hematocrit and uric acid, the count and percentage of subjects with PCI values will be 
presented for each gender as well as for both genders combined.   


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Table 3 
Criteria for Potentially Clinically Important 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 (White 
Blood Cell 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 
Lactate 
Dehydrogenase 
(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 
Not 
Applicable 
>1.5 ULN 
umol/L 
Not 
Applicable 
>1.5 ULN 
Triglycerides 
mg/dL 
Not 
Applicable 
>300 
mmol/L 
Not 
Applicable 
>3.39 
Gamma-Glutamyl 
Transferase (GGT) 
U/L 
Not 
Applicable 
≥3 ULN 
U/L 
Not 
Applicable 
≥3 ULN 
 


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Table 4 
Criteria for Potentially Clinically Important Laboratory Values - Urinalysis 
Urinalysis  
(Occult Blood) 
Low PCI Criteria 
High PCI Criteria 
Blood (occult blood) 
Not Applicable 
≥+2 
Protein 
Not Applicable 
≥+2 
Glucose 
Not Applicable 
≥+2 
13.2.5.4 
Data Listings 
All laboratory test results will be listed. The listings will include date and study day of 
collection. Out of range values will be flagged in the data listings (e.g., as ‘L’ or ‘H’). 
A listing of all PCI values will be provided. This listing will include all observations for those 
subjects and parameters for which at least one PCI value was observed. 
The pregnancy results (positive or negative) for female subjects of childbearing potential will 
be presented in a listing. 
13.2.6 Vital Signs and Height, Weight, and BMI 
13.2.6.1 
Vital Signs Variables 
Vital signs will be collected throughout the study, and include body temperature, resting 
respiration rate, sitting or supine systolic and diastolic blood pressure, and pulse rate. Blood 
pressure should be measured after the subject has been sitting or supine for at least 3 minutes.  
13.2.6.2 
Height, Weight, and BMI 
Height and weight will be measured at Screening, Baseline, and Week 16/EOT.  
BMI will be derived as: Weight (kg)/ [height (m)]2. 
13.2.6.3 
Vital Signs Methods of Analysis 
Vital signs will be summarized using descriptive statistics at Baseline and all scheduled 
post-Baseline visits. The change from Baseline values will also be summarized at the 
scheduled post-Baseline visits. The overall post-Baseline minimum, maximum, and last 
post-Baseline observed and change from Baseline values will also be summarized. 
Vital signs and weight values will be considered PCI if they meet the criteria listed in 
Table 5. The number and percentage of subjects with post-Baseline vital signs that are PCI 
will be summarized at scheduled post-Baseline visits and for overall post-Baseline. For the 
overall post-Baseline summaries, all post-Baseline values 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 


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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 
value for the given parameter, and the denominator is the number of subjects with at least 
1 post-Baseline value for the given parameter.   
A listing of all PCI values will be provided. This listing will include all observations for those 
subjects and parameters for which at least one PCI value was observed. 
Table 5 
Criteria for Potentially Clinically Important Vital Signs 
 
Vital Sign Parameter 
 
Unit 
Criteria 
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% 
13.2.7 Electrocardiogram (ECG) 
12-lead ECGs are collected at Screening, Baseline, Week 4, and Week 16. 
All 12-lead ECGs will be complete, standardized recordings. All ECGs will be centrally read; the 
interpretation by the central cardiologist is considered the official interpretation. Each ECG will 
be recorded continuously for 5 minutes. For subjects enrolled under the original Protocol, a 
12-lead ECG was completed in triplicate at Screening, and as a single ECG at other timepoints. 
All tracings will be evaluated by a central reading laboratory. At the Baseline visit the 
machine-read results will also be recorded. ECG data summaries, including the cardiologist’s 
interpretation, will be analyzed using the centrally evaluated data. All data, including the 
machine-read Baseline results, will be listed. 
13.2.7.1 
ECG Variables 
ECG variables include heart rate, PR interval, RR interval, QRS interval, QT interval, and 
QTc intervals. QTc intervals include QTcB (Bazett’s formula) and QTcF (Fridericia’s 
formula). QTcF will also be categorized into the following categories (msec): 


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• Observed: ≤450, 451 to 480, 481 to 500, and >500 
• Change from Baseline: ≤10, 11 to 30, 31 to 60, and >60 
13.2.7.2 
ECG Methods of Analysis 
13.2.7.2.1 
Observed Values and Change from Baseline 
Observed values and the changes from Baseline of ECG variables will be summarized using 
descriptive statistics at Baseline and all scheduled post-Baseline visits. The overall 
post-Baseline minimum, maximum, and last post-Baseline observed and change from 
Baseline values will also be summarized.  
For the QTcF categorical analysis, the number and percentage of subject in each category will 
be summarized at each scheduled visit as well as overall post-Baseline maximum and last 
post-Baseline visit. 
13.2.7.2.2 
PCI Values 
Electrocardiogram values will be considered PCI if they meet or exceed the criteria listed in 
Table 6. The number and percentage of subjects with PCI values will be summarized at each 
scheduled post-Baseline visits and for overall post-Baseline.  
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 value for the given parameter, and the denominator 
is the number of subjects with at least 1 post-Baseline value for the given parameter; all 
post-Baseline values will be considered, including unscheduled and out-of-window values. 
A listing of all subjects with any PCI value will be provided for those parameters for which at 
least 1 PCI value was observed. 
Table 6 
Criteria for Potentially Clinically Important ECG Values 
ECG Parameter 
Unit 
High PCI Criteria 
QRS Interval 
msec 
≥120 
PR Interval 
msec 
≥220 
QTcB or QTcF 
msec 
>500 
QTcB or QTcF: change from baseline 
msec 
>60 
 


