Conditions: Neuropsychiatric Symptoms Related to Neurodegenerative Disease
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 595
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the long-term safety and tolerability of pimavanserin in adult and elderly subjects with neuropsychiatric symptoms related to neurodegenerative disease exposed to open-label pimavanserin for up to 52 weeks.

Detailed description:

Arms:
arm 1: Pimavanserin 34 mg is provided as 2×17 mg tablets as single dose, once daily by mouth. Dose adjustments of pimavanserin down to 20 mg (provided as 2×10 mg tablets as a single dose, once daily by mouth) and up to 34 mg are permitted based on Investigator assessment of clinical response.

Interventions: intervention 1: Pimavanserin
Intervention descriptions: intervention 1: • Pimavanserin 34 mg is provided as 2×17 mg tablets as single dose, once daily by mouth. Dose adjustments of pimavanserin down to 20 mg (provided as 2×10 mg tablets as a single dose, once daily by mouth) and up to 34 mg are permitted based on Investigator assessment of clinical response.

Protocol document:
Prot_000.pdf: 
Official Title: A 52-Week Open-Label Extension Study of Pimavanserin in Adult and 
Elderly Subjects With Neuropsychiatric Symptoms Related to Neurodegenerative 
Disease 
NCT Numbers: NCT03623321 
Document Date: 5 March 2021 


 
 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc. 
Page 1 of 62 
 
 
 
CLINICAL STUDY PROTOCOL 
 
A 52-Week Open-Label Extension Study of Pimavanserin in Adult and 
Elderly Subjects With Neuropsychiatric Symptoms Related to 
Neurodegenerative Disease 
 
Protocol Number: ACP-103-047 
Amendment 4 
EudraCT Number: 2017-004439-36 
 
Original Protocol Date: 16 November 2017 
Protocol Amendment 1 Date: 30 January 2018 
Protocol Amendment 2 Date: 1 May 2018 
Protocol Amendment 3 Date: 23 July 2019 
Protocol Amendment 4 Date: 5 March 2021 
 
 
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-103-047 
 
Final Version: 1.0 
Protocol Amendment 4 
 
Date: 5 March 2021 
 
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SPONSOR SIGNATURE PAGE 
Title: A 52-Week Open-Label Extension Study of Pimavanserin in Adult and Elderly 
Subjects With Neuropsychiatric Symptoms Related to Neurodegenerative Disease 
 
Acadia Head of R&D: 
  
Executive Vice President 
Acadia Pharmaceuticals Inc. 
  
 
  
                                      See electronic signature page     
 
Signature 
 
Date 
 
 
Acadia Study Lead: 
 
Director, Clinical Development 
Acadia Pharmaceuticals Inc. 
 
 
 
                                      See electronic signature page     
 
Signature 
 
Date 
 
 


Study: ACP-103-047 
 
Final Version: 1.0 
Protocol Amendment 4 
 
Date: 5 March 2021 
 
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Page 3 of 62 
Placeholder electronic signature page 


Study: ACP-103-047 
 
Final Version: 1.0 
Protocol Amendment 4 
 
Date: 5 March 2021 
 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc. 
Page 4 of 62 
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 Practice, as required by International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) Guideline E6 and as 
described in United States (US) Code of Federal Regulations (CFR) 21 CFR parts 50, 54, 56, 
and 312, according to applicable local requirements. 
Confidentiality Statement 
The confidential information in this document is provided to you as a Principal Investigator 
or Consultant for review by you, your staff, and the applicable Institutional Review 
Board/Ethics Committee. Your acceptance of this document constitutes agreement that you 
will not disclose the information contained herein to others without written authorization 
from the Sponsor. 
Principal Investigator 
 
 
Signature 
 
Date 
 
 
 
Name (printed) 
 
 
 
 


Study: ACP-103-047 
 
Final Version: 1.0 
Protocol Amendment 4 
 
Date: 5 March 2021 
 
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PROTOCOL SYNOPSIS 
Protocol Number 
ACP-103-047 
EudraCT Number 
2017-004439-36 
Protocol Title 
A 52-Week Open-Label Extension Study of Pimavanserin in Adult 
and Elderly Subjects With Neuropsychiatric Symptoms Related to 
Neurodegenerative Disease 
Name of 
Investigational 
Product 
Pimavanserin 
Phase of 
Development 
3b 
Sponsor 
Acadia Pharmaceuticals Inc. 
 
 
Primary Objective 
• To assess the safety and tolerability of 
long-term pimavanserin treatment in 
adult and elderly subjects with 
neuropsychiatric symptoms related to 
neurodegenerative disease 
Primary Endpoints 
• Treatment emergent adverse events (TEAEs) 
Exploratory Objectives 
The exploratory objectives of this study 
are: 
• to explore the safety and tolerability of 
long-term pimavanserin treatment in 
adult and elderly subjects with 
neuropsychiatric symptoms related to 
neurodegenerative disease on the 
following: 
o suicidality 
o cognition 
o extrapyramidal symptoms 
• to explore the benefit of long-term 
pimavanserin treatment in adult and 
elderly subjects with neuropsychiatric 
symptoms related to neurodegenerative 
disease on: 
Exploratory Endpoints 
Safety and tolerability are described by: 
• Columbia-Suicide Severity Rating Scale 
(C-SSRS) score or Global Clinician 
Assessment of Suicidality (GCAS) scale 
(if the subject is not able to complete the 
C-SSRS in the Investigator’s judgment) 
• Mini-Mental State Examination (MMSE) 
• Extrapyramidal Symptom Rating Scale A 
(ESRS-A) 
 
 
Benefits of long-term pimavanserin treatment 
are described by: 
• Change from Baseline in Clinical Global 
Impression-Severity (CGI-S) score for 
neuropsychiatric symptoms 


Study: ACP-103-047 
 
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Protocol Amendment 4 
 
Date: 5 March 2021 
 
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o clinical global impression of 
neuropsychiatric symptoms 
o quality of life 
o sleep 
• Change from Baseline in 5-level EuroQol 5D 
(EQ-5D-5L) score 
• Change from Baseline in Sleep Disorders 
Inventory (SDI) score 
Number of Study 
Sites 
Approximately 100 global sites will participate in this study. 
Number of Subjects 
Planned 
Approximately 750 male and female adult and elderly subjects   
Test Product, Dose, 
and Administration 
Pimavanserin 20 mg is provided as 2×10 mg tablets and 
pimavanserin 34 mg is provided as 2×17 mg tablets. It is 
recommended that the subject take the study drug at approximately 
the same time each day. Tablets will be administered orally as a 
single dose once daily. 
Study Design 
This study will be a 52-week open-label extension study to evaluate 
the long-term safety and tolerability of pimavanserin in adult and 
elderly subjects with neuropsychiatric symptoms related to 
neurodegenerative disease. 
The study will have two periods (Figure S–1): 
• Open-label treatment period (52 weeks) 
• Safety follow-up (30 [+4] days) 
 
Treatment Period (Baseline through Week 52) 
Eligible subjects will begin pimavanserin once-daily dosing at 
34 mg. 
Dose adjustments of pimavanserin down to 20 mg and up to 34 mg 
are permitted at any study visit (scheduled or unscheduled) after 
Baseline based on Investigator assessment of clinical response. 
During the Treatment period, clinic visits will be conducted at 
Baseline and Weeks 2, 4, 8, 12, 16, 28, 40, and 52 (end of treatment 
[EOT]), or upon early termination (ET) from the study. 
Study drug will be dispensed to the subject to take home at the 
Baseline visit. The subject and study partner/caregiver will be 
provided instructions to take the first dose of study drug on the day 
after the Baseline visit.   
All concomitant permitted medications should remain stable during 
the study but can be adjusted or discontinued, if clinically 
appropriate. These changes should be discussed with the Medical 
Monitor or designee as appropriate. 


Study: ACP-103-047 
 
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Protocol Amendment 4 
 
Date: 5 March 2021 
 
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Safety Follow-up Period (30 Days) 
A safety follow-up telephone call to the subject and study 
partner/caregiver should be conducted 30 (+4) days after the last 
dose of study drug. 
The schedule of assessments is provided in Table S–1. 
Planned Duration of 
Treatment 
The duration of participation for individual study subjects will be 
up to approximately 56 weeks.  
Each subject will participate in a 52-week treatment period 
followed by a safety follow-up period of 30 (+4) days. The end of 
the clinical study will be when the last subject completes the last 
scheduled assessment (i.e., safety follow up). 
The total duration of exposure to pimavanserin may be greater than 
52 weeks as subjects may have been treated with pimavanserin in a 
previous study. 
Main Criteria for 
Inclusion and 
Exclusion 
To be eligible for this study subjects must meet all of the inclusion 
and none of the exclusion criteria below, unless specified 
otherwise:  
Inclusion Criteria: 
1. Subject satisfied all entry criteria for the antecedent 
pimavanserin study 
2. The subject may benefit from longer term therapy with 
open-label pimavanserin treatment in the judgment of the 
Investigator 
3. Subject completed the antecedent study; or was 
participating in a pimavanserin study that the Sponsor ended 
early 
4. Has a designated study partner/caregiver who meets the 
following requirements: 
a. In the Investigator’s opinion, is in contact with the 
subject frequently enough to accurately report on the 
subject’s symptoms and whether or not the subject is 
taking the study drug 
b. In the Investigator’s opinion, is considered reliable 
in providing support to the subject to help ensure 
compliance with study treatment, study visits, and 
protocol procedures 
c. Is fluent in the local language in which study 
assessments will be administered 


Study: ACP-103-047 
 
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Date: 5 March 2021 
 
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d. Agrees to participate in study assessments, has the 
capacity to provide informed consent, and provides 
written consent to participate in the study 
5. Subject can come to the clinic for study visits with a study 
partner/caregiver 
6. Subject is willing and able to provide informed consent. 
Consent for the present study must be obtained prior to the 
final procedures being performed at antecedent study’s EOT 
visit or ET visit (if the study was ended early by the 
Sponsor). If the subject is deemed not competent to provide 
informed consent, the following requirements for consent 
must be met: 
a. The subject’s legally acceptable representative 
(LAR) (or study partner/caregiver, if local 
regulations allow) must provide written informed 
consent 
b. The subject must provide written (if capable) 
informed assent  
7. If the subject is female, she must not be pregnant or 
breastfeeding. She must also be of non-childbearing 
potential (defined as either surgically sterilized or at least 
1 year postmenopausal) or must agree to use a clinically 
acceptable method of contraception or be abstinent during 
the study and 1 month following completion of the study.  
Abstinence as a method of contraception is defined as 
refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatments. This 
option is usually made for a specific moral, religious, legal, 
or health reason. If heterosexual intercourse does occur, an 
acceptable method of birth control is required. 
Acceptable methods of birth control include the following: 
a. Condom, diaphragm, or cervical cap with 
spermicide 
b. Hormonal contraception, including oral, injectable, 
transdermal, or implantable methods 
c. Intrauterine device (IUD) 
 
Exclusion Criteria: 
1. Subject is judged by the Investigator or the Medical 
Monitor to be inappropriate for the study, due to AEs, 
medical condition, or noncompliance with investigational 


Study: ACP-103-047 
 
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Date: 5 March 2021 
 
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product or study procedures in the antecedent study, or is 
judged to be a danger to self or others  
2. Is in hospice, is receiving end-of-life palliative care, or has 
become bedridden 
3. Has any of the following ECG results at the EOT/ET visit 
of the antecedent study:   
a. If the subject is not on citalopram, escitalopram, or 
venlafaxine: 
i. QTcF >450 ms, if QRS duration <120 ms 
ii. QTcF >470 ms, if QRS duration ≥120 ms 
b. If the subject is on citalopram, escitalopram, or 
venlafaxine: 
i. QTcF >425 ms, if QRS duration <120 ms 
ii. QTcF >450 ms, if QRS duration ≥120 ms 
4. Has a heart rate <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 at the 
EOT/ET visit of the antecedent study. 
5. Has a body mass index (BMI) <18.5 kg/m2 or known 
unintentional clinically significant weight loss (i.e., ≥7% of 
body weight) over past 6 months 
6. Has clinically significant laboratory abnormalities in the 
antecedent study that, in the judgment of the Investigator or 
Medical Monitor, would either: 
a. jeopardize the safe participation of the subject in the 
study; OR  
b. would interfere with the conduct or interpretation of 
safety or efficacy evaluations in the study  
7. Is suicidal as defined below at Visit 1 (Baseline) of the 
ACP-103-047 study: 
a. If the subject was assessed in the antecedent study 
using the Columbia-Suicide Severity Rating Scale 
(C-SSRS), he or she must not be actively suicidal at 
Visit 1 (Baseline) (including an answer of “yes” to 
C-SSRS questions 4 or 5) and must not have 
attempted suicide (using the “Since Last Visit” 
version) prior to Visit 1 (Baseline) of the present 
study; OR 
b. If the subject is not able to reliably complete the 
C-SSRS in the Investigator’s judgment or if the 


Study: ACP-103-047 
 
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Global Clinician Assessment of Suicidality (GCAS) 
scale was used in the antecedent study, the subject 
must not be suicidal as assessed by the GCAS score 
(i.e., a score of 3 or 4) based on Investigator’s 
assessment of behavior since-last-visit at Visit 1 
(Baseline); OR 
c. The subject is actively suicidal in the Investigator’s 
judgment 
8. Has developed a neurologic, cardiovascular, respiratory, 
gastrointestinal, renal, hepatic, hematologic, or other 
medical or mental disorder, including cancer or 
malignancies that, in the judgment of the Investigator, 
would increase the risk associated with taking study 
medication or significantly interfere with the conduct or 
interpretation of the study 
9. Requires treatment with a medication or other substance 
that is prohibited by the protocol 
10. Has a significant sensitivity or allergic reaction to 
pimavanserin or its excipients 
11. Is an employee of Acadia, or has a family member who is 
an employee of Acadia 
Sample Size 
Calculations 
Approximately 750 subjects will be enrolled. The sample size for 
this study is not based on statistical power, but will depend on the 
number of subjects who transition into this open-label extension 
study from the antecedent study.   
Statistical Methods 
The purpose of this study is to collect safety data from subjects 
exposed to pimavanserin for up to 52 weeks in this study. 
Exploratory objectives include assessment of efficacy outcome 
measures over time. No statistical testing is planned. 
All endpoints will be summarized for the Safety Analysis Set. 
Additional summaries by prior treatment may be included. 
Descriptive Statistics 
Continuous measurement results will be reported using the number 
of subjects with data values, mean, standard error of the mean, 
median, standard deviation, minimum, and maximum. For each 
categorical outcome, the frequency and percentage of subjects in 
each category will be reported.  
Primary Analyses 
Adverse events will be classified into standard terminology using 
the Medical Dictionary for Regulatory Activities (MedDRA). 


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Adverse events leading to discontinuation, AEs related to study 
drug, AEs by maximum severity, SAEs, and SAEs related to study 
drug will be reported. 
Exploratory Analyses 
For the C-SSRS, the number and percentage of subjects with 
suicidal ideation or suicidal behavior during this study will be 
tabulated. For the GCAS, the number and percentage of subjects 
with a score of 3 or 4 during this study will also be tabulated. 
Descriptive summary statistics for MMSE and ESRS-A observed 
values and change from Baseline will be provided by timepoint. 
Descriptive summary statistics for CGI-S, EQ-5D-5L, and SDI 
observed values and change from Baseline will also be provided by 
timepoint. 
Other Safety Analyses 
Descriptive summary statistics for ECG, vital signs and body 
weight, and clinical laboratory parameters, including observed 
values and changes from Baseline, will be tabulated by timepoint. 
Additionally, categorical analyses will be conducted on the 
incidence of subjects with prolonged QTc intervals and changes in 
QTc intervals in accordance with International Council for 
Harmonisation (ICH) guidelines. 
Date 
5 March 2021 
 


Study: ACP-103-047 
 
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Date: 5 March 2021 
 
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Figure S–1 
Schematic of Study Design for ACP-103-047 
 
 
* Eligible subjects will begin pimavanserin dosing at 34 mg. Dose adjustments of pimavanserin down to 20 mg and up to 34 mg are permitted at any study visit 
(scheduled or unscheduled) after Baseline based on Investigator assessment of clinical response.  
 
 
 
 
 


Study: ACP-103-047 
 
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Table S–1 
Schedule of Assessments for ACP-103-047 
Visit Number 
Baselineb 
Treatment Period 
 
Safety 
Follow-Upk 
1 
2 
3 
4 
5 
6 
7 
8 
(EOT/ET) 
9 
Unscheduled 
Visit 
10 
Visit Weeka 
Week 
0 
Week 
2 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
28 
Week 
40 
Week  
52 
Week 
56 
Type of visit 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Phone call 
Allowable visit window (# days) 
 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
 
+4 
Informed consentb 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
Medical history and demographics 
X 
 
 
 
 
 
 
 
 
 
 
Psychiatric, dementia, and 
neurological history 
X 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
X 
 
X 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ECGc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Clinical laboratory tests 
X 
 
 
 
X 
 
 
 
X 
 
 
Pregnancy testd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Urine drug screen 
X 
 
 
 
X 
 
 
 
X 
 
 
MMSE 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ESRS-A 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRSe or GCASe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CGI-S 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
EQ-5D-5L 
X 
 
 
 
X 
 
X 
 
X 
 
 
Sleep Disorders Inventoryf 
X 
 
 
 
X 
 
X 
 
X 
 
 
Assessment of concomitant 
medications/procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of AEsg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense study drugh 
Xi,j 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Study drug accountability 
Xj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Table footnotes and abbreviations on next page 


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Abbreviations: AE(s)=adverse event(s); CGI-S=Clinical Global Impression-Severity; C-SSRS=Columbia-Suicide Severity Rating Scale; 
ECG=electrocardiogram; EOT/ET=end-of-treatment/early termination; EQ-5D-5L=5-level EuroQol-5D; ESRS-A=Extrapyramidal Symptom Rating Scale -
Abbreviated; GCAS=Global Clinician Assessment of Suicidality; MMSE=Mini-Mental State Examination 
a 
Study visits are designated by weeks and have a ±3-day window (Visits 2 through 5), or a ±7-day window (Visits 6 through 9), or a +4-day window 
(Visit 10) calculated from the Baseline Visit. 
b  
Subject and study partner/caregiver consent for the present study must be obtained for entry into the present study prior to the final procedures being 
performed at the end of treatment (EOT) visit in the antecedent study or early termination (ET) visit (if the study was ended early by the Sponsor). Data from 
the EOT/ET visit procedures of the antecedent study will be carried over as baseline information in the present study, as applicable. 
c 
A single 12-lead ECG can be performed any time before blood sampling or at least 30 minutes after blood sampling during clinic visits. 
d 
A urine pregnancy test may be performed for female study subjects of childbearing potential. If urine cannot be obtained in women of childbearing potential, 
a serum pregnancy test should be done in its place. 
e 
The scale used in the antecedent study should also be used in the ACP-103-047 study. If the subject was previously assessed with the C-SSRS and is no 
longer able to reliably complete the C-SSRS in the Investigator’s judgment, the GCAS should be administered and used thereafter in the present study. 
f 
Appropriate consent/assent needs to be collected before assessment at Baseline.  
g  
All ongoing AEs from the antecedent study will be carried over after informed consent has been obtained for the ACP-103-047 study and recorded from 
Baseline for the present study until resolution or the follow-up safety assessment. AEs occurring after the first dose of open-label study drug until 30 days 
after the last dose of open-label study drug will be recorded as an AE in the ACP-103-047 study. 
h 
Study drug will be dispensed to the subject at either scheduled or unscheduled visits. 
i 
Study drug will be dispensed to the subject to take home at the Baseline visit. The subject and study partner/caregiver will be provided instructions to take 
the first dose of study drug on the following day. 
j 
The used and unused treatment kits, blister cards, and tablets from the antecedent study are to be collected by the Investigator as part of the EOS/ET visit of 
the antecedent study before study drug for the present study can be dispensed. 
k 
This visit is a safety follow-up telephone call visit for subjects who complete the study or who discontinue prematurely from the study. This visit will occur 
30 (+4) days after the last dose of study drug. 
 
 


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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ............................................................................................... 2 
DECLARATION OF INVESTIGATOR ................................................................................... 4 
PROTOCOL SYNOPSIS ........................................................................................................... 5 
TABLE OF CONTENTS ......................................................................................................... 15 
LIST OF TABLES ................................................................................................................... 19 
LIST OF FIGURES ................................................................................................................. 19 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................. 20 
1 
INTRODUCTION .................................................................................................... 21 
1.1 
Background Information ........................................................................................... 21 
1.2 
Investigational Product ............................................................................................. 23 
1.3 
Previous Clinical Experience .................................................................................... 23 
1.4 
Study Rationale ......................................................................................................... 24 
2 
STUDY OBJECTIVES AND ENDPOINTS ............................................................ 24 
2.1 
Primary Objective ..................................................................................................... 24 
2.1.1 
Primary Endpoints .................................................................................................... 24 
2.2 
Exploratory Objectives ............................................................................................. 24 
2.2.1 
Exploratory Endpoints .............................................................................................. 25 
3 
STUDY DESCRIPTION .......................................................................................... 25 
3.1 
Overview of Study Design ........................................................................................ 25 
3.1.1 
Open-label Treatment Period (52 Weeks) ................................................................. 26 
3.1.2 
Safety Follow-up Period (30 Days) .......................................................................... 26 
4 
SUBJECT ELIGIBILITY AND WITHDRAWAL CRITERIA ................................ 26 
4.1 
Subject Selection and Withdrawal ............................................................................ 26 
4.2 
Inclusion Criteria ...................................................................................................... 26 
4.3 
Exclusion Criteria ..................................................................................................... 28 
4.4 
Subject Withdrawal or Termination .......................................................................... 29 
4.4.1 
Handling of Subject Withdrawal or Termination ...................................................... 30 
4.5 
Prior and Concomitant Therapy ................................................................................ 31 
4.5.1 
Prior Medications ...................................................................................................... 31 
4.5.2 
Concomitant Medications ......................................................................................... 31 
4.5.2.1 Permitted, Restricted, and Prohibited Medications .................................................. 31 


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5 
INVESTIGATIONAL PRODUCT ........................................................................... 32 
5.1 
Investigational Product Description.......................................................................... 32 
5.1.1 
Formulation, Appearance, Packaging, and Labeling ................................................ 32 
5.1.2 
Product Storage and Stability ................................................................................... 32 
5.1.3 
Dosing and Administration ....................................................................................... 32 
5.1.4 
Method of Assigning Subject Numbers .................................................................... 33 
5.1.5 
Blinding .................................................................................................................... 33 
5.1.6 
Study Drug Compliance............................................................................................ 33 
5.1.7 
Overdose ................................................................................................................... 33 
5.2 
Investigational Product Accountability Procedures .................................................. 33 
6 
STUDY PROCEDURES .......................................................................................... 34 
6.1 
Baseline Assessments ............................................................................................... 34 
6.1.1 
Medical History and Demographics ......................................................................... 34 
6.1.2 
Psychiatric, Dementia, and Neurological History .................................................... 34 
6.2 
Efficacy Assessments ................................................................................................ 35 
6.2.1 
Clinical Global Impression – Severity Scale ............................................................ 35 
6.2.2 
EQ-5D-5L ................................................................................................................. 35 
6.2.3 
Sleep Disorders Inventory ........................................................................................ 35 
6.3 
Safety Assessments ................................................................................................... 35 
6.3.1 
Physical Examinations .............................................................................................. 35 
6.3.2 
Vital Signs ................................................................................................................. 36 
6.3.3 
Weight ....................................................................................................................... 36 
6.3.4 
Electrocardiograms ................................................................................................... 36 
6.3.5 
Suicidal Ideation and Behavior ................................................................................. 36 
6.3.5.1 Columbia-Suicide Severity Rating Scale .................................................................. 36 
6.3.5.2 Global Clinician Assessment of Suicidality ............................................................. 37 
6.3.6 
Mini-Mental State Examination................................................................................ 37 
6.3.7 
Extrapyramidal Symptom Rating Scale - Abbreviated ............................................. 37 
6.3.8 
Laboratory Evaluations ............................................................................................. 38 
6.4 
Safety Follow-up....................................................................................................... 39 
6.5 
Unscheduled Visits ................................................................................................... 40 
7 
ADVERSE EVENTS ................................................................................................ 40 
7.1 
Adverse Events ......................................................................................................... 40 
7.2 
Specification of Safety Parameters ........................................................................... 40 
7.2.1 
Definition of Adverse Event ..................................................................................... 40 
7.2.2 
Definition of Serious Adverse Event ........................................................................ 41 


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7.3 
Classification of an Adverse Event ........................................................................... 42 
7.3.1 
Severity of Event ...................................................................................................... 42 
7.3.2 
Relationship to Study Drug....................................................................................... 42 
7.3.2.1 Duration .................................................................................................................... 43 
7.3.2.2 Frequency.................................................................................................................. 43 
7.3.2.3 Action Taken with Study Drug ................................................................................. 43 
7.3.2.4 Therapy ..................................................................................................................... 43 
7.3.2.5 Outcome .................................................................................................................... 43 
7.3.2.6 Seriousness................................................................................................................ 44 
7.3.3 
Definition of Unexpectedness ................................................................................... 44 
7.4 
Time Period and Frequency for Event Assessment and Follow-up .......................... 44 
7.5 
Reporting Procedures ................................................................................................ 44 
7.5.1 
Adverse Event Reporting .......................................................................................... 44 
7.5.2 
Serious Adverse Event Reporting ............................................................................. 45 
7.5.3 
Reporting of Pregnancy ............................................................................................ 45 
7.5.4 
Overdose ................................................................................................................... 46 
8 
CLINICAL MONITORING ..................................................................................... 46 
9 
STATISTICAL METHODS AND DATA ANALYSIS ............................................. 46 
9.1 
Statistical and Analytical Plans ................................................................................. 46 
9.2 
Statistical Hypotheses ............................................................................................... 46 
9.3 
Sample Size Determination ...................................................................................... 46 
9.4 
Subject Populations for Analysis .............................................................................. 46 
9.5 
Statistical Analyses ................................................................................................... 46 
9.5.1 
Primary Analyses ...................................................................................................... 47 
9.5.2 
Exploratory Analyses ................................................................................................ 47 
9.5.3 
Other Safety Analyses ............................................................................................... 47 
9.5.3.1 Exposure to Study Drug ............................................................................................ 47 
9.5.3.2 Clinical Laboratory Values ....................................................................................... 47 
9.5.3.3 Vital Signs and Body Weight .................................................................................... 48 
9.5.3.4 Electrocardiograms ................................................................................................... 48 
9.5.3.5 Physical Examinations .............................................................................................. 48 
9.5.4 
Interim Analyses ....................................................................................................... 48 
9.6 
Measures to Minimize Bias ...................................................................................... 48 
9.7 
Breaking the Study Blind/Subject Code ................................................................... 48 
10 
STUDY MANAGEMENT AND DATA COLLECTION ......................................... 48 


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10.1 
Data Collection and Management Responsibilities .................................................. 48 
10.2 
Source Documents .................................................................................................... 49 
10.3 
Case Report Forms.................................................................................................... 49 
10.4 
Confidentiality .......................................................................................................... 49 
10.5 
Study Records Retention .......................................................................................... 49 
10.6 
Protocol Exceptions and Deviations ......................................................................... 50 
10.7 
Protocol Amendments ............................................................................................... 50 
11 
QUALITY MANAGEMENT ................................................................................... 50 
11.1 
Risk Management ..................................................................................................... 50 
11.2 
Quality Control and Quality Assurance .................................................................... 51 
12 
ETHICAL CONSIDERATIONS .............................................................................. 52 
12.1 
Ethical Standard ........................................................................................................ 52 
12.2 
Institutional Review Board/Ethics Committee ......................................................... 52 
12.3 
Informed Consent Process ........................................................................................ 52 
12.3.1 
Consent and Other Informational Documents Provided to Subjects ........................ 53 
12.3.2 
Consent Procedures and Documentation .................................................................. 53 
13 
PUBLICATION PLAN ............................................................................................. 53 
14 
CONFLICT OF INTEREST POLICY ...................................................................... 53 
14.1 
Finance, Insurance, and Indemnity ........................................................................... 53 
15 
LITERATURE REFERENCES ................................................................................ 54 
16 
APPENDICES .......................................................................................................... 57 
Appendix A 
Prohibited and Restricted Medications ............................................................ 57 
Appendix B Prohibited and Restricted Concomitant Medications: Inhibitors and 
Inducers of Cytochrome P450 Enzyme 3A4 .................................................... 61 
 


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LIST OF TABLES 
Table S–1 
Schedule of Assessments for ACP-103-047 .................................................... 13 
Table 1–1 
Prevalence of Delusions and Hallucinations in Dementia, Alzheimer’s 
Disease, Parkinson’s Disease Dementia, and Dementia With Lewy Bodies ... 22 
Table 6–1 
Safety Laboratory Evaluations......................................................................... 39 
 
LIST OF FIGURES 
Figure S–1 
Schematic of Study Design for ACP-103-047 ................................................. 12 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Term 
Definition 
AD 
Alzheimer’s disease 
AE 
adverse event 
CATIE-AD 
Clinical Antipsychotic Trials of Intervention Effectiveness-
Alzheimer's Disease 
CGI-S 
Clinical Global Impression-Severity 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DLB 
dementia with Lewy bodies 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOT 
end of treatment 
EQ-5D-5L 
5-level EuroQol-5D 
ESRS-A 
Extrapyramidal Symptom Rating Scale - Abbreviated 
ET 
early termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GCAS  
Global Clinician Assessment of Suicidality  
ICF 
informed consent form 
ICH 
International Council for Harmonisation  
IRB 
institutional review board 
LAR 
legally acceptable representative 
MMSE 
Mini-Mental State Examination 
PDP 
Parkinson’s disease psychosis 
PR interval 
PR interval of ECG 
QRS interval  
QRS interval of ECG 
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 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SDI 
Sleep Disorders Inventory 
US 
United States 
 


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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 
Neuropsychiatric symptoms, including behavioral symptoms, such as hallucinations, 
delusions, irritability, apathy and agitation, are common in patients with neurodegenerative 
disease. Almost all individuals with dementia exhibit neuropsychiatric symptoms over the 
course of the disease (Steinberg et al. 2008; Lanctot et al. 2017), causing distress for the 
patient and their caregivers, as they are “associated with impairment in activities of daily 
living, poor quality of life, earlier institutionalization, accelerated disease progression, 
increased mortality, caregiver stress, and increased cost of care” (Lanctot et al. 2017). 
Psychosis, apathy, agitation, depression and sleep disturbances are common neuropsychiatric 
symptoms associated with Alzheimer’s disease. The emergence of neuropsychiatric 
symptoms typically occurs in three phases: “(1) irritability, depression, and nighttime 
behavior changes; (2) anxiety, appetite changes, agitation, and apathy; and (3) elation, motor 
disturbances, hallucinations, delusions, and disinhibition” (Masters et al. 2015). 
Psychosis is a common neuropsychiatric symptom in patients with neurodegenerative 
diseases, particularly in patients with dementia associated with neurodegenerative disease. 
Psychotic symptoms are typical of dementia with Lewy bodies (DLB), very common in 
Alzheimer’s disease (AD) and occur, although to a lesser degree, in vascular dementia (VaD) 
and frontotemporal dementia (FTD) (Table 1–1). In one study, 67% of patients with dementia 
had psychotic symptoms (Ballard et al. 1995). It is also a frequent complication of 
Parkinson’s disease patients, with or without dementia. The psychosis in neurodegenerative 
diseases is typically dominated by visual hallucinations, with delusions often consisting of 
the reactions or rationalizations that follow. However, delusions do occur as distinct 
phenomena, often taking the form of misinterpretations of real or imaginary objects, 
delusions of infidelity or abandonment, or beliefs such as thinking that spouses or relatives 
are duplicates of the original person. Among AD patients, delusions are more common than 
hallucinations (Fischer et al. 2016; Ballard et al. 1995) while hallucinations are more 
common in patients with DLB and Parkinson’s disease dementia. Patients with psychosis 
who had a clinical diagnosis of AD are often found on autopsy to have Lewy bodies or 
vascular lesions (Fischer et al. 2016; Kim et al. 2017). 


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Table 1–1 
Prevalence of Delusions and Hallucinations in Dementia, Alzheimer’s 
Disease, Parkinson’s Disease Dementia, and Dementia With Lewy Bodies 
Dementia—prevalence 
Delusions 
60% 
Hallucinations 
20% 
Alzheimer's Disease—prevalence 
Delusions 
36% 
Hallucinations 
18% 
Parkinson's Disease —prevalence 
Hallucinations 
42% 
Visual hallucinations 
15.8-50% 
Delusions 
21% 
Dementia with Lewy Bodies—prevalence 
Hallucinations 
13-92% 
Paranoid delusions 
25-28.6% 
Source: Adapted from Jellinger (2012) 
There is evidence that psychotic features in Parkinson’s disease, AD, and DLB are associated 
with polymorphisms in the serotonergic pathway genes, in particular the 5HTTLPR 
polymorphism in SLA6A4, which codes for the serotonin transporter (Sweet et al. 2001; 
Quaranta et al. 2009; DeMichele-Sweet and Sweet 2010; Creese et al. 2014). This 
observation raises the possibility that there is a common biological link among those 
dementia patients who have psychotic features, regardless of subtype, and provides 
mechanistic support for the finding that pimavanserin, a compound with serotonergic but not 
dopaminergic activity, can have an effect on delusions and hallucinations. 
Treatment of neuropsychiatric symptoms associated with neurodegenerative disease 
represents an area of high unmet need. There are no approved therapies for psychosis 
associated with DLB or AD. A substantial number of these patients receive off-label 
antipsychotic drug treatment to control their symptoms. However, many of these drugs have 
not demonstrated efficacy in controlled trials, worsen patients’ motor symptoms, require 
extensive monitoring, or have other safety concerns. The lack of target engagement in a 
degenerating brain may limit the effectiveness of currently approved treatments, such as 
antidepressants and antipsychotics, for mood and psychotic symptoms (Lanctot et al. 2017). 
The CATIE-AD study concluded that the adverse effects of risperidone, olanzapine, and 
quetiapine limited their overall effectiveness (Schneider et al. 2006). 
Limited options are available for the treatment of neuropsychiatric symptoms in 
neurodegenerative disease. While atypical antipsychotics are sometimes used in clinical 
practice, none are approved in the United States (US) for this use, with the exception of 
pimavanserin which is approved for the treatment of hallucinations and delusions associated 
with Parkinson’s disease psychosis (PDP). In Europe, atypical antipsychotics are generally 


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not approved in this population based on their equivocal efficacy and poor benefit-risk 
assessment, particularly in elderly patients with dementia. In severe cases, limited indications 
exist for some antipsychotics; however, they are restricted to short-term treatment in patients 
with severe and persistent symptoms when non-pharmacological treatments have failed, and 
when there is risk of harm to self or others. For example, risperidone is approved in Canada 
and Europe for short-term treatment of persistent aggression in moderate to severe 
Alzheimer’s disease unresponsive to non-pharmacological approaches and when there is a 
risk of harm to self or others.  
Robust efficacy with pimavanserin was demonstrated without worsening the motor 
symptoms of Parkinson’s disease. In addition, a recently completed Phase 2 study 
(ACP-103-019) in AD psychosis reported statistical superiority of pimavanserin over placebo 
on the primary efficacy endpoint of improvement in psychotic symptoms at Week 6 of 
treatment (Ballard et al. 2018). With its highly targeted and selective receptor binding profile, 
pimavanserin represents a new pharmacologic paradigm to treat psychotic symptoms across 
neurodegenerative diseases. 
1.2 
Investigational Product 
Pimavanserin is an atypical antipsychotic that is present in the investigational product as 
pimavanserin tartrate salt with the chemical name, urea, N-[(4-fluorophenyl)methyl]-N-(1-
methyl-4-piperidinyl)-N’-[[4-(2-methylpropoxy)phenyl]methyl]-,(2R,3R)-2,3-
dihydroxybutanedioate (2:1). In April 2016, pimavanserin was approved in the United States 
for the treatment of hallucinations and delusions associated with PDP. 
Pimavanserin is a novel small molecule designed to specifically block serotoninergic 
neurotransmission mediated by the 5-hydroxytryptamine (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. 
1.3 
Previous Clinical Experience 
Pimavanserin is an atypical antipsychotic that is approved for the treatment of hallucinations 
and delusions associated with PDP. Studies have also been conducted in AD psychosis, 