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13.2.7.2.3 
Cardiologist Interpretations 
For cardiologist’s interpretations, the number and percentage of subjects with ECG results 
that are determined as normal or abnormal will be summarized at scheduled visits. The 
overall post-baseline worst interpretation will also be summarized (i.e. if a subject has one or 
more ECG results that are considered as abnormal, this subject will be counted in the 
abnormal category). Cardiologist’s interpretations will also be summarized in a shift table to 
determine the number and percentage of subjects with ECG results classified as normal or 
abnormal at scheduled post-Baseline visits relative to the same classification at the Baseline 
visit. The shifts from Baseline to overall post-Baseline worst interpretation will also be 
presented. For the by-visit shift summary, the denominator is the number of subjects with 
non-missing cardiologist’s interpretation at Baseline and the given visit. For the summaries of 
shift from Baseline to the overall post-Baseline worst interpretation, the denominator is the 
number of subjects with non-missing Baseline and at least 1 post-Baseline cardiologist’s 
interpretation.  
13.2.8 Physical Examinations 
A physical examination, including neurological examination (cranial nerves, motor, sensory, 
reflexes, gait, and coordination), will be performed at Screening and Week 16/ET visits.  
Physical and neurological examination results (normal, abnormal, and not done) at Screening 
and Week 16/ET will be summarized in a frequency table by body system and visit. For 
purposes of the PCI analysis, any abnormal result will be considered as PCI. 
13.2.9 C-SSRS 
The C-SSRS will be used to assess suicidal ideations and behaviors. The C-SSRS monitors 
changes in suicidal thinking and behavior over time, in order to determine risk. Four 
constructs are measured: the severity of ideation, the intensity of ideation, behavior, and 
lethality. 
There are 5 questions about suicidal ideation, representing 5 types of suicidal ideation: wish 
to be dead; non-specific active suicidal thoughts; active suicidal ideation with any methods 
(not plan) without intent to act; active suicidal ideation with some intent to act, without 
specific plan; active suicidal ideation with specific plan and intent. If a subject answers “yes” 
to any of these 5 questions, that subject will be counted as having suicidal ideation. 
The C-SSRS will be administered at Screening, Baseline, Weeks 2, 4, 8, 12 and 16/ET. The 
C-SSRS Baseline/Screening version will be used at the Screening visit, and the version 
assessing suicidality since the last visit will be used at all following visits (including the 
Baseline visit). 


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The event counts and the number and percentage of subjects reporting any post-Baseline 
suicidal ideation (wish to be dead; non-specific active suicidal thoughts; active suicidal 
ideation with any methods (not plan) without intent to act; active suicidal ideation with some 
intent to act, without specific plan; active suicidal ideation with specific plan and intent), 
suicidal behavior (preparatory acts or behavior; aborted attempt; interrupted attempt; actual 
attempt; suicide), or suicidality (any suicidal ideation or behavior) will be tabulated. 
The event counts and the number and percentage of subjects reporting any post-Baseline 
non-suicidal self-injurious behavior will also be tabulated. 
For calculating the percentages, the denominator will be the number of subjects with at least 
one post-Baseline C-SSRS. 
14 CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
No pharmacokinetic samples are collected in this study. 
15 INTERIM ANALYSIS 
An efficacy analysis may be performed when 50% of subjects have completed the study or 
terminated early. Additional analyses may be performed as necessary throughout the course 
of the study. 
16 DATA MONITORING/REVIEW COMMITTEE 
There is no data monitoring/review committee for this open-label study. 
17 COMPUTER METHODS  
Statistical analyses will be performed using Version 9.4 (or newer) of SAS software 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. 
18 CHANGES TO ANALYSES SPECIFIED IN PROTOCOL 
No changes are made to the analyses specified in the protocol. 
19 REFERENCES 
Erratum. Journal of General Internal Medicine. 1986; 1: 427. 
FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 
Pandemic. March 2020; updated May 14, 2020. 


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Jette AM, Davies AR, Cleary PD, Calkins DR, Rubenstein LV, Fink A, Kosecoff J, Young RT, 
Brook RH, Delbanco TL. The Functional Status Questionnaire: Reliability and Validity When 
Used in Primary Care. J Gen Intern Med. 1986; 1(3):143-149. 
Tedesco C, Manning S, Lindsay R, Alexander C, Owen R, Smucker ML. Functional 
assessment of elderly patients after percutaneous aortic balloon valvuloplasty: New York 
Heart Association classification versus functional status questionnaire. Heart Lung. 1990; 
19:118-125. 
 