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schizophrenia, and major depressive disorder. A more complete discussion of these studies, as 
well as the schizophrenia program, is available in the Investigator’s brochure. 
1.4 
Study Rationale 
Pimavanserin is the only atypical antipsychotic approved in the US for the treatment of 
hallucinations and delusions associated with PDP. The safety database supporting the PDP 
development program consisted of >1200 patients and healthy subjects, including >600 PDP 
patients, representing the largest development program in PDP ever conducted. Pimavanserin 
has demonstrated a substantial improvement on measures of psychotic symptoms in patients 
with dementia-related psychosis in two clinical studies. In addition, pimavanserin has a 
selective pharmacology and distinct safety profile compared with other antipsychotics, 
including no detrimental effects on cognitive and motor symptoms and lack of off-target 
toxicities. This safety profile offers the potentially unique and significant advantages over 
currently used antipsychotics in patients with neuropsychiatric symptoms associated with 
neurodegenerative disease. 
ACP-103-047 will further expand the safety database in adult and frail, elderly patients. It 
will enroll patients with prominent neuropsychiatric symptoms (e.g., delusions, hallucination, 
depression/dysphoria, apathy/indifference, disinhibition, irritability/lability, sleep disorder) 
associated with Parkinson’s disease and other neurodegenerative diseases, for whom there are 
no approved antipsychotic therapies. 
2 STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objective 
The primary objective of this study is to assess the safety and tolerability of long-term 
pimavanserin treatment in adult and elderly subjects with neuropsychiatric symptoms related 
to neurodegenerative disease.  
2.1.1 
Primary Endpoints 
The primary safety measure for this study is treatment emergent adverse events (TEAEs). 
2.2 
Exploratory Objectives 
The exploratory objectives of this study are: 
• 
to explore the safety and tolerability of long-term pimavanserin treatment in adult and 
elderly subjects with neuropsychiatric symptoms related to neurodegenerative disease 
on the following: 
o suicidality 
o cognition 


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o extrapyramidal symptoms 
• 
to explore the benefit of long-term pimavanserin treatment in adult and elderly 
subjects with neuropsychiatric symptoms related to neurodegenerative disease on: 
o clinical global impression of neuropsychiatric symptoms 
o quality of life 
o sleep 
2.2.1 
Exploratory Endpoints 
Safety and tolerability are described by: 
• 
Columbia-Suicide Severity Rating Scale (C-SSRS) score or Global Clinician 
Assessment of Suicidality (GCAS) scale (if the subject is not able to complete the 
C-SSRS in the Investigator’s judgment) 
• 
Mini-Mental State Examination (MMSE) 
• 
Extrapyramidal Symptom Rating Scale A (ESRS-A) 
Benefits of long-term pimavanserin treatment are described by: 
• 
Change from Baseline in Clinical Global Impression-Severity (CGI-S) score for 
neuropsychiatric symptoms 
• 
Change from Baseline in 5-level EuroQol 5D (EQ-5D-5L) score 
• 
Change from Baseline in Sleep Disorders Inventory (SDI) score 
3 STUDY DESCRIPTION 
3.1 
Overview of Study Design 
This Phase 3b study will be conducted as a 52-week, open-label extension safety study to 
evaluate the long-term safety and tolerability of pimavanserin in adult and elderly subjects 
with neuropsychiatric symptoms related to neurodegenerative disease. The total duration of 
exposure to pimavanserin may be greater than 52 weeks as subjects may have been treated 
with pimavanserin in a previous study. The duration of participation for individual study 
subjects will be up to approximately 56 weeks. The end of the clinical study will be when the 
last subject completes the last scheduled assessment (i.e., safety follow up). 
Approximately 100 global sites will participate in this study. 
Subject and study partner/caregiver consent for the present study must be obtained prior to 
the final procedures being performed at the antecedent study’s end of treatment (EOT) visit 
or early termination (ET) visit (if the study was ended early by the Sponsor). Data from the 
EOT/ET procedures of the antecedent study will be carried over to the ACP-103-047 study to 


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be included as baseline information for the present study and this visit will be considered 
Baseline (Visit 1). 
The study will have two periods (Figure S–1): 
• 
Open-label treatment period (52 weeks) 
• 
Safety follow-up (30 [+4] days) 
3.1.1 
Open-label Treatment Period (52 Weeks) 
Eligible subjects will begin pimavanserin once-daily dosing at 34 mg. 
Dose adjustments of pimavanserin down to 20 mg and up to 34 mg are permitted at any study 
visit (scheduled or unscheduled) after Baseline based on Investigator assessment of clinical 
response. 
During the Treatment period, clinic visits will be conducted at Baseline and Weeks 2, 4, 8, 
12, 16, 28, 40, and 52 (EOT), or upon early termination from the study. 
Study drug will be dispensed to the subject to take home at the Baseline visit. The subject and 
study partner/caregiver will be provided instructions to take the first dose of study drug on 
the day after the Baseline visit.   
All concomitant permitted medications should remain stable during the study but can be 
adjusted or discontinued, if clinically appropriate. These changes should be discussed with 
the Medical Monitor or designee as appropriate. 
3.1.2 
Safety Follow-up Period (30 Days) 
A safety follow-up telephone call to the subject and study partner/caregiver should be 
conducted 30 (+4) days after the last dose of study drug. 
4 SUBJECT ELIGIBILITY AND WITHDRAWAL CRITERIA 
4.1 
Subject Selection and Withdrawal 
To be eligible for this study subjects must meet all of the inclusion and none of the exclusion 
criteria below, unless specified otherwise. 
4.2 
Inclusion Criteria 
1. Subject satisfied all entry criteria for the antecedent pimavanserin study 
2. The subject may benefit from longer term therapy with open-label pimavanserin 
treatment in the judgment of the Investigator 
3. Subject completed the antecedent study; or was participating in a pimavanserin study 
that the Sponsor ended early 


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4. Has a designated study partner/caregiver who meets the following requirements: 
a. In the Investigator’s opinion, is in contact with the subject frequently enough 
to accurately report on the subject’s symptoms and whether or not the subject 
is taking the study drug 
b. In the Investigator’s opinion, is considered reliable in providing support to the 
subject to help ensure compliance with study treatment, study visits, and 
protocol procedures 
c. Is fluent in the local language in which study assessments will be administered 
d. Agrees to participate in study assessments, has the capacity to provide 
informed consent, and provides written consent to participate in the study 
5. Subject can come to the clinic for study visits with a study partner/caregiver 
6. Subject is willing and able to provide informed consent. Consent for the present study 
must be obtained prior to the final procedures being performed at antecedent study’s 
EOT visit or ET visit (if the study was ended early by the Sponsor). If the subject is 
deemed not competent to provide informed consent, the following requirements must 
be met: 
a. The subject’s legally acceptable representative (LAR) (or study 
partner/caregiver, if local regulations allow) must provide written informed 
consent 
b. The subject must provide written (if capable) informed assent 
7. If the subject is female, she must not be pregnant or breastfeeding. She must also be of 
non-childbearing potential (defined as either surgically sterilized or at least 1 year 
postmenopausal) or must agree to use a clinically acceptable method of contraception 
or be abstinent during the study and 1 month following completion of the study. 
Abstinence as a method of contraception is defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatments. This 
option is usually made for a specific moral, religious, legal, or health reason. If 
heterosexual intercourse does occur, an acceptable method of birth control is required. 
Acceptable methods of birth control include the following: 
a. Condom, diaphragm, or cervical cap with spermicide 
b. Hormonal contraception, including oral, injectable, transdermal, or 
implantable methods 
c. Intrauterine device (IUD) 


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4.3 
Exclusion Criteria 
A subject must meet none of the following exclusion criteria to be eligible for the study: 
1. Subject is judged by the Investigator or the Medical Monitor to be inappropriate for 
the study, due to AEs, medical condition, or noncompliance with investigational 
product or study procedures in the antecedent study, or is judged to be a danger to self 
or others  
2. Is in hospice, is receiving end-of-life palliative care, or has become bedridden 
3. Has any of the following ECG results at the EOT/ET visit of the antecedent study:  
a. If the subject is not on citalopram, escitalopram, or venlafaxine: 
i. QTcF >450 ms, if QRS duration <120 ms 
ii. QTcF >470 ms, if QRS duration ≥120 ms 
b. If the subject is on citalopram, escitalopram, or venlafaxine: 
i. QTcF >425 ms, if QRS duration <120 ms 
ii. QTcF >450 ms, if QRS duration ≥120 ms 
4. Has a heart rate <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 at 
the EOT/ET visit of the antecedent study. 
5. Has a body mass index (BMI) <18.5 kg/m2 or known unintentional clinically 
significant weight loss (i.e., ≥7% of body weight) over past 6 months 
6. Has clinically significant laboratory abnormalities in the antecedent study that, in the 
judgment of the Investigator or Medical Monitor, would either: 
a. jeopardize the safe participation of the subject in the study; OR  
b. would interfere with the conduct or interpretation of safety or efficacy 
evaluations in the study  
7. Is suicidal as defined below at Visit 1 (Baseline) of the ACP-103-047 study: 
a. If the subject was assessed in the antecedent study using the Columbia-Suicide 
Severity Rating Scale (C-SSRS), he or she must not be actively suicidal at 
Visit 1 (Baseline) (including an answer of “yes” to C-SSRS questions 4 or 5) 
and must not have attempted suicide (using the “Since Last Visit” version) 
prior to Visit 1 (Baseline) of the present study; OR 
b. If the subject is not able to reliably complete the C-SSRS in the Investigator’s 
judgment or if the Global Clinician Assessment of Suicidality (GCAS) scale 
was used in the antecedent study, the subject must not be suicidal as assessed 
by the GCAS score (i.e., a score of 3 or 4) based on Investigator’s assessment 
of behavior since-last-visit at Visit 1 (Baseline); OR 


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c. The subject is actively suicidal in the Investigator’s judgment 
8. Has developed a neurologic, cardiovascular, respiratory, gastrointestinal, renal, 
hepatic, hematologic, or other medical or mental disorder, including cancer or 
malignancies that, in the judgment of the Investigator, would increase the risk 
associated with taking study medication or significantly interfere with the conduct or 
interpretation of the study 
9. Requires treatment with a medication or other substance that is prohibited by the 
protocol 
10. Has a significant sensitivity or allergic reaction to pimavanserin or its excipients 
11. Is an employee of Acadia, or has a family member who is an employee of Acadia 
4.4 
Subject Withdrawal or Termination 
In accordance with the Declaration of Helsinki and other applicable regulations, a subject has 
the right to withdraw from the study at any time, and for any reason, without prejudice to his 
or her future medical care. 
If consent has been given by a LAR because the subject is not competent to provide informed 
consent, the LAR has the right to withdraw the subject from the study at any time, and for 
any reason, without prejudice to the subject’s future medical care or any penalty or loss of 
benefits to the LAR. 
The study partner/caregiver has the right to withdraw his or her agreement to participate in 
the study at any time, and for any reason, without prejudice to the subject’s future medical 
care or any penalty or loss of benefits to the study partner/caregiver. If the study 
partner/caregiver withdraws agreement to participate, the subject must be discontinued unless 
another suitable study partner/caregiver is available to sign the agreement to participate. 
Subjects may be discontinued or withdrawn 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 
• Noncompliance with study drug 
• Physician decision 
• Pregnancy 
• Protocol deviation 


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• Study terminated by sponsor 
• Subject (or LAR) withdraws consent 
• Other 
If at any time the C-SSRS or GCAS 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 6.3.5).  
4.4.1 
Handling of Subject Withdrawal or Termination 
Every reasonable effort should be made to complete Visit 9/ET and the safety follow-up 
period if a subject discontinues prematurely from the study for any reason. 
If a subject is lost to follow-up, every reasonable effort should be made to phone the subject 
and study partner/caregiver approximately 4 weeks after last known contact with the subject 
in order to assess the subject’s current status. All phone contact with the subject and study 
partner/caregiver should be documented. 
For subjects who continue to be followed for safety, serious adverse events (SAEs) should 
continue to be reported as described in Section 7.5.2. 
If a subject is discontinued from the study because of an AE, every reasonable attempt should 
be made to follow the subject until the AE resolves or until the Investigator deems the AE to 
be chronic or stable. 
All SAEs will continue to be followed until such events have resolved or the Investigator 
deems them to be chronic or stable. 
Should a subject request or decide to withdraw, every reasonable effort should be made to 
complete and report observations as thoroughly as possible up to the date of withdrawal, 
including the evaluations specified at the ET visit outlined in Table S–1. Unless the subject 
has withdrawn consent to be contacted for this study, every reasonable effort should be made 
to complete the 30-day safety follow-up telephone call for all subjects who withdraw 
prematurely. All information will be reported on the applicable pages of the eCRF. 
The Sponsor reserves the right to discontinue the study at any time for any reason. Such 
reasons may be any of, but not limited to, the following: 
• Occurrence of AEs unknown to date in respect of their nature, severity, and duration 
or the unexpected incidence of known AEs 
• Medical, ethical, or business reasons affecting the continued performance of the study  


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Regulatory authorities also have the right to terminate the conduct of the study in their region 
for any reason. 
4.5 
Prior and Concomitant Therapy 
4.5.1 
Prior Medications 
Prior medications are defined as any medication taken before the date of the first dose of 
study drug. 
4.5.2 
Concomitant Medications 
Concomitant medications are 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). 
4.5.2.1 
Permitted, Restricted, and Prohibited Medications 
Prohibitions and restrictions for concomitant medications should be followed between the 
initial Baseline visit and Visit 9/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. 
Medications that can prolong QT interval are prohibited (or restricted if approved by the 
Medical Monitor) as specified in Appendix A. 
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. 
The Investigator may prescribe, adjust, or discontinue appropriate medication to treat or 
manage AEs. Subjects who require current treatment with a prohibited medication will be 
withdrawn from the study.  
Subjects who have previously taken a prohibited medication during the study will be 
withdrawn from the study unless:  
• the prohibited medication has been discontinued AND   


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• 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 a subject is allowed to remain in the trial, this will be reported as a major protocol 
deviation and not a waiver. 
Permitted concomitant medications should remain at a stable dose throughout the study. 
Benzodiazepines (lorazepam up to 1 mg/day or equivalent) are allowed as rescue medication 
as needed for severe neuropsychiatric or behavioral disturbances (Appendix A). 
5 INVESTIGATIONAL PRODUCT 
5.1 
Investigational Product Description 
The investigational product will be pimavanserin 20 mg (provided as 2×10 mg tablets) or 
pimavanserin 34 mg (provided as 2×17 mg tablets). Tablets will be administered orally as a 
single dose once daily. 
5.1.1 
Formulation, Appearance, Packaging, and Labeling 
The Sponsor will supply pimavanserin 10 mg and 17 mg tablets. 
Pimavanserin tartrate is a white to off-white powder. Pimavanserin tablets include the active 
compound (pimavanserin) and the following excipients: starch, microcrystalline cellulose, 
magnesium stearate, and the tablet coating is 
 
 The drug product 
is formulated with standard pharmaceutical excipients at 10 mg strength (11.8 mg of 
pimavanserin tartrate) and 17 mg strength (20 mg of pimavanserin tartrate). 
Pimavanserin used for the tablets is manufactured under current Good Manufacturing 
Practice. 
During the treatment period, study drug will be supplied in 1 month treatment kits. Kits will 
be distributed in a quantity sufficient to ensure the subject has an adequate supply of study 
drug between study visits. 
5.1.2 
Product Storage and Stability 
Investigational product must be stored between 15°C to 30°C (59°F to 86°F) in a secure area 
with restricted access and according to local and national regulations. 
5.1.3 
Dosing and Administration 
Eligible subjects will begin pimavanserin once-daily dosing at 34 mg. 
Dose adjustments of pimavanserin down to 20 mg and up to 34 mg are permitted at any study 
visit (scheduled or unscheduled) after Baseline based on Investigator assessment of clinical 


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response. The reason for dose titration should be captured in the eCRF. A dose change at a 
time other than at a scheduled clinical visit will require an unscheduled visit to dispense the 
appropriate dose of study drug. Unscheduled visits may occur as needed. 
Study drug will be dispensed to the subject to take home at the Baseline visit. The subject and 
study partner/caregiver will be provided instructions to take the first dose of study drug on 
the day after the Baseline visit. It is recommended that the subject take the study drug at 
approximately the same time each day. 
5.1.4 
Method of Assigning Subject Numbers 
All subjects will receive once daily doses of pimavanserin over 52 weeks of treatment. 
Details of pimavanserin dosing and administration are provided in Section 5.1.3. 
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. 
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 7.5.4). 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 
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 treatment kits, blister cards, and unused tablets to the Investigator at regularly 
scheduled clinic visits and any ET visits. Any study drug supplied is for use in this study only 
and should not be used for any other purpose. 


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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, as allowed by country specific regulations. 
Documentation of study drug destruction will be recorded and maintained by both the 
Sponsor and the Sponsor’s designee. 
6 STUDY PROCEDURES 
6.1 
Baseline Assessments 
Subject and study partner/caregiver consent for the present study must be obtained prior to 
the final procedures being performed at the antecedent study’s EOT or ET visit (if the study 
was ended early by the Sponsor) and before any new procedures are performed for the 
ACP-103-047 study. Data from the EOT/ET procedures of the antecedent study will be 
carried over to the ACP-103-047 study to be included as baseline information for the present 
study and this visit will be considered Baseline (Visit 1). 
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. 
6.1.1 
Medical History and Demographics 
A complete medical and psychiatric history will be obtained from each potential subject at 
Baseline (Visit 1). Demographic information, including date of birth, gender, race, and 
ethnicity (if allowed by local regulations) will be recorded as well. Any new medical 
condition beginning after the informed consent form (ICF) has been signed will be captured 
as an AE. Subjects may be asked to provide pharmacy or medical records to substantiate the 
medication history. 
6.1.2 
Psychiatric, Dementia, and Neurological History 
Details of the subject’s psychiatric, dementia, and neurological history and treatment will be 
collected at Baseline (Visit 1). 


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6.2 
Efficacy Assessments 
6.2.1 
Clinical Global Impression – Severity Scale 
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 condition (Guy 1976). 
The CGI-S will be assessed at Baseline (Visit 1) and at all scheduled and unscheduled visits. 
6.2.2 
EQ-5D-5L 
The EQ-5D-5L is a standardized instrument used as a measure of health outcome 
(Kind 1996). It measures 5 dimensions (mobility, self-care, usual activities, pain/discomfort, 
anxiety/depression) each of which has 5 potential responses. The responses record 5 levels of 
severity (no problems/slight problems/moderate problems/severe problems/extreme 
problems) within a particular EQ-5D dimension. The EQ-5D-5L Proxy version 1 will be 
used. For this version, a study partner/caregiver (the proxy) is asked to rate the subject’s 
health-related quality of life in their (the proxy’s) opinion. 
The EQ-5D-5L will be assessed at Baseline (Visit 1) and at Weeks 12, 28, and 52. 
6.2.3 
Sleep Disorders Inventory 
The Sleep Disorders Inventory (SDI) is an expanded version of one subscale of the 
Neuropsychiatric Inventory (NPI; Tractenberg et al. 2003). It consists of the 7 questions from 
the NPI sleep behavior domain. Each question includes a study partner/caregiver rating of 
frequency, severity, and study partner/caregiver distress with respect to the patient-participant 
sleep behavior for the 2 weeks prior to the visit. Thus, in contrast to a single rating for 
frequency and severity for all sleep disturbance-related behaviors, which would be 
incorporated into an overall NPI score, the SDI total score is derived after the study 
partner/caregiver rates the frequency and severity of each of the 7 separate sleep questions. 
Study partner/caregiver distress ratings are not part of the SDI total score, but distress is 
measured.  
The SDI will be assessed at Baseline and at Weeks 12, 28, and 52. 
6.3 
Safety Assessments 
6.3.1 
Physical Examinations 
A physical examination will be conducted at Baseline and at Weeks 28 and 52. 


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6.3.2 
Vital Signs 
Vital signs will include resting respiration rate, sitting systolic and diastolic blood pressure, 
pulse rate, and temperature and will be performed at all scheduled visits. The sitting blood 
pressure should be measured after the subject has been sitting for ≥3 minutes. 
6.3.3 
Weight  
Weight will be reported (in kilograms) at all scheduled visits. 
6.3.4 
Electrocardiograms 
All 12-lead electrocardiograms (ECGs) will be complete, standardized recordings. A single 
12-lead ECG will be completed at all scheduled visits during the present study (Table S–1). 
All ECGs will be centrally read; the interpretation by the central cardiologist is considered 
the official interpretation. If a site performs additional ECGs beyond the single ECG 
prescribed at Baseline, the mean QTcF/QRS values of all the tracings of adequate quality will 
be used to determine 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 this will not be 
considered a protocol deviation. 
The subject must rest in a supine position before the ECG is obtained. ECG tracings (paper or 
electronic) will be reviewed and interpreted by a qualified clinician. ECG tracings and results 
(heart rate, RR, PR, QRS, QT, QTcF, and QTcB interval duration) will be included and 
summarized in the subject's study records. 
6.3.5 
Suicidal Ideation and Behavior 
6.3.5.1 
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 in subjects who are able 
to reliably complete the assessment, according to the judgment of the Investigator. Whether 
or not the subject can complete the C-SSRS should be documented in the eCRF for each 
subject at each visit. If the subject is not able to complete the C-SSRS, the GCAS should be 
used thereafter in the study to assess suicidality. 
For subjects who completed the Baseline/Screening Version in the antecedent study and are 
still able to complete the C-SSRS assessment in the present study, the Since Last Visit 


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version will be administered at all 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). 
6.3.5.2 
Global Clinician Assessment of Suicidality 
The GCAS is a clinician-rated, 5-point scale that is designed to rate the subject’s suicidality 
based on the report of the subject, the report of the study partner/caregiver, and the clinician’s 
global assessment. Ratings can be 0 (“Absent”), 1 (“Feels life is not worth living”), 
2 (“Wishes he/she were dead or any thoughts of possible death to self”), 3 (“Suicidal ideas or 
gesture”), or 4 (“Attempt at suicide”). The Investigator will record a subject rating, a study 
partner/caregiver rating, and a clinician rating. 
If the GCAS was used in the antecedent study, suicidality since-last-visit will be assessed at 
Visit 1 (Baseline) and at all other visits. 
If the subject is not able to reliably complete the C-SSRS at any point in the study in the 
Investigator’s judgment, the GCAS will be administered and used thereafter in the study. The 
first assessment with the GCAS should assess lifetime suicidality and suicidality for the past 
3 months and at all other visits, suicidality since the previous visit will be assessed.  
As with the C-SSRS, if at any time the GCAS 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). 
6.3.6 
Mini-Mental State Examination 
The Mini-Mental State Examination (MMSE) is a brief 30-point questionnaire that is used to 
quantitatively assess cognition (Folstein et al. 1975). The MMSE includes simple questions 
and problems in a number of areas: the time and place of testing, repeating lists of words, 
arithmetic, language use and comprehension, and copying a drawing. The MMSE is being 
used in this study to screen for cognitive impairment and as a safety measure. 
The MMSE will be administered at all scheduled visits. 
6.3.7 
Extrapyramidal Symptom Rating Scale - Abbreviated 
The Extrapyramidal Symptom Rating Scale (ESRS; Chouinard and Margolese 2005) was 
developed to assess drug induced movement disorders such as parkinsonism, akathisia, 
dystonia, and tardive dyskinesia with established reliability, validity, and sensitivity. It 


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consists of a questionnaire of parkinsonian symptoms, physician examination of 
parkinsonism, dyskinetic movements, and global impression of tardive dyskinesia. The 
ESRS-A, an accepted modified form of the original ESRS, will be used during the study to 
monitor for any worsening in extrapyramidal symptoms or signs at scheduled and 
unscheduled visits. 
6.3.8 
Laboratory Evaluations 
Clinical labs are 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), carbon 
dioxide (CO2), blood urea nitrogen (BUN), creatinine (CR), uric acid 
o Alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), total 
bilirubin (TBIL), lactate dehydrogenase (LDH) 
o Glucose 
o Albumin (ALB), total protein 
o Prolactin 
o Creatine kinase (CK)/creatine phosphokinase (CPK) 
o Lipid panel 
 Total cholesterol, HDL-cholesterol, triglycerides, LDL-cholesterol, very low 
density lipoprotein cholesterol 
Pregnancy test 
o A urine pregnancy test should be performed at all designated visits (Table 6–1) for 
women of childbearing 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 
 Absolute neutrophil 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, leukocyte 
esterase 
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 Subjects who test positive for amphetamines are not eligible to participate in the 
study. Stimulants are prohibited per protocol during the study. 
o Subjects who test positive for benzodiazepines, THC, or opiates may continue in 
the study and last usage should be noted at the study visit. In addition, restrictions 
listed in Appendix A should be followed. 
o Reasonable efforts should be made to collect a urine sample at all scheduled visits 
as described in “Urinalysis” above 
Laboratory evaluations will be completed according to the schedule presented in Table 6–1 
and procedures detailed in the study Manual of Procedures. Additional safety testing may be 
performed at the discretion of the Investigator or designee. 
Table 6–1 
Safety Laboratory Evaluations 
Visit 
Tests 
Visit 1 (Baseline) 
CHEM, CBC, UA, urine toxicity screen, and urine pregnancy 
testa 
Visit 5 (Week 12) and 
Visit 9 (EOT/ET) 
CHEM, CBC, UA, urine toxicity screen 
Weeks 2, 4, 8, 12, 16, 28, 
40, and 52 (EOT/ET) 
Urine pregnancy testa 
Abbreviations: CBC=complete blood count; CHEM=clinical chemistry serum tests; EOT=end of treatment; 
ET=early termination; UA=urinalysis 
a 
To be completed only if female is of childbearing potential. If urine cannot be obtained in women of 
childbearing potential, a serum pregnancy test should be done in its place. 
6.4 
Safety Follow-up 
A 30-day safety follow-up telephone call with the subject and study partner/caregiver is to be 
completed for subjects who complete the study as well as those who discontinue prematurely 
from the study. Subjects should have the following completed 30 (+4) days after last dose of 
study drug: 


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• Assessment of concomitant medications/treatments 
• Assessment of AEs 
6.5 
Unscheduled Visits 
Unscheduled visits may occur as determined by the Investigator. The following assessments 
generally should be recorded at each unscheduled visit: assessment of AEs, assessment of 
concomitant medications/treatments, measurement of vital signs, CGI-S, ESRS-A, C-SSRS 
(Since Last Visit version) or the GCAS if the C-SSRS cannot be completed. The Investigator 
may perform any additional safety evaluations deemed to be clinically indicated. 
7 ADVERSE EVENTS 
7.1 
Adverse Events 
Adverse events occurring after the first dose of open-label study drug in ACP-103-047 until 
safety follow-up assessment (conducted by telephone call) 30 days after the last dose of study 
drug, will be recorded as an AE in the ACP-103-047 study. 
All ongoing AEs from the antecedent study (ACP-103-046) will be carried over and recorded 
from Baseline for the ACP-103-047 study until resolution or the follow-up safety assessment. 
All AEs must be either resolved or stable at end of study. If ongoing at the end of the study, 
the subject should be referred for appropriate treatment. 
7.2 
Specification of Safety Parameters 
7.2.1 
Definition of Adverse Event 
An AE is defined as “any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related” (US FDA 2012). 
An AE can therefore be any unfavorable and unintended sign (e.g., an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a drug, without any 
judgment about causality or seriousness. An AE can arise from any use of the drug 
(e.g., off-label use, use in combination with another drug) and from any route of 
administration, formulation, or dose, including an overdose. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
drug caused the AE. 
AEs do not include the following: 
• Stable or intermittent chronic conditions (such as myopia requiring eyeglasses) that 
are present prior to Baseline of the ACP-103-047 study and do not worsen during the 
study 


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• 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 of the ACP-103-047 study. 
• 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 
7.2.2 
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 
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 


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• 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. 
7.3 
Classification of an Adverse Event 
7.3.1 
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 
7.3.2 
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). 


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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 
7.3.2.1 
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 
7.3.2.2 
Frequency 
The frequency of the AE should be indicated according to the following definitions: 
• Single: Experienced once, without recurrence 
• Recurrent: More than one discrete episode with the same severity 
7.3.2.3 
Action Taken with Study Drug 
• Dose reduced: Dose of study drug reduced 
• Dose not changed: No change in study drug 
• Drug interrupted: Study drug temporarily stopped 
• Drug withdrawn: Study drug discontinued permanently 
7.3.2.4 
Therapy 
• None: No new treatment instituted 
• Medication: New treatment initiated as a direct result of AE 
• Other: Other action required 
7.3.2.5 
Outcome 
• Recovered/resolved: Recovered or resolved 
• Recovered/resolved with sequelae: Recovered or resolved with sequelae 


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• Not recovered/not resolved: Not recovered or not resolved 
• Fatal: Death related to AE 
• Unknown: Unknown 
7.3.2.6 
Seriousness 
• Not serious 
• Serious 
7.3.3 
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. 
7.4 
Time Period and Frequency for Event Assessment and Follow-up 
In the event that a subject is withdrawn from the study because of an AE, the subject should 
be followed and treated by the Investigator until the AE has resolved, stabilized, or a new 
chronic baseline has been established. 
7.5 
Reporting Procedures 
7.5.1 
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. 


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7.5.2 
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/ethics committee (IRB/EC), as per applicable regulations. These 
will be provided by the Sponsor after their assessment. For European Union (EU) member 
states, the Sponsor or its designee will provide reports of suspected unexpected serious 
adverse reactions (SUSARs) directly to the ECs, as required by local legislation. In all other 
countries, it is the Investigator’s responsibility to provide these expedited reports to the 
responsible IRB/EC. It is also the Investigator’s responsibility to notify the responsible 
IRB/EC regarding any new and significant safety information. 
For this study, sites will complete the paper SAE form (for initial and/or follow-up 
information) including available supporting documentation relevant to the event and fax or 
email (within 24 hours of discovery) to the contact information provided on the SAE form. 
Subjects will be followed until EOT/ET for any SAEs and/or other reportable information or 
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 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 after the study Follow-up Period should be reported if in the judgment 
of the Investigator there is “a reasonable possibility” that the event may have been caused by 
the product. 
SAEs should also be reported to the IRB/EC according to local regulations. 
7.5.3 
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 first well-baby visit. 


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Any AEs that are the consequence of pregnancy and which meet the criteria for serious 
should also be reported via the SAE form. 
7.5.4 
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. 
8 CLINICAL MONITORING  
Routine monitoring of study sites is described in Section 11.2. 
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 hypotheses is planned. All outcomes will be summarized descriptively. 
9.3 
Sample Size Determination 
Approximately 750 subjects will be enrolled. The sample size for this study is not based on 
statistical power, but will depend on the number of subjects who transition into this 
open-label extension study from the antecedent study. 
9.4 
Subject Populations for Analysis 
The Safety Analysis Set will consist of all enrolled subjects who have taken at least 1 dose of 
study drug. The Safety Analysis Set will be used for all analyses. 
9.5 
Statistical Analyses 
All endpoints will be summarized for the Safety Analysis Set. Additional summaries by prior 
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Continuous measurement results will be reported using the number of subjects with data 
values, mean, standard error of the mean, median, standard deviation, minimum, and 
maximum. For each categorical outcome, the frequency and percentage of subjects in each 
category will be reported.  
9.5.1 
Primary Analyses 
Adverse events will be classified into standard terminology using the Medical Dictionary for 
Regulatory Activities (MedDRA). All AEs will be listed and summarized by system organ 
class and preferred term. Summaries by maximum severity will also be provided. Adverse 
events leading to discontinuation, AEs related to study drug, SAEs, and fatal AEs will also be 
summarized. 
9.5.2 
Exploratory Analyses 
For the C-SSRS, the number and percentage of subjects with suicidal ideation or suicidal 
behavior during the study will be tabulated. For the GCAS, the number and percentage of 
subjects with a score of 3 or 4 during the study will be tabulated. The number and percentage 
of subjects for each GCAS rating (0-4) will also be tabulated by timepoint and informant 
(subject, study partner/caregiver, and clinician). 
Descriptive summary statistics for MMSE and ESRS-A observed values and change from 
Baseline will be provided by timepoint. 
Descriptive summary statistics for CGI-S, EQ-5D-5L, and SDI observed values and change 
from Baseline will also be provided by timepoint. 
9.5.3 
Other Safety Analyses 
9.5.3.1 
Exposure to Study Drug 
For each subject, the duration of exposure to study drug in this study will be calculated as the 
number of days from first dose date to last dose date inclusive. A categorical summary will 
also be provided using categories defined in the SAP. 
In addition, the maximum dose, final dose, and mean daily dose will be determined for each 
subject and summarized. For maximum dose and final dose, a categorical summary by dose 
level (20 mg and 34 mg) will be provided. For mean daily dose, summary statistics will be 
tabulated. 
9.5.3.2 
Clinical Laboratory Values 
Descriptive statistics for clinical laboratory parameters, including changes from Baseline, 
will be tabulated by timepoint. 


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For selected parameters, the number and percentage of subjects with potentially clinically 
important laboratory values will be summarized by timepoint, as well as across all 
post-Baseline timepoints. The potentially clinically important criteria will be specified in the 
SAP. 
9.5.3.3 
Vital Signs and Body Weight 
Descriptive statistics for vital signs and body weight, including changes from Baseline, will 
be tabulated by timepoint. The number and percentage of subjects with changes from 
Baseline (increases and decreases separately) in body weight of 7% or more will also be 
provided by timepoint. 
9.5.3.4 
Electrocardiograms 
Descriptive statistics for ECG parameters, including changes from Baseline, will be tabulated 
by timepoint. Additionally, categorical analyses will be conducted on the incidence of 
subjects with prolonged QTc intervals and changes in QTc intervals in accordance with 
ICH guidelines. 
9.5.3.5 
Physical Examinations 
The results of the physical examinations will be tabulated by timepoint. 
9.5.4 
Interim Analyses 
One or more interim analyses may be conducted in order to support safety and efficacy 
evaluations for regulatory submissions. 
9.6 
Measures to Minimize Bias 
Not applicable. The present study is open-label. 
9.7 
Breaking the Study Blind/Subject Code 
Not applicable. The present study is open-label. 
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 


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reports that are needed for the evaluation of the study. The Investigator must ensure the 
reliability and availability of source documents from which the information on the eCRF was 
derived. 
10.2 Source Documents 
All study specific information obtained at each study visit must be recorded in the subject’s 
record (source documentation), and then entered into a validated electronic data capture 
(EDC) database by trained site personnel. The source documentation may consist of source 
notes captured by site personnel as well as laboratory reports, ECG reports, and electronic 
source data. 
10.3 Case Report Forms 
Subject data required by this protocol are to be recorded in an EDC system on eCRFs. The 
Investigator and his or her site personnel will be responsible for completing the eCRFs. The 
Investigator is responsible for the accuracy and reliability of all the information recorded on 
the eCRFs. All information requested on the eCRFs needs to be supplied, including subject 
identification data, visit date(s), assessment values, etc., and any omission or discrepancy will 
require explanation. All information on eCRFs must be traceable to source documentation at 
the site. 
10.4 Confidentiality 
The Investigator must ensure that each subject’s anonymity is maintained 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) should 
be kept in strict confidence by the Investigator in compliance with Federal regulations or 
other applicable laws or ICH Guidance on GCP. 
10.5 Study Records Retention 
Investigators are required to maintain all essential study documentation as per ICH GCP 
guidelines. This includes, but is not limited to, copies of signed, dated and completed eCRFs, 
documentation of eCRF corrections, signed ICFs, audio recordings, subject-related source 
documentation, and adequate records for the receipt and disposition of all study drug. 
Investigators should maintain all essential study documentation, for a period of at least 
2 years following the last approval of marketing application in an ICH region (US, Europe, 
and Japan), or until at least 2 years after the drug investigational program is discontinued, 
unless a longer period is required by applicable law or regulation. Only the Sponsor can 


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notify an Investigator or vendor when any records may be discarded. Investigators should 
contact the Sponsor before destroying any files. 
10.6 Protocol Exceptions and Deviations 
No prospective entry criteria protocol deviations are allowed; all subjects must meet all 
eligibility criteria in order to participate in the study. 
Protocol waivers for eligibility will not be granted by the Sponsor under any circumstances. 
If, during the course of a subject’s 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 with a focus on critical processes and critical study data: 
• 
Risk Identification: identification of risks to critical study processes, governing 
systems, investigational product, study design, data collection, and recording. 