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20 APPENDICES 
20.1 Summary of Version Changes   
Version No: 
Document History 
Description of Update 
Author(s) 
Version Date 
1.0 
Original version 
 
01 March 2022 


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20.2 Schedule of Events and Assessments for ACP-103-063 
Period Screening 
Treatment 
        Baseline 
Safety  
Follow-up 
Visit Week 
-5 to 0 
0 
2 
4 
8 
12 
16/EOT 
20a 
Visit Number 
1 
2 
3 
4 
5 
6 
7/ETb 
8 
Visit window (days) 
 
 
±3 
±3 
±3 
±3 
±3 
+4 
Type of Visit 
clinic 
clinic 
clinic 
clinic 
clinic 
clinic 
clinic 
telephone 
Informed consent of subject 
X 
 
 
 
 
 
 
 
Informed consent of caregiver or study 
partner 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
Medical history and demographics 
X 
 
 
 
 
 
 
 
Weight, height, BMI 
X 
X 
 
 
 
 
X 
 
Physical examination 
X 
 
 
 
 
 
X 
 
12-lead ECGc 
X 
X 
 
X 
 
 
X 
 
Vital signsd 
X 
X 
X 
X 
X 
X 
X 
 
Clinical laboratory tests 
X 
X 
 
X 
 
 
X 
 
Urine drug screen 
X 
 
 
 
 
 
 
 
Pregnancy teste 
X 
X 
 
X 
X 
X 
X 
 
MMSE 
X 
 
 
 
 
 
 
 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
 
FSQ 
X 
X 
 
X 
X 
X 
X 
 
Schwab & England ADL Scale (Patient) 
X 
X 
X 
X 
X 
X 
X 
 
Schwab 
& 
England 
ADL 
Scale 
(Caregiver)  
X 
X 
X 
X 
X 
X 
X 
 
NPI domains A and B 
X 
X 
 
 
 
 
 
 
NPI-Q Nighttime Behavior Domain only 
 
X 
X 
X 
 
X 
X 
X 
 
 


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20.2 
Schedule of Events and Assessments for ACP-103-063 (continued) 
Period Screening 
Treatment 
        Baseline 
Safety  
Follow-up 
Visit Week 
-5 to 0 
0 
2 
4 
8 
12 
16/EOT 
20a 
Visit Number 
1 
2 
3 
4 
5 
6 
7/ETb 
8 
Visit window (days) 
 
 
±3 
±3 
±3 
±3 
±3 
+4 
Type of Visit 
clinic 
clinic 
clinic 
clinic 
clinic 
clinic 
clinic 
telephone 
MDS-UPDRS Parts I and II (Patient) 
X 
X 
X 
X 
 
X 
X 
X 
 
MDS-UPDRS Parts I and II (Caregiver) 
X 
X 
X 
X 
X 
X 
X 
 
CGI-S specific to H&D 
X 
X 
X 
X 
X 
X 
X 
 
CGI-I specific to H&D 
 
 
X 
X 
X 
X 
X 
 
PGI-I specific to H&D 
 
 
X 
X 
X 
X 
X 
 
VRFCAT 
X 
X 
 
X 
 
 
X 
 
Caregiver Strain Index 
X 
X 
X 
X 
X 
X 
X 
 
Geriatric Depression Scale (Short Form) 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of adverse events 
 
X 
X 
X 
X 
X 
X 
X 
Dispense study drug 
 
X 
X 
X 
X 
X 
 
 
Study drug return 
 
 
X 
X 
X 
X 
X 
 
Study drug accountability 
 
 
X 
X 
X 
X 
X 
 
Abbreviations: ADL=activities of daily living; BMI=body mass index; CGI-I=clinical global impression – improvement; CGI-S=clinical global impression – 
severity; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; EOT=end of trial; ET=early termination; FSQ= functional status 
questionnaire; H&D=hallucinations and delusions; MMSE=mini-mental state examination; NPI=neuropsychiatric inventory; NPI-Q=neuropsychiatric inventory 
– questionnaire; PGI-I=patient global impression – improvement; MDS-UPDRS=Movement Disorders Society – Unified Parkinson’s Disease Rating Scale; 
VRFCAT=virtual reality functional capacity assessment tool 
a 
The safety follow-up telephone call visit is to occur 30 (+4) days after the last dose of study drug, nominally at Week 20 for completers and earlier for ET 
subjects. 
b 
A subject terminating early should at a minimum complete assessments of safety (vital signs, ECG, AEs, clinical laboratories, C-SSRS) and, if possible, 
complete all Week 16 assessments. 


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c 
The ECG may be repeated once at Screening in consultation with the Medical Monitor. ECGs can be performed any time before blood sampling or at least 
30 minutes after blood sampling during clinic visits.  
d 
Vital signs (sitting or supine [>3 minutes]) blood pressure, pulse rate, oral temperature, and respiratory rate) will be performed at Screening and each study 
visit. 
e 
Applicable only to women of childbearing potential. A serum pregnancy test is performed at Screening and a urine pregnancy test at Baseline and all 
subsequent visits (except Visit 3 at which neither serum nor urine pregnancy test is performed).