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• 
Risk Evaluation: identified risks are evaluated by considering the following factors: 
(a) likelihood of error occurrence, (b) impact on human subject protection and data integrity, 
and (c) detectability of errors. 
• 
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. 
The study will be performed in accordance with US Health Insurance Portability and 
Accountability Act (HIPAA) regulations, US FDA GCP Regulations (US 21 CFR parts 50, 
54, 56, and 312), and ICH Guidance on GCP (E6) and clinical safety data management 
(E2A). 
In accordance with Directive 75/318/EEC, as amended by Directive 91/507/EEC, the final 
clinical study report will be signed by an Investigator and/or Coordinating Investigator who 
will be designated prior to the writing of the clinical study report. 
12.2 Institutional Review Board/Ethics Committee 
The Investigator or designee will provide the IRB/EC with all requisite material, including a 
copy of the protocol, informed consent, and any subject information or advertising materials. 
The study will not be initiated until the IRB/EC provides written approval of the protocol and 
the informed consent and until approved documents have been obtained by the Investigator 
and copies received by the Sponsor. All amendments will be sent to the IRB/EC for 
information (minor amendment) or for submission (major amendment) before 
implementation. The Investigator will supply the IRB/EC and the Sponsor with appropriate 
reports on the progress of this study, including any necessary safety updates, in accordance 
with the applicable government regulations and in agreement with policy established by the 
Sponsor. 
12.3 Informed Consent Process 
Properly executed, written informed consent must be obtained from each subject (or subject’s 
LAR) prior to the final procedures being performed at the EOT visit in the antecedent study. 
The subject’s study partner/caregiver must also provide written agreement prior to any study 
procedures. 
The informed consent must, at a minimum, include the elements of consent described in the 
ICH Guidance on GCP and the US CFR 21 part 50.25. A copy of the ICF planned for use will 
be reviewed by the Sponsor or designee for acceptability and must be submitted by the 
Investigator or designee together with the protocol, to the appropriate IRB/EC for review and 
approval prior to the start of the study at that investigational site. Consent forms must be in a 
language fully comprehensible to the prospective subject. The Investigator must provide the 


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Sponsor or designee with a copy of the IRB/EC letter approving the protocol and the ICF 
before the study drug supplies will be shipped and the study can be initiated. 
The consent form must be revised if new information becomes available during the study that 
may be relevant to the subject. Any revision must be submitted to the appropriate IRB/EC for 
review and approval in advance of use. 
12.3.1 
Consent and Other Informational Documents Provided to Subjects 
The subject (or subject’s LAR) must be given a copy of the signed informed consent/assent 
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 (or LAR) after adequate explanation of the aims, methods, anticipated benefits, and 
potential hazards of the study. The subject (or LAR) must be given ample time to decide 
about study participation and opportunity to inquire about details of the study. The 
IRB/EC-approved consent form must be personally signed and dated by the subject (or LAR 
with subject assent) and by the person who conducted the informed-consent discussion. The 
Investigator or appropriate site personnel must document the details of obtaining informed 
consent/assent, as applicable, 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 caregiver to the subject during the study. The subject’s study partner/caregiver 
must provide written agreement prior to any study procedures being performed indicating 
their agreement to participate in the study in the caregiver role. 
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 
Ballard C, Bannister C, Graham G, Oyebode F, Wilcock, G. Associations of psychotic 
symptoms in dementia sufferers. Br J Psychiatry. 1995;167:537-540. 
Ballard C, Banister C, Khan Z, et al. Evaluation of the safety, tolerability, and efficacy of 
pimavanserin versus placebo in patients with Alzheimer's disease psychosis: a phase 2, 
randomised, placebo-controlled, double-blind study. Lancet Neurol. 2018;17(3):213-222. 
Chouinard G, Margolese HC. Manual for the Extrapyramidal Symptom Rating Scale (ESRS). 
Schizophr Res. 2005;76(2-3):247-265. 
Creese B, Ballard C, Aarsland D, Londos E, Sharp S, Jones E. Determining the association of 
the 5HTTLPR polymorphism with delusions and hallucinations in Lewy body dementias. 
Am J Geriatr Psychiatry. 2014;22(6):580-586. 
DeMichele-Sweet MA, Sweet RA. Genetics of psychosis in Alzheimer disease: a review. 
J Alzheimers Dis. 2010;19(3):761-780. 
Fischer CE, Qian W, Schweizer TA, et al. Lewy bodies, vascular risk factors, and subcortical 
arteriosclerotic leukoencephalopathy, but not Alzheimer pathology, are associated with 
development of psychosis in Alzheimer's disease. J Alzheimers Dis. 2016;50(1):283-295. 
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. 
Guy W. Clinical Global Impression. In: ECDEU Assessment Manual for 
Psychopharmacology – Revised (DHEW publication number ADM 76-338). Rockville, MD: 
US Department of Health, Education, and Welfare. 1976; 218-222. 
Jellinger KA. Cerebral correlates of psychotic syndromes in neurodegenerative diseases. 
J Cell Mol Med. 2012;16(5):995-1012. 
Kim J, Schweizer TA, Fischer CE, Munoz DG. The role of cerebrovascular disease on 
cognitive and functional status and psychosis in severe Alzheimer’s disease. J Alzheimers 
Dis. 2017;55(1):381-389. 
Kind P. The EuroQol instrument: An index of health related quality of life. In: Spiker B, 
ed. Quality of Life and PharmacoEconomics in Clinical Trials. 2nd ed. Philadelphia, PA: 
Lippincott-Raven Publishers; 1996. 
Lanctot KL, Amatniek J, Ancoli-Israel S, et al. Neuropsychiatric signs and symptoms of 
Alzheimer’s disease: New treatment paradigms. Alzheimer’s & Dementia: Translational 
Research & Clinical Interventions. 2017;3(3):440-449. 


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Masters MC, Morris JC, Roe CM. “Noncognitive” symptoms of early Alzheimer disease: 
a longitudinal analysis. Neurology. 2015;84(6):617-622. 
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. 
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. 
Quaranta D, Bizzarro A, Marra C, et al. Psychotic symptoms in Alzheimer's disease and 
5-HTTLPR polymorphism of the serotonin transporter gene: evidence for an association. 
J Alzheimers Dis. 2009;16(1):173-180. 
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. 
Schneider LS, Tariot PN, Dagerman KS, et al. Effectiveness of atypical antipsychotic drugs 
in patients with Alzheimer’s disease. N Engl J Med. 2006;355(15):1525-1538. 
Steinberg M, Shao H, Zandi P, et al. Point and 5-year period prevalence of neuropsychiatric 
symptoms in dementia: the Cache County Study. Int J Geriatr Psychiatry. 2008;23(2):170–
177. 
Sweet RA, Pollock BG, Sukonick DL, et al. The 5-HTTPR polymorphism confers liability to 
a combined phenotype of psychotic and aggressive behavior in Alzheimer disease. 
Int Psychogeriatr. 2001;13(4):401-409. 
Tractenberg RE, Singer CM, Cummings JL, Thai LJ. The Sleep Disorders Inventory: an 
instrument for studies of sleep disturbance in persons with Alzheimer’s disease. J Sleep Res. 
2003;12(4):331-337. 
US Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for 
Industry and Investigators: Safety Reporting Requirements for INDs and BA/BE Studies. 
Rockville, MD: US Dept of Health and Human Services;2012. 
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) 


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carbamide (2R,3R)-dihydroxybutanedioate (2:1) (ACP-103), a novel 5-
hydroxytryptamine(2A) receptor inverse agonist. J Pharmacol Exp Ther. 2006;317(2):910-
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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. 


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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.  
The Investigator may prescribe, adjust, or discontinue appropriate medication to treat or 
manage AEs. Subjects who require current treatment with a prohibited medication will be 
withdrawn from the study.  
Subjects who 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 a subject is 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 
Antipsychotics other 
than pimavanserin 
PROHIBITED 
All in class 
• 
Must be washed out 2 weeks or 5 half-lives 
(whichever is longer) prior to Baseline 
• 
Prohibited throughout the study 
Anticholinergics 
PROHIBITED 
• 
Centrally acting 
anticholinergics 
o 
benztropine 
o 
biperiden 
o 
trihexiphenidyl 
o 
oral 
diphenhydramine 
• 
Anticholinergic medications whose primary 
mechanism of action is centrally acting are 
prohibited and should be washed out and 
discontinued at least 2 weeks or 5 half-lives 
(whichever is longer) prior to Baseline 
UNRESTRICTED 
• 
Peripherally acting 
anticholinergics 
• 
Topical 
diphenhydramine 
• 
Peripherally acting anticholinergic medications 
and topical diphenhydramine are allowed 
without restriction 
Anticonvulsant and 
mood stabilizers 
PROHIBITED 
• 
carbamazepine 
• 
lamotrigine 
• 
lithium 
• 
Must be washed out 5 half-lives prior to Baseline 
• 
Prohibited throughout the study 


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Medication Class 
Medicationa 
Prohibition/restrictions 
• 
phenytoin 
RESTRICTED 
• 
valproate 
• 
Valproate may be used if dose unchanged for at 
least 4 weeks prior to Baseline and dose should 
be expected to remain unchanged until the 
subject’s final visit. 
Antidepressants 
PROHIBITED 
• 
mirtazapine 
• 
nefazadone 
• 
fluvoxamine 
• 
mianserin 
• 
trazodone 
• 
amitriptyline 
• 
nortriptyline 
• 
imipramine 
• 
trimipramine 
• 
desipramine 
• 
clomipramine 
• 
esketamine 
• 
Prohibited throughout the study 
• 
Must be discontinued at least 2 weeks or 5 
half-lives (whichever is longer) prior to the 
Baseline visit 
RESTRICTED 
• 
citalopram 
• 
escitalopram 
• 
venlafaxine 
• 
If subject is remaining on these medications, the 
dose of the permitted antidepressants on the left 
must be unchanged for at least 4 weeks prior to 
Baseline and should be expected to remain 
unchanged until the subject’s final visit. If the 
medication is being discontinued, it must be 
discontinued at least 2 weeks or 5 half-lives 
(whichever is longer) prior to the Baseline visit. 
o 
Citalopram is restricted to a 
maximum dose of 20 mg/day  
o 
Escitalopram is restricted to a 
maximum dose of 10 mg/day  
o 
Venlafaxine is restricted to a 
maximum dose of 225 mg/day 
Anxiolytics 
PROHIBITED 
• 
chlordiazepoxide 
• 
diazepam 
• 
flurazepam 
• 
Prohibited at study entry and throughout the 
study 
RESTRICTED 
• 
alprazolam 
• 
clonazepam 
• 
lorazepam 
• 
oxazepam 
• 
temazepam 
• 
midazolam 
• 
triazolam 
• 
Short- or medium-acting benzodiazepine may be 
used for acute anxiety. Reasonable efforts should 
be made to use minimum dose necessary for 
symptom management. 
o 
Benzodiazepines (lorazepam up to 
1 mg/day or equivalent) are 
allowed as rescue medication as 
needed for severe neuropsychiatric 
or behavioral disturbances. 


Study: ACP-103-047 
 
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Date: 5 March 2021 
 
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Medication Class 
Medicationa 
Prohibition/restrictions 
• 
May not be used within 12 hours prior to an 
assessment visit 
Hypnotics and 
sleeping agents 
PROHIBITED 
• 
zolpidem 
• 
zopiclone 
• 
eszopiclone 
• 
Prohibited at study entry and throughout the 
study 
RESTRICTED 
• 
zaleplon 
• 
ramelteon 
• 
May not be used within 12 hours of a cognitive 
assessment, and efforts should be made to limit 
agents to lowest dose for the shortest time 
needed. 
Stimulants and wake-
promoting agents 
PROHIBITED 
• 
methylphenidate 
• 
modafinil 
• 
armodafinil 
• 
amphetamine 
• 
Prohibited at study entry and throughout the 
study  
Non-stimulant 
ADHD medications 
PROHIBITED 
• 
atomoxetine 
• 
Prohibited at study entry and throughout the 
study 
Serotonin antagonists  PROHIBITED 
• 
cyproheptadine 
• 
Prohibited throughout the study 
• 
Must be discontinued at least 3 weeks prior to 
the Baseline visit 
Antiarrhythmic drugs 
PROHIBITED 
• 
ajmaline 
• 
amakalant, semantilide 
• 
amiodarone 
• 
bretylium 
• 
disopyramide 
• 
dofetilide 
• 
dronedarone 
• 
flecainide 
• 
ibutilide 
• 
procainamide 
• 
propafenone 
• 
quinidine 
• 
sotalol, d-sotalol 
• 
Prohibited at study entry and throughout the 
study 
Opioids 
PROHIBITED 
• 
methadone 
• 
Prohibited at study entry and throughout the 
study 
Antimicrobials, 
antifungals, and 
antimalarials 
PROHIBITED 
• 
clarithromycin 
• 
erythromycin 
• 
levofloxacin 
• 
moxifloxacin 
• 
pentamidine 
• 
Prohibited at study entry and throughout the 
study 


Study: ACP-103-047 
 
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Date: 5 March 2021 
 
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Medication Class 
Medicationa 
Prohibition/restrictions 
• 
roxithromycin 
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.  
The Investigator may prescribe, adjust, or discontinue appropriate medication to treat or 
manage AEs. Subjects who require current treatment with a prohibited medication will be 
withdrawn from the study.  
Subjects who 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 a subject is allowed to remain in the trial, 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, whichever is 
longer, prior to the administration of study drug. Strong inducers of CYP3A4 are to be 
stopped 30 days or 5 half-lives, whichever is longer, prior to the administration of study drug.  
Moderate inhibitors and inducers of CYP3A4 may be allowed but should be used with 
caution. 
STRONG 
INHIBITORS 
grapefruit juice a  
boceprevir (Victrelis®) 
clarithromycin (Biaxin®)  
cobicistat (part of Stribild®) 
conivaptan (Vaprisol®) 
fluvoxamine (Luvox®) 
indinavir (Crixivan®)  
itraconazole (Sporanox®)  
ketoconazole (Nizoral®)  
lopinavir and Ritonavir (Kaletra®) 
mibefradil (Posicor®) 
nefazodone (Serzone®)  
MODERATE 
INHIBITORS 
grapefruit juice a 
amprenavir (Agenerase®) 
aprepitant (Emend®) 
atazanavir (Reyataz®) 
ciprofloxacin (Cipro®) 
darunavir/ritonavir 
(Prezista®/ritonavir) 
diltiazem 
erythromycin (Erythrocin® 
lactobionate) 
fluconazole (Diflucan®) 
fosamprenavir (Lexiva®) 


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Date: 5 March 2021 
 
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STRONG 
INHIBITORS 
(continued) 
nelfinavir (Viracept®)  
posaconazole (Noxafil®) 
quinupristin (Synercid®) 
ritonavir (Norvir®, part of Viekira 
Pak™)  
saquinavir (Invirase®)  
telaprevir (Incivek®) 
telithromycin (Ketek®)  
voriconazole (Vfend®) 
 
imatinib (Gleevec®) 
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 52-Week Open-Label Extension Study of Pimavanserin in Adult and 
Elderly Subjects With Neuropsychiatric Symptoms Related to Neurodegenerative 
Disease 
NCT Numbers: NCT03623321 
Document Date: 8 March 2021 
 


 
 
STATISTICAL ANALYSIS PLAN 
 
Protocol No.: 
ACP-103-047 
Protocol Title:  
A 52-Week Open-Label Extension Study of 
Pimavanserin in Adult and Elderly Subjects With 
Neuropsychiatric Symptoms Related to 
Neurodegenerative Disease 
Drug: 
Pimavanserin 
Sponsor:  
Acadia Pharmaceuticals Inc. 
 
Version No. and Date: 
Version 3.0, 08 March 2021 
 
 
 
 
 
 
 
 
 
 
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Protocol ACP-103-047 
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SIGNATURE/APPROVAL PAGE 
AUTHOR 
 
_____________________________________________ 
____________ 
 
Date 
Director, Biostatistics  
Acadia Pharmaceuticals Inc. 
 
 
APPROVERS 
 
_____________________________________________ 
____________ 
 
Date 
Vice President, Biometrics 
Acadia Pharmaceuticals Inc. 
 
 
 
 
 
 


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PLACEHOLDER FOR 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 ......................................................................................................... 9 
2 
OBJECTIVES ................................................................................................................ 9 
2.1 
Primary Objective ............................................................................................................ 9 
2.1.1 
Primary Endpoint ......................................................................................................... 9 
2.2 
Secondary Objectives ...................................................................................................... 9 
2.2.1 
Secondary Endpoints ................................................................................................... 9 
2.3 
Exploratory Objectives .................................................................................................... 9 
2.3.1 
Exploratory Endpoints ............................................................................................... 10 
3 
STUDY DESIGN ......................................................................................................... 10 
3.1 
General Study Design .................................................................................................... 10 
3.2 
Schedule of Assessments ............................................................................................... 13 
3.3 
Randomization ............................................................................................................... 17 
3.4 
Blinding ......................................................................................................................... 17 
3.5 
Determination of Sample Size ....................................................................................... 17 
3.6 
Coronavirus Disease 2019 ............................................................................................. 17 
4 
ANALYSIS SETS ........................................................................................................ 17 
4.1 
Enrolled Subjects ........................................................................................................... 17 
4.2 
Safety Analysis Set ........................................................................................................ 17 
5 
DATA HANDLING CONVENTIONS ........................................................................ 17 
5.1 
General Data Reporting Conventions ............................................................................ 17 
5.2 
Treatment Cohorts ......................................................................................................... 18 
5.3 
Derived Variables........................................................................................................... 18 
5.3.1 
CGI-S ......................................................................................................................... 19 
5.3.2 
EQ-5D-5L Proxy Version 1 ....................................................................................... 19 
5.3.3 
SDI ............................................................................................................................. 19 
5.3.4 
C-SSRS ...................................................................................................................... 20 
5.3.5 
GCAS ......................................................................................................................... 21 
5.3.6 
ESRS-A ..................................................................................................................... 21 


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5.3.7 
MMSE ....................................................................................................................... 22 
5.4 
Analysis Visit Windows ................................................................................................. 23 
5.4.1 
Unscheduled Assessments ......................................................................................... 23 
5.4.2 
Multiple Measurements within Visit Windows ......................................................... 24 
5.5 
Data Handling Conventions........................................................................................... 24 
5.5.1 
Missing or Incomplete Date for Last Dose of Study Drug ........................................ 24 
5.5.2 
Missing or Incomplete Dates for Concomitant or Post-Treatment Medications ....... 24 
5.5.3 
Missing or Incomplete Dates for Adverse Events ..................................................... 25 
5.5.4 
Missing Severity Assessment for Adverse Events ..................................................... 25 
5.5.5 
Missing Relationship to Study Drug for Adverse Events .......................................... 25 
5.5.6 
Character Values of Clinical Laboratory Variables.................................................... 25 
6 
SUBJECT ENROLLMENT and DISPOSITION ........................................................ 25 
7 
PROTOCOL DEVIATIONS ........................................................................................ 26 
8 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS .................... 26 
8.1 
Demographics ................................................................................................................ 26 
8.2 
Disease Characteristics and Neuropsychiatric History .................................................. 26 
9 
MEDICAL HISTORY ................................................................................................. 27 
10 
CONCOMITANT AND POST-TREATMENT MEDICATION ................................. 27 
10.1 Concomitant Medication ............................................................................................... 27 
10.2 Post-Treatment Medication ........................................................................................... 28 
10.3 COVID-19 Related Medications ................................................................................... 28 
11 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE ............................. 28 
11.1 Exposure to Study drug ................................................................................................. 28 
11.1.1 
Exposure to OL pimavanserin ................................................................................... 28 
11.1.2 
Total exposure to double-blind and OL pimavanserin ............................................... 29 
11.2 Measurement of Study Drug Compliance ..................................................................... 30 
12 
EFFICACY ANALYSES ............................................................................................. 30 
12.1 Exploratory Efficacy Endpoints .................................................................................... 30 
12.2 Adjustment for Covariates ............................................................................................. 30 
12.3 Handling of Missing Data .............................................................................................. 30 
12.4 Multiple Comparisons / Multiplicity ............................................................................. 30 
13 
METHODS OF EFFICACY ANALYSES .................................................................. 30 
13.1 Analysis of Efficacy Endpoints ..................................................................................... 30 


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13.1.1 
EQ-5D-5L .................................................................................................................. 31 
14 
SAFETY ANALYSES ................................................................................................. 32 
14.1 Adverse Events .............................................................................................................. 33 
14.1.1 
Assessment of the Impact of COVID-19 on Adverse Events .................................... 34 
14.2 Clinical Laboratory Variables ........................................................................................ 35 
14.2.1 
Chemistry ................................................................................................................... 35 
14.2.2 
Miscellaneous ............................................................................................................ 35 
14.2.3 
Hematology ............................................................................................................... 35 
14.2.4 
Urinalysis ................................................................................................................... 36 
14.2.5 
Methods of Analysis for Clinical Laboratory Variables ............................................ 36 
14.3 Vital Signs ...................................................................................................................... 39 
14.3.1 
Vital Signs Variables .................................................................................................. 39 
14.3.2 
Vital Signs Methods of Analysis ............................................................................... 39 
14.4 Electrocardiogram (ECG) .............................................................................................. 40 
14.4.1 
ECG Variables ........................................................................................................... 41 
14.4.2 
ECG Methods of Analysis ......................................................................................... 41 
14.5 Physical Examination .................................................................................................... 42 
14.6 Other Safety Variables ................................................................................................... 42 
14.6.1 
ESRS-A ..................................................................................................................... 42 
14.6.2 
MMSE ....................................................................................................................... 43 
14.6.3 
Suicidality .................................................................................................................. 43 
15 
CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES .. 44 
16 
INTERIM ANALYSIS ................................................................................................. 44 
16.1 Interim Analyses ............................................................................................................ 44 
17 
DATA MONITORING/REVIEW COMMITTEE ....................................................... 44 
18 
COMPUTER METHODS ........................................................................................... 44 
19 
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL ....................................... 45 
20 
REFERENCES ............................................................................................................ 46 
21 
APPENDICES ............................................................................................................. 47 
21.1 Summary of Version Changes ....................................................................................... 47 
 


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LIST OF TABLES 
Table 1 
Schedule of Events and Assessments for ACP-103-047 .................................. 14 
Table 2 
Analysis Visit Windows ................................................................................... 23 
Table 3 
Scheduled Assessment Timepoints for Efficacy Endpoints Across ACP-
103-046 (DB) and ACP-103-047 (OL) ............................................................ 31 
Table 4 
Scheduled Assessment Timepoints for Safety Endpoints Across ACP-103-
046 (DB) and ACP-103-047 (OL) ................................................................... 33 
Table 5 
Criteria for Potentially Clinically Important Laboratory Values – 
Hematology and Chemistry ............................................................................. 38 
Table 6 
Criteria for Potentially Clinically Important Laboratory Values - 
Urinalysis ......................................................................................................... 39 
Table 7 
Criteria for Potentially Clinically Important Vital Signs ................................. 40 
Table 8 
Criteria for Potentially Clinically Important ECG Values ............................... 41 
 
LIST OF FIGURES 
Figure 1 Schematic of Study Design ....................................................................................... 12 
 


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ABBREVIATIONS 
AE 
adverse event 
ATC 
Anatomical Therapeutic Chemical 
BMI 
body mass index 
CGI-S 
Clinical Global Impression Scale – Severity 
COVID-19 
coronavirus disease 2019 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DB 
double-blind 
DMP 
Data Management Plan 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOT 
end-of-treatment 
EQ-5D-5L 
5-level EuroQoL-5D 
ESRS-A 
Extrapyramidal Symptom Rating Scale-Abbreviated 
ET 
early termination 
GCAS 
Global Clinical Assessment of Suicidality 
IA 
interim analysis 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMSE 
Mini-Mental State Examination 
Msec 
Milliseconds 
NPI 
Neuropsychiatric Inventory 
OL 
open-label 
PCHC 
Pareto Classification of Health Change 
PCI 
potentially clinically important 
PT 
preferred term 
QTcB 
QT interval corrected for heart rate using Bazett’s formula 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
SAE 
serious adverse event 
SD 
standard deviation 
SDI 
Sleep Disorders Inventory 
SE 
standard error 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
VAS 
visual analogue scale 


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1 INTRODUCTION 
This statistical analysis plan provides a technical and detailed elaboration of the statistical 
analyses of efficacy and safety data as described in the study protocol amendment 4 dated 
05 March 2021. Specifications for tables, figures, and listings are contained in a separate 
document. 
For the Czech republic, a country-specific protocol amendment (Amendment 4-CZ dated 
23 July 2019) specified additional supervision requirements for subjects with mild, moderate, 
or severe dementia; added exclusion criteria for tachycardia and blood pressure 
measurements; and added temperature to list of vital signs assessments. 
For Bulgaria, a country-specific protocol amendment (Amendment 3-BG dated 23 July 2019) 
specified that the designated study partner/caregiver must be in daily contact with the subject. 
This Amendment also added further details regarding the definitions of prior and concomitant 
therapies, and clarified the Investigator’s options for the use of concomitant medications. 
2 OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to assess the safety and tolerability of long-term 
pimavanserin treatment in adult and elderly subjects with neuropsychiatric symptoms related 
to neurodegenerative disease. 
2.1.1 
Primary Endpoint 
The primary safety measure for this study is treatment-emergent adverse events (TEAEs). 
2.2 
Secondary Objectives 
Not applicable. 
2.2.1 
Secondary Endpoints 
Not applicable. 
2.3 
Exploratory Objectives 
The exploratory objectives of this study are: 
• to explore the safety and tolerability of long-term pimavanserin treatment in adult and 
elderly subjects with neuropsychiatric symptoms related to neurodegenerative disease 
on the following: 
o suicidality 


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o cognition 
o extrapyramidal symptoms 
• to explore the benefit of long-term pimavanserin treatment in adult and elderly 
subjects with neuropsychiatric symptoms related to neurodegenerative disease on  
o clinical global impression of neuropsychiatric symptoms 
o quality of life 
o sleep 
2.3.1 
Exploratory Endpoints 
The exploratory endpoints to assess the safety and tolerability of long-term treatment 
pimavanserin are described by: 
• Columbia-Suicide Severity Rating Scale (C-SSRS) or Global Clinician Assessment of 
Suicidality (GCAS) scale (if the subject is not able to complete the C-SSRS in the 
Investigator’s judgement) 
• Mini-Mental State Examination (MMSE) 
• Extrapyramidal Symptom Rating Scale-Abbreviated (ESRS-A) 
Benefits of long-term pimavanserin treatment are described by: 
• Change from Baseline in Clinical Global Impression-Severity (CGI-S) score for 
neuropsychiatric symptoms 
• Change from Baseline in the 5-level EuroQol 5D (EQ-5D-5L) score  
• Change from Baseline in Sleep Disorder Inventory (SDI) score 
3 STUDY DESIGN 
3.1 
General Study Design 
The ACP-103-047 study is a Phase 3b, open-label (OL) extension study to evaluate the 
long-term safety and tolerability of pimavanserin in adult and elderly subjects with 
neuropsychiatric symptoms related to neurodegenerative disease.  This study will be 
conducted as a 52-week OL extension of the ACP-103-046 study (antecedent study), 
consisting of two periods: a 52 week OL treatment period, and a 4 week safety follow-up 
period. The total duration of exposure to pimavanserin may be greater than 52 weeks as 
subjects may have been treated with pimavanserin in the antecedent study.  Approximately 
100  global sites will participate in this study. 


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Eligible subjects will be those subjects who completed the ACP-103-046 study and, in the 
Investigator’s judgement, may continue to benefit from longer term therapy with 
pimavanserin. Subject and study partner/caregiver consent for the present study must be 
obtained prior to the final procedures being performed at the antecedent study’s end of 
treatment (EOT or early termination (ET) visit (if the study was ended early by the Sponsor). 
Data from the EOT/ET procedures of the antecedent study will be transferred over to the 
ACP-103-047 study for inclusion as baseline information, and this antecedent EOT visit will 
be considered the Baseline visit (Visit 1). 
Eligible subjects will receive once daily doses of pimavanserin during the treatment period, 
starting with 34 mg of pimavanserin at the Baseline visit. Dose adjustments of pimavanserin 
down to 20 mg and up to 34 mg are permitted at any study visit (scheduled or unscheduled) 
after Baseline. 
During the Treatment Period, clinic visits will be conducted at Baseline and Weeks 2, 4, 8, 
12, 16, 28, 40 and 52 (EOT), or upon ET from the study. 
Study drug will be dispensed to the subject to take home at the Baseline visit and at each 
subsequent visit (with the exception of Week 52).  The subject and their study 
partner/caregiver will be provided instructions to take the first dose of study drug on the day 
after the Baseline visit.   It is recommended that the subject take the study drug at 
approximately the same time each day as a single, oral dose.   
All concomitant permitted medications should remain stable during the study but can be 
adjusted or discontinued, if clinically appropriate. These changes should be discussed with 
the Medical Monitor or designee as appropriate.  
A safety follow-up  telephone call  to the subject and study partner/caregiver should at 30 (+4) 
days after the last dose of study drug. 
 
Figure 1 illustrates the study design. 


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Figure 1 Schematic of Study Design 
 
* Eligible subjects will begin pimavanserin dosing at 34 mg. Dose adjustments of pimavanserin down to 20 mg and up to 34 mg are permitted at any study visit 
(scheduled or unscheduled) after Baseline based on Investigator assessment of clinical response. 
 
 


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3.2 
Schedule of Assessments 
The schedule of events and assessments for the study is presented in Table 1. 


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Table 1 
Schedule of Events and Assessments for ACP-103-047 
 
Visit Number 
Baselineb 
Treatment Period 
 
Follow-
Upk 
1 
2 
3 
4 
5 
6 
7 
8 
(EOT/ET) 
9 
Unscheduled 
Visit 
10 
Visit Weeka 
Week 
0 
Week 
2 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
28 
Week 
40 
Week  
52 
Week 
56 
Type of visit 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Phone call 
Allowable visit window (# days) 
 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
 
+4 
Informed consentb 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
Medical history and demographics 
X 
 
 
 
 
 
 
 
 
 
 
Psychiatric, dementia, and 
neurological history 
X 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
X 
 
X 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ECGc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Clinical laboratory tests 
X 
 
 
 
X 
 
 
 
X 
 
 
Pregnancy testd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Urine drug screen 
X 
 
 
 
X 
 
 
 
X 
 
 
MMSE 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ESRS-A 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRSe or GCASe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CGI-S 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
EQ-5D-5L 
X 
 
 
 
X 
 
X 
 
X 
 
 
Sleep Disorders Inventoryf 
X 
 
 
 
X 
 
X 
 
X 
 
 
Assessment of concomitant 
medications/procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Visit Number 
Baselineb 
Treatment Period 
 
Follow-
Upk 
1 
2 
3 
4 
5 
6 
7 
8 
(EOT/ET) 
9 
Unscheduled 
Visit 
10 
Visit Weeka 
Week 
0 
Week 
2 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
28 
Week 
40 
Week  
52 
Week 
56 
Type of visit 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Phone call 
Allowable visit window (# days) 
 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
 
+4 
Assessment of AEsg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense study drugh 
Xi,j 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Study drug accountability 
Xj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Table footnotes and abbreviations on next page 
 


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Abbreviations: AE(s)=adverse event(s); CGI-S=Clinical Global Impression-Severity; C-SSRS=Columbia-Suicide Severity Rating Scale; 
ECG=electrocardiogram; EOT/ET=end-of-treatment/early termination; EQ-5D-5L=5-level EuroQol-5D; ESRS-A=Extrapyramidal Symptom Rating Scale -
Abbreviated; GCAS=Global Clinician Assessment of Suicidality; MMSE=Mini-Mental State Examination 
a 
Study visits are designated by weeks and have a ±3-day window (Visits 2 through 5), or a ±7-day window (Visits 6 through 9), or a +4-day window 
(Visit 10) calculated from the Baseline Visit. 
b  
Subject and study partner/caregiver consent for the present study must be obtained for entry into the present study prior to the final procedures being 
performed at the end of treatment (EOT) visit in the antecedent study or early termination (ET) visit (if the study was ended early by the Sponsor). Data from 
the EOT/ET visit procedures of the antecedent study will be carried over as baseline information in the present study, as applicable. 
c 
A single 12-lead ECG can be performed any time before blood sampling or at least 30 minutes after blood sampling during clinic visits. 
d 
A urine pregnancy test may be performed for female study subjects of childbearing potential. If urine cannot be obtained in women of childbearing potential, 
a serum pregnancy test should be done in its place. 
e 
The scale used in the antecedent study should also be used in the ACP-103-047 study. If the subject was previously assessed with the C-SSRS and is no 
longer able to reliably complete the C-SSRS in the Investigator’s judgment, the GCAS should be administered and used thereafter in the present study. 
f 
Appropriate consent/assent needs to be collected before assessment at Baseline.  
g  
All ongoing AEs from the antecedent study will be carried over after informed consent has been obtained for the ACP-103-047 study and recorded from 
Baseline for the present study until resolution or the follow-up safety assessment. AEs occurring after the first dose of open-label study drug until 30 days 
after the last dose of open-label study drug in the antecedent study will be recorded as an AE in the ACP-103-047 study. 
h 
Study drug will be dispensed to the subject at either scheduled or unscheduled visits. 
i 
Study drug will be dispensed to the subject to take home at the Baseline visit. The subject and study partner/caregiver will be provided instructions to take 
the first dose of study drug on the following day. 
j 
The used and unused treatment kits, blister cards, and tablets from the antecedent study are to be collected by the Investigator as part of the EOS/ET visit of 
the antecedent study before study drug for the present study can be dispensed. 
k 
This visit is a safety follow-up telephone call visit for subjects who complete the study or who discontinue prematurely from the study. This visit will occur 
30 (+4) days after the last dose of study drug. 
 
 
 


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3.3 
Randomization 
Not applicable. 
3.4 
Blinding 
This is an open-label study. 
3.5 
Determination of Sample Size 
Up to approximately 750 subjects will be enrolled. The sample size for this study is not based 
on statistical power, but will depend on the number of subjects who transition into this 
OL extension study from the antecedent study. 
3.6 
Coronavirus Disease 2019 
In March, 2020, the emerging coronavirus disease 2019 (COVID-19) pandemic resulted in 
implementation of urgent safety measures designed to ensure subject safety. 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 the Data Management Plan 
[DMP] Appendix B). Recruitment efforts into the antecedent study (ACP-103-046), and 
roll-overs into the open-label extension study (ACP-103-047), were paused. The impact of 
COVID-19 on statistical analysis is discussed in each of the relevant sections of this SAP. 
4 ANALYSIS SETS 
4.1 
Enrolled Subjects 
Enrolled subjects are defined as those subjects who signed informed consent (from either the 
subject or legally accepted representative) for Study ACP-103-047,  excluding rollover 
failures. Data listings will include all enrolled subjects. 
4.2 
Safety Analysis Set 
The Safety Analysis Set will include all enrolled subjects who have taken at least 1 dose of 
OL study drug. The Safety Analysis Set will be used for all analyses.  
5 DATA HANDLING CONVENTIONS 
All data collected in this 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 of the mean (SE), standard deviation (SD), minimum, 


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maximum, and median. Unless specified otherwise, means, medians, and confidence 
intervals 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. 
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). Categories with zero counts will not have zero 
percentages displayed. Percentages will be presented to 1 decimal place.  
When converting number of days to months, it will be calculated as the number of days 
divided by 365.25 and then multiplied by 12. When converting number of days to years, it 
will be calculated as the number of days divided by 365.25. 
All endpoints will be summarized using the Safety Analysis Set. 
No hypothesis testing is planned. Descriptive summaries of all safety and efficacy endpoints 
will be provided.  
5.2 
Treatment Cohorts 
Summaries by cohort based on the antecedent study treatment group will also be provided. 
The cohorts are defined as follows: 
• Cohort 1: DB placebo – OL pimavanserin 
• Cohort 2: DB pimavanserin – OL pimavanserin 
The DB treatment group will be based on the treatment actually received in the antecedent 
study, in the event that it is different from the randomized treatment assignment. 
For each continuous measure in safety and efficacy analyses, change from Baseline results 
will be presented in two ways: 
• Using the Baseline from Study ACP-103-047 and reporting the changes across 
OL Study ACP-103-047 timepoints. 
• Using the Baseline from the antecedent study and reporting changes (observed 
values) across the timepoints of both the antecedent study and the OL Study 
ACP-103-047. 
5.3 
Derived Variables 
In general, all assessment scale total scores and subscores will be derived within the analysis 
datasets. In the event that total scores and/or subscores are also collected on the electronic 
case report form (eCRF), the derived values will be used for all analyses. Both the raw and 
derived total scores will be presented in data listings. 


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5.3.1 
CGI-S 
The CGI-S scale is assessed at Baseline, Weeks 2, 4, 8, 12, 16, 28, 40 and Week 52/ET visits.  
The CGI-S 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 condition. The 7-point scores 
are: 1=normal, not at all ill; 2=borderline ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 
6 =severely ill; 7=among the most extremely ill.  
Missing CGI-S scores will not be imputed. 
5.3.2 
EQ-5D-5L Proxy Version 1 
The EQ-5D-5L is assessed at Baseline, Week 12, Week 28, and Week 52/ET. 
The EQ-5D-5L is a standardized instrument used as a measure of health outcome. The 
EQ-5D-5L Proxy version 1 will be used in this study. In this version, a caregiver (the proxy) 
is asked to rate the subject’s health-related quality of life in their (the proxy’s) opinion. The 
EQ-5D-5L consists of 2 components: the descriptive system, and the visual analogue scale 
(VAS).  
The EQ-5D-5L descriptive system consists of 5 dimensions (mobility, self-care, usual 
activities, pain/discomfort, anxiety/depression) each of which has 5 potential responses. The 
responses record 5 levels of severity within a particular EQ-5D-5L dimension: 1=no 
problems; 2=slight problems; 3=moderate problems; 4=severe problems; 5=extreme 
problems.  The responses for the 5 dimensions are combined into a single 5-digit code that 
describes the subject’s health state. 
The EQ-5D-5L VAS records the subject’s health on a vertical visual analogue scale, where 
the upper endpoint is labeled “The best health you can imagine” and is numbered 100, while 
the lower endpoint is labeled “The worst health you can imagine” and is numbered 0. The 
EQ-5D-5L VAS will be treated as a continuous endpoint. 
Missing values will not be imputed for either the EQ-5D-5L descriptive system or the VAS. 
5.3.3 
SDI 
The SDI is assessed at Baseline, Week 12, Week 28, and Week 52/ET. 
The SDI is an expanded version of one item of the Neuropsychiatric Inventory (NPI), 
consisting of the 7 subquestions from the NPI sleep disturbance item. Each of the 
subquestions was made into a separate question with frequency, severity, and caregiver 
distress rated by the caregiver with respect to the patient-participant for the 2 weeks prior to 
the visit. Thus, in contrast to a single rating for frequency and severity for all sleep 


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disturbance-related behaviors, which would be incorporated into an overall NPI score, the 
SDI score is derived after the caregiver rates the frequency and severity of each of the 
7 separate sleep disturbance symptoms. Caregiver distress ratings are not part of the SDI total 
score, but distress is measured. The SDI total score is calculated as the average of seven 
frequency ratings × average of seven severity ratings, with a range of 0-12. 
If the frequency rating and/or the severity rating is missing for a single item, then the total 
score will be imputed as the average of the non-missing frequency ratings × the average of 
the non-missing severity ratings. Otherwise, if more than one item has a missing frequency 
and/or severity rating, the total score will not be derived. 
5.3.4 
C-SSRS 
The C-SSRS is assessed (when applicable) at Baseline, Weeks 2, 4, 8, 12, 16, 28, 40 and 
Week 52/ET visits.  
The Columbia-Suicide Severity Rating Scale (C-SSRS) will be used to assess suicidal 
ideations and behaviors in subjects who are able to complete the assessment (subjects without 
dementia, defined as an MMSE≥25), and subjects with dementia who the Investigator has 
determined can complete the C-SSRS. 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. 
The C-SSRS version assessing information since the last visit will be completed at all visits 
(including the Baseline visit). 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. 
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, this subject will be counted as having suicidal ideation. 
There are 5 questions about suicidal behavior, representing 5 types of suicidal behavior: 
preparatory acts or behavior; aborted attempt; interrupted attempt; actual attempt; suicide. If 
a subject answers “yes” to any of these 5 questions, this subject will be counted as having 
suicidal behavior. 
Missing C-SSRS item scores will not be imputed. 


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5.3.5 
GCAS 
The GCAS (when applicable) is assessed at Baseline, Weeks 2, 4, 8, 12, 16, 28, 40 and 
Week 52/ET visits.  
If the subject is not able, in the Investigator’s judgement, to reliably complete the C-SSRS the 
Global Clinical Assessment of Suicidality (GCAS) will be administered and used thereafter 
in the study. If the GCAS was used in the antecedent study, suicidality since last visit will be 
assessed at Baseline and at all other visits. The first assessment with the GCAS should assess 
lifetime suicidality and suicidality for the past 3 months, and at all other visits suicidality 
since the previous visit will be assessed. 
The GCAS is a clinician-rated, 5-point scale that is designed to rate the subject’s suicidality 
based on the report of the subject, the report of the study partner/caregiver, and the clinician’s 
global assessment. Ratings are scored as follows:0=absent; 1=feels life is not worth living; 
2=wishes he/she were dead or any thoughts of possible death to self; 3=suicidal ideas or 
gesture; 4=attempt at suicide. The Investigator will record a subject rating, a study 
partner/caregiver rating, and a clinician rating. 
Missing scores will not be imputed. 
5.3.6 
ESRS-A 
The ESRS-A is assessed at Baseline, Weeks 2, 4, 8, 12, 16, 28, 40 and Week 52/ET visits. 
The ESRS was developed to assess 4 types of drug-induced movement disorders 
(Parkinsonism, akathisia, dystonia, and tardive dyskinesia) with established reliability, 
validity, and sensitivity. The ESRS-A, an accepted modified form of the original ESRS, will 
be used during the study to monitor for any worsening in extrapyramidal symptoms or signs 
at scheduled and unscheduled visits. 
The ESRS-A consists of 4 subscales and 4 clinical global impression movement severity 
(CGI-S) scales of Parkinsonism, dyskinesia, dystonia, and akathisia. Each item of the subscales 
and each CGI-S rating is scored on a 6-point scale with higher scores denoting more severe 
drug-induced movement disorders: 0=absent; 1=minimal; 2=mild; 3=moderate; 4=severe; 
5=extreme. 
The 4 ESRS-A subscales are defined as follows.   
• Parkinsonism subscale: 10 items (minimum=0, maximum=50) 
o P1 
Rigidity: Upper limbs 
o P2 
Rigidity: Lower limbs 
o P3 
Rigidity: Neck 


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o P4 
Tremor: Face, jaw/chin, lips, head 
o P5 
Tremor: Upper limbs/hands 
o P6 
Tremor: Lower limbs/feet 
o P7 
Reduced facial expression/speech 
o P8 
Impaired Gait/Posture 
o P9 
Postural Instability 
o P10 
Bradykinesia/Hypokinesia 
• Dystonia subscale: 6 items (minimum=0, maximum=30) 
o DT1  Tongue 
o DT2 
Jaw 
o DT3  Eyes, upper face, lower face, larynx 
o DT4 
Shoulders, upper limbs, hands 
o DT5 
Hips, lower limbs, feet 
o DT6  Trunk, neck 
• Dyskinesia subscale: 6 items (minimum=0, maximum=30) 
o DK1  Tongue 
o DK2  Jaw 
o DK3 
Eyes, upper face, lower face 
o DK4  Shoulders, upper limbs, hands 
o DK5  Hips, lower limbs, feet 
o DK 6  Trunk, neck 
• Akathisia subscale: 2 items (minimum=0, maximum=10) 
o A1  
Objective (observed during patient examination) 
o A2 
Subjective 
The ESRS-A total score is calculated as the sum of the 24 item scores with a possible range of 
0 to 120. If 4 or fewer items are missing, then the total score for a given subject and timepoint 
will be imputed as the mean of the non-missing items multiplied by 24 and rounded to the 
nearest integer. If more than 4 items are missing, the total score will not be derived.  
Missing ESRS-A item scores, subscale total scores, and CGI-S scores will not be imputed. 
5.3.7 
MMSE 
The MMSE is assessed at Baseline, Weeks 2, 4, 8, 12, 16, 28, 40 and Week 52/ET visits.  
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 


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and comprehension, and copying or drawing. The MMSE is being used in this study to screen 
for cognitive impairment and as a safety measure. 
Each of the 30 items has 2 possible values: 0=incorrect; 1=correct. 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, with lower scores indicating more severe cognitive impairment. 
If 6 or fewer items are missing, then the total score for a given subject and timepoint will be 
imputed as the mean of the non-missing items multiplied by 30 and rounded to the nearest 
integer. If more than 6 items are missing, the total score will not be imputed. 
5.4 
Analysis Visit Windows  
In general, the OL Baseline assessment is defined as the last non-missing, including those 
from repeated and unscheduled measurements, within 30 days before the first OL dose date 
or on the first OL dose date. Exceptions to this definition will be handled on a case-by-case 
basis. 
Efficacy and safety assessments will be summarized by analysis visit as presented in Table 2 
below. 
Table 2 
Analysis Visit Windows 
Open-label (OL) Analysis 
Visit Name 
Target Study Day1 
Study Day Interval 
OL Baseline  
1 
≤1 (based on the first OL 
dose date) 
OL Week 2 
15 
2 to 21 
OL Week 4 
29 
22 to 42 
OL Week 8 
57 
43 to 70 
OL Week 12 
85 
71 to 98 
OL Week 16 
113 
99 to 154 
OL Week 28 
197 
155 to 238 
OL Week 40 
281 
239 to 322 
OL Week 52 
365 
323 to 379 
Follow-up 
395 
380 to maximum 
1 
If the assessment date ≥ first OL dose date, study day = assessment date - first OL dose date + 1, 
otherwise study day = assessment date – first OL dose date. Study day 1 is the first OL dose date. 
5.4.1 
Unscheduled Assessments 
Both scheduled and unscheduled assessments, including early termination visits, will be 
considered for planned timepoint summaries. All assessments will be presented in data 
listings. 


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5.4.2 
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.  Details are provided in a separate programming 
conventions document. 
For safety summaries where the most extreme values should be selected, e.g. overall post-OL 
Baseline minimum, and overall post-OL Baseline maximum, all non-missing post-OL 
Baseline values should be considered, regardless of whether the value is selected for the 
by-visit summaries. All results will be presented in data listings. 
When 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. 
5.5 
Data Handling Conventions 
5.5.1 
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 date of the end-of-study/early 
termination visit will be used in the calculation of treatment duration. For the incomplete last 
dose date of the study drug, the imputation algorithms will be detailed in the analysis dataset 
specification document. The missing or incomplete dates will be displayed in the data listings 
as reported on the eCRF rather than the imputed dates. 
For any data summarization before final database lock, if a subject is still ongoing, then the 
last dose date will be imputed using the database extract date.  
5.5.2 
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 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. 


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5.5.3 
Missing or Incomplete Dates for Adverse Events  
Missing or incomplete AE start dates will be imputed for the purpose of determining whether 
the AEs are TE (see Section 14.1 for definition). When the chronological order of an AE 
onset relative to the study drug treatment period is unclear due to missing or incomplete 
date(s), the AE will be considered as TE. 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. 
5.5.4 
Missing Severity Assessment for Adverse Events 
If the severity is missing for a TEAE a severity of “Severe” will be assigned. The imputed 
values for severity assessment will be used for incidence summaries, and the actual (missing) 
values will be presented in data listings. 
5.5.5 
Missing Relationship to Study Drug for Adverse Events 
If the relationship to study drug is missing for a TEAE, a causality of “Related” will be 
assigned. The imputed values for relationship to study drug will be used for incidence 
summaries, and the actual (missing) values will be presented in data listings. 
5.5.6 
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 ENROLLMENT AND DISPOSITION 
The number of sites that enrolled at least 1 subject and the number of subjects enrolled will 
be summarized by region (North America, Europe, and rest of world) and overall.  For 
enrolled subjects, the number and percentage of subjects in the Safety Analysis Set will be 
summarized by region (North America, Europe, or rest of world). A listing will be provided 
displaying all subjects excluded from the Safety Analysis Set (if any), and will include 
reason(s) for exclusion.  
The number and percentage of subjects who completed or discontinued (all discontinued and 
by discontinuation reason) the study will also be summarized by region and overall for the 
Safety Analysis Set. Early terminations of subjects due to COVID-19 related reasons will be 
captured in the eCRFs and summarized.    


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7 PROTOCOL DEVIATIONS 
Protocol deviations that occur during Study ACP-103-047 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 Protocol Deviation 
Management Plan. Protocol deviations will also be assessed with respect to relationship to 
COVID-19. 
For enrolled subjects, a summary of the number and percentage of subjects with major 
protocol deviations for each deviation category will be presented in three ways: all protocol 
deviations, COVID-19 related protocol deviations, and non COVID-19 related protocol 
deviations.  
Similarly, three data listings of major protocol deviations will be provided: All deviations, 
COVID-19 related protocol deviations, and non COVID-19 related protocol deviations. 
Additionally, a data listing of all minor COVID-19 related protocol deviations will be 
provided.  
A listing of protocol deviations will also be presented in three ways as described above. 
8 DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
Demographics and OL Baseline characteristics will be summarized using descriptive 
statistics. Summaries by region (North America, Europe, or rest of world) will also be 
presented.  
8.1 
Demographics 
Demographic variables include age, sex, primary race (subjects of multi-racial background 
can only identify/select one primary race on eCRF, or choose “other” and specify), ethnicity, 
height, weight, body mass index (BMI), region, subject living situation, and partner/caregiver 
relationship. 
The reported age reflects a subject’s age at the OL Baseline visit date. Age and BMI will be 
presented as both continuous and categorical variables. Age categories will be presented as 
<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. 
8.2 
Disease Characteristics and Neuropsychiatric History 
Disease characteristics at OL Baseline will be summarized using descriptive statistics. 
MMSE total score, CGI-S, EQ-5D-5L VAS, SDI total score, and ESRS-A total score will be 
presented as continuous variables. In addition, CGI-S will be presented as a categorical 


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variable using categories of 1 to 7, and MMSE will be presented as a categorical variable 
using categories of≤10, 11 to 17, 28 to 24, and 25 to 30. For the C-SSRS the number and 
percentage of subjects having suicidal ideation or behavior since the last visit will  be 
presented. For the GCAS, the number and percentage of subjects within each rating since the 
last visit (absent, feels life is not worth living, wishes he/she were dead or any thoughts of 
possible death to self, suicidal ideas or gestures, and attempts at suicide) will be presented.   
Neuropsychiatric history will be summarized descriptively for continuous and categorical 
variables. The OL Baseline visit date will be used as the reference date for calculation of 
durations. For both the Disease Characteristics and Neuropsychiatric History, summaries by 
region (North America, Europe, and rest of world) will also be presented. The 
Neuropsychiatric history will be pushed into the -047 database from the -046 study. If there 
have been any changes in the subject’s neuropsychiatric history since completing this form 
for the -046 study, appropriate updates should be made by editing the affected fields. 
9 MEDICAL HISTORY 
Medical and surgical history data will be coded using Medical Dictionary for Regulatory 
Activities (MedDRA) version 20.0 or newer. The subject incidence will be summarized for 
each system organ class (SOC) and preferred term (PT). A subject will be counted only once 
per SOC or per PT for the summary. 
A listing of the SOC, PT, 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 OL Baseline will be provided. 
10 CONCOMITANT AND POST-TREATMENT MEDICATION 
Medications will be coded using WHO Drug Dictionary (WHODRUG-DDE-B2) 2019 
March or newer version. For concomitant medications, the number and percentage of 
subjects taking each drug class (ATC Level 3) and medication PT will be tabulated. A subject 
will be counted only once per drug class or per medication PT for the summary. Concomitant 
and post-treatment medications will be summarized separately. 
10.1 Concomitant Medication 
Concomitant medication is defined as any medication with a start date prior to the date of the 
OL first dose date and continuing after the OL first dose date, or with a start date between the 
OL first dose date and OL last dose date, inclusive.   


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10.2 Post-Treatment Medication 
Post-treatment medication is defined as any medication with a start date after the OL last 
dose date.  
10.3 COVID-19 Related Medications 
Relationship to COVID-19 will be assessed by the investigator as detailed in the DMP 
Appendix B. Concomitant and post-treatment medication analyses described in Section 10.1 
and Section 10.2 above will also be summarized by relationship to COVID-19 (Not related to 
COVID-19 vs. Related to COVID-19).  
11 EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE 
Summaries of exposure and compliance to OL study drug will be provided for the Safety 
Analysis Set. 
11.1 Exposure to Study drug  
Pimavanserin dose levels are expressed as free base.  
For each subject the duration of exposure will be calculated as the number of days from first 
dose date to last dose date inclusive. See Sections 11.1.1 and 11.1.2 for further details. 
11.1.1 Exposure to OL pimavanserin 
Formulas to calculate subject level exposure-related quantities for OL pimavanserin are given 
as follows: 
Duration of OL exposure (days) = OL last dose date – OL first dose date + 1 
 
Average OL daily dose (mg/day) = 
𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑂𝑂𝑂𝑂 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 (𝑚𝑚𝑚𝑚)
𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑂𝑂𝑂𝑂 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑒𝑒𝑥𝑥𝑥𝑥𝑥𝑥𝑥𝑥𝑥𝑥𝑥𝑥𝑥𝑥 (𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑) 
 
The total cumulative dose of pimavanserin will be calculated by first multiplying the number 
of tablets taken by the dose level (in mg) for each kit returned to the site during the OL study 
period and then summing the results for all kits. 
If a subject has an unreturned kit then the overall cumulative dose and average daily dose will 
be set to missing 
Duration of OL pimavanserin exposure will be summarized as both continuous and 
categorical variables. For the categorical presentation of duration of OL exposure the number 
and percentage of subjects in each of the following categories will be displayed: <2 weeks 


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(1 to 13 days), 2 to <4 weeks (14 to 27 days), 4 to <8 weeks (28 to 55 days), 8 to <12 weeks 
(56 to  83 days), 12 to <16 weeks (84 to 111), 16 to <28 weeks (112 to 195), 28 to <40 weeks 
(196 to 279), 40 to <52 weeks (280 to 363), and ≥52 weeks (≥364 days). 
In addition, whether a subject had any dose changes (yes vs. no), and last dose level (20 mg 
vs. 34 mg) will be tabulated. 
Kaplan-Meier curves of duration of exposure to OL pimavanserin will be provided. 
11.1.2 Total exposure to double-blind and OL pimavanserin 
For subjects who received pimavanserin in the antecedent study, formulas to calculate subject 
level total pimavanserin (DB+OL) exposure-related quantities are as follows: 
Total duration of exposure (days) = (OL last dose date – OL first dose date + 1) 
+ (DB last dose date – DB first dose date + 1)  
Total average daily dose(mg/day) = 
𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 (𝑚𝑚𝑚𝑚)
𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 (𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑) 
In case a subject whose last dose date in the antecedent study is equal to the first dose date in 
the OLE, the total duration of exposure will be the above calculation minus one. 
The total cumulative dose of pimavanserin will be calculated by first multiplying the number 
of tablets taken by the dose level (in mg) for each kit returned to the site during both the DB 
and OL study periods and then summing the results for all kits. 
For subjects who received placebo in the antecedent study, the pimavanserin total duration of 
exposure, total cumulative dose, and the average daily dose across the DB and OL periods 
will use the same values as calculated for the OL study alone (see Section 11.1.1). 
Total duration of DB+OL exposure to pimavanserin will be summarized as both continuous 
and categorical variables. For the categorical presentation, the number and percentage of 
subjects in each of the following categories will be displayed: <2 weeks (1 to 13 days), 2 to 
<4 weeks (14 to 27 days), 4 to <8 weeks (28 to 55 days), 8 to <12 weeks (56 to  83 days), 
12 to <16 weeks (84 to 111 days), 16 to <24 weeks (112 to 195 days), 28 to <40 weeks 
(196 to 279 days), 40 to <52 weeks (280 to 363 days), 52 to <60 (364 to 419 days), and 
≥60 weeks (≥420 days). 
In addition, summaries of whether subjects had any dose change (yes vs. no), their highest 
dose level (20 mg or 34 mg), and their last dose level (20 mg or 34 mg) will also be provided. 


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11.2 Measurement of Study Drug Compliance 
Study drug compliance (in percentage) during the OL study period for a given subject is 
calculated as follows: 
𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶= ൤𝑂𝑂𝑂𝑂  𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑−𝑂𝑂𝑂𝑂 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑛𝑛𝑛𝑛𝑛𝑛
2 × 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑂𝑂𝑂𝑂 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒
൨× 100% 
Study drug 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 Safety Analysis Set. No hypothesis testing 
is planned. Descriptive summaries of all efficacy endpoints will be provided. 
12.1 Exploratory Efficacy Endpoints 
The exploratory endpoints for this study to assess the benefit of pimavanserin are: 
• Change from Baseline in CGI-S scale for neuropsychiatric symptoms 
• Change from Baseline in SDI score 
• Change from Baseline in EQ-5D-5L score 
12.2 Adjustment for Covariates 
Not applicable. 
12.3 Handling of Missing Data 
Any derived scores (i.e. total, domain, or subscale scores) that are missing after the 
imputation of individual missing items as described in Section 5.3 will not be imputed. 
12.4 Multiple Comparisons / Multiplicity 
No hypothesis testing is planned.  
13 METHODS OF EFFICACY ANALYSES 
13.1 Analysis of Efficacy Endpoints 
Descriptive statistics for all exploratory efficacy endpoints listed in Section 12.1 will be 
tabulated by cohorts based on antecedent study and DB treatment group at scheduled 
timepoints. The summaries of the change from Baseline results will be presented by cohort at 


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scheduled timepoints in two ways as specified in Section 5.2. The scheduled timepoints 
across the DB and OL study periods for all efficacy endpoints are presented in Table 3 below. 
Table 3 
Scheduled Assessment Timepoints for Efficacy Endpoints Across 
ACP-103-046 (DB) and ACP-103-047 (OL) 
 
CGI-S 
SDI 
EQ-5D-5L 
DB Baseline 
x 
x 
x 
DB Week 1 
x 
 
 
DB Week 2 
x 
 
 
DB Week 4 
x 
x 
 
DB Week 6 
x 
 
 
DB Week 8/OL Baseline  
(-046 EOT) 
x 
x 
x 
OL Week 2 
x 
 
 
OL Week 4 
x 
 
 
OL Week 8 
x 
 
 
OL Week 12 
x 
x 
x 
OL Week 16 
x 
 
 
OL Week 28 
x 
x 
x 
OL Week 40 
x 
 
 
OL Week 52 
x 
x 
x 
 
13.1.1 EQ-5D-5L  
The change from Baseline in the EQ-5D-5L VAS score will be summarized descriptively at 
each timepoint as described in Section 13.1. 
For each EQ-5D-5L dimension the proportion of subjects reporting no, slight, moderate, 
severe, and extreme/unable to perform activity will be summarized descriptively at each 
timepoint. 
Change from OL Baseline in EQ-5D-5L health state will be assessed with the Pareto 
classification of health change (PCHC) method. Using this methodology, at each scheduled 


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timepoint, each EQ-5D health state will be classified into one of four categories, relative to 
the OL Baseline health state: 
• Improved = improved on at least one dimension and not worsened on any other 
dimension 
• Mixed = improved on at least one dimension and worsened on at least one other 
dimension 
• No change = no changes in any dimension 
• Worsened = deterioration on at least one dimension and no improvement on any other 
dimension 
If one or more dimensions are missing a valid response, then the PCHC category will not be 
derived. 
The proportion of subjects in each PCHC category will be summarized descriptively at each 
scheduled timepoint. 
The above analyses will also be presented based on the DB cohorts as described in 
Section 5.2. 
14 SAFETY ANALYSES 
Safety variables include AEs, TEAEs, clinical laboratory variables, vital signs, body weight, 
BMI, physical examinations, electrocardiogram (ECG), C-SSRS, GCAS, MMSE, and 
ESRS-A variables. The safety summaries will be presented for the Safety Analysis Set using 
descriptive statistics. Safety variables will be summarized by cohorts based on the antecedent 
study and DB treatment group (see Section 5.2 ). For each continuous variable in clinical 
laboratory, vital signs, and electrocardiograms, the change from Baseline will be presented in 
two ways as specified in Section 5.2.  
The scheduled timepoints across the DB and OL study periods for all safety endpoints are 
presented in Table 4 below. 


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Table 4 
Scheduled Assessment Timepoints for Safety Endpoints Across ACP-103-046 
(DB) and ACP-103-047 (OL) 
 
Vitals 
Lab 
ECG 
MMSE 
ESRS-A 
DB Baseline 
x 
x 
x 
x 
x 
DB Week 1 
x 
 
 
x 
x 
DB Week 2 
x 
 
x 
x 
x 
DB Week 4 
x 
x 
  
x 
x 
DB Week 6 
x 
 
  
x 
x 
DB Week 8/OL 
Baseline  
(-046 EOT) 
x 
x 
x 
x 
x 
OL Week 2 
x 
 
x 
x 
x 
OL Week 4 
x 
 
x 
x 
x 
OL Week 8 
x 
 
x 
x 
x 
OL Week 12 
x 
x 
x 
x 
x 
OL Week 16 
x 
 
x 
x 
x 
OL Week 28 
x 
 
x 
x 
x 
OL Week 40 
x 
 
x 
x 
x 
OL Week 52 
x 
x 
x 
x 
x 
 
For by-visit summaries, all scheduled and unscheduled values within a visit window will be 
considered. For the overall post-Baseline summaries, all post-Baseline values will be 
considered, including unscheduled and out of window values. 
14.1 Adverse Events  
All AEs, classified by preferred term, will be coded using MedDRA version 23.0 or newer. 
An AE (classified by PT) will be considered a TEAE if it started on or after the OL first dose 
of study drug and no later than the OL last dose date + 30. AEs reported on Day 1 based on 
pre-dose findings 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 by cohort and overall: 


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• TEAEs by SOC and PT 
• Most frequently reported TEAEs by SOC and PT 
− 
PTs reported by ≥5% and ≥2% (overall) of subjects in the Safety Analysis Set  
• TEAEs by PT 
• TEAEs by SOC, PT, and maximum severity  
− 
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 discontinuation of study drug 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 
For tabulations that include SOC and PT the display will be sorted alphabetically by SOC and 
then by descending subject frequency for the PTs based on counts in the Safety Analysis Set 
within each SOC. SOCs will not be included in the TEAEs by PT tabulation. This display 
will be sorted by descending subject frequency based on counts in the Safety Analysis Set. 
An AE listing by subject will display all events, including those which are not TE, 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, dose level at 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 AEs leading to 
discontinuation and subjects who died (if any). In these listings, an indicator for TEAEs will 
also be included. 
14.1.1 Assessment of the Impact of COVID-19 on Adverse Events 
The relationship of selected AEs to COVID-19 will be assessed by investigator as detailed in 
the DMP Appendix B.  Each of the primary safety analyses described in Section 14.1 will be 
additionally summarized by relationship to COVID-19 (Not related to COVID-19 vs. Related 
to COVID-19). 


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14.2 Clinical Laboratory Variables 
Clinical laboratory tests are performed at Baseline, Week 12, and Week 52/ET visits. In 
general, laboratory test results are from a central laboratory.  Due to COVID-19 disruptions it 
is possible that some test results may be collected from a local laboratory. A separate eCRF 
will capture local laboratory results in order to facilitate medical monitoring of subject safety. 
Local laboratory results will not be included in any summary data analysis; they will, 
however, be included in data listings, as well as a separate local laboratory PCI listing.  All 
results (central and local)  will be displayed in Système International [SI] units. It is 
encouraged, but not required, that clinical labs be completed under fasting conditions. 
14.2.1 Chemistry 
Clinical chemistry serum tests include the following: 
• Sodium (Na), potassium (K), chloride (Cl), phosphorus (P), calcium (Ca),), blood 
urea nitrogen (BUN), creatinine (CR), uric acid, , bicarbonate 
• Alaninine 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) 
14.2.2 Miscellaneous 
• Prolactin  
• Lipid panel 
– total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, very 
low density lipoprotein cholesterol 
14.2.3 Hematology 
Hematology tests include the following: 
• Complete blood count (CBC) including: 
− 
White blood cell (WBC) count, absolute neutrophil count, complete 
differential (relative and absolute), hematocrit (Hct), hemoglobin (Hgb), red 
blood cells (RBC), platelets, reticulocyte count  


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14.2.4 Urinalysis 
Urinalysis tests include the following: 
• Blood, RBCs, WBCs, protein, glucose, ketones, specific gravity, pH, leukocyte 
esterase 
• A urine pregnancy test should be performed at all designated visits for women of 
childbearing potential 
– If urine cannot be obtained in women of childbearing potential, a serum 
pregnancy test should be done in its place 
• Urine drug screen will be performed at Baseline, Week 12, and Week 52  
14.2.5 Methods of Analysis for Clinical Laboratory Variables 
14.2.5.1 
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 scheduled post- 
Baseline visits. The change from Baseline values will also be summarized at scheduled 
post-Baseline visits. The overall minimum and maximum post-Baseline observed and change 
from Baseline values will also be summarized (for OL study period only).  
For hemoglobin, hematocrit and uric acid, by-visit as well as post-OL Baseline minimum and 
maximum 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, visit, and cohort.  
Summaries of the above will also be presented for OL timepoints only using OL Baseline, 
and DB+OL timepoints using the DB Baseline from the antecedent study (see Section 5.2 and 
Table 4). 
14.2.5.2 
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.  Shift tables will be presented for shift from OL Baseline as well as shift from DB 
Baseline. 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 and cohort.  


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The shifts from Baseline to overall post-Baseline minimum and overall post-Baseline 
maximum will also be presented. The denominator is the number of subjects with 
non-missing Baseline and at least 1 post-Baseline value for the given parameter and cohort.  
For hemoglobin, hematocrit and uric acid, by-visit as well as post-Baseline minimum and 
maximum will be presented for each gender as well as for both genders combined. 
Shift tables will be presented for OL timepoints only using OL Baseline, and DB+OL 
timepoints using the DB Baseline from the antecedent study (see Table 4). 
14.2.5.3 
Potentially Clinically Important Laboratory Values 
The number and percentage of subjects with potentially clinically important (PCI) laboratory 
values at scheduled post-Baseline visits and overall post-Baseline will be summarized by 
Baseline status (all or within normal range) for selected parameters. PCI criteria are listed in 
Table 5 and Table 6.  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. PCI tables will be presented for OL timepoints only 
using OL Baseline, and DB+OL timepoints using the DB Baseline from the antecedent study 
(see Section 5.2 and Table 4). 
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, visit, and cohort, and the denominator is the 
number of subjects with non-missing values for the given parameter, visit, and cohort. 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 cohort, and the 
denominator is the number of subjects with at least 1 post-Baseline value for the given 
parameter and cohort. 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.  A listing of all PCI values in study ACP-103-047 will be provided. This listing 
will include all observations from study ACP-103-047 for those subjects and parameters for 
which at least one PCI value (including OL Baseline) was observed. 


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Table 5 
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 6 
Criteria for Potentially Clinically Important Laboratory Values - Urinalysis 
Urinalysis  
Low PCI Criteria 
High PCI Criteria 
Blood (occult blood) 
Not Applicable 
≥Moderate 
Protein 
Not Applicable 
≥100 mg/dL 
Glucose 
Not Applicable 
≥500 mg/dL 
 
14.2.5.4 
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’). Central 
and local laboratory values will be presented separately. 
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 (including Baseline) was observed. 
Central and local laboratory PCI listings will be presented separately. 
The pregnancy results (positive or negative) for female subjects of childbearing potential will 
be presented in a listing. 
14.3 Vital Signs 
Vital signs are assessed at Baseline and Weeks 2, 4, 8, 12, 16, 28, 40 and Week 52/ET visits. 
Due to COVID-19 disruptions it may be necessary for vital signs to be collected outside of 
the clinic by persons other than study site staff. These results will not be included in any 
summary data analysis; they will, however, be presented in data listings, and in a separate 
PCI listing of vitals measured by persons other than study site staff.  
14.3.1 Vital Signs Variables 
Vital signs include weight, height (measured at Screening of antecedent study), derived BMI, 
sitting systolic blood pressure (SBP), sitting diastolic blood pressure (DBP), pulse rate, 
temperature, and respiratory rate. The sitting blood pressure should be measured after the 
subject has been sitting for ≥3 minutes. 
14.3.2 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. 
Vital sign values will be considered PCI if they meet the criteria listed in Table 7. The 
number and percentage of subjects with post-Baseline vital signs that are PCI will be 


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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 numerator for the 
percentage is the number of subjects with a post-Baseline PCI value for the given parameter, 
visit and cohort, and the denominator is the number of subjects with non-missing values for 
the given parameter, visit and cohort. 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 cohort, and the denominator is the number of subjects with at least 
1 post-Baseline value for the given parameter and cohort.   
Vitals change from Baseline and PCI tables will be presented for OL timepoints only using 
OL Baseline, and DB+OL timepoints using the DB Baseline from the antecedent study (see 
Section 5.2 and Table 4). 
A listing of all PCI values will be provided (excluding those vitals collected by persons other 
than study site staff). There will be a separate PCI listing for vitals collected by persons other 
than study site staff. These listings will include all observations for those subjects and 
parameters for which at least one PCI value (including Baseline) was observed 
Table 7 
Criteria for Potentially Clinically Important Vital Signs 
 
Vital Sign Parameter 
 
Unit 
Criteriaa 
Observed 
Value 
And/Or 
Change Relative to Baseline 
Systolic blood pressure 
(supine or sitting) 
mmHg 
≥180 
And 
Increase of ≥20 
≤90 
And 
Decrease of ≥20 
Diastolic blood pressure 
(supine or sitting) 
mmHg 
≥105 
And 
Increase of ≥15 
≤50 
And 
Decrease of ≥15 
Pulse (supine or sitting) 
bpm 
≥120 
And 
Increase of ≥15 
≤50 
And 
Decrease of ≥15 
Weight 
kg 
Not Applicable 
Increase of ≥7% 
Decrease of ≥7% 
a 
A post-baseline value is considered as a PCI value if it meets both criteria for observed value and change 
from baseline. 
14.4 Electrocardiogram (ECG) 
ECG is performed at Baseline, Weeks 2, 4, 8, 12, 16, 28, 40, and Week 52/ET.  
All tracings will be evaluated by a central reading laboratory, including any collected outside 
of the clinic due to COVID-19 disruptions when possible.. At the Baseline visit the 


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machine-read results will also be recorded. ECG data summaries, including the cardiologist’s 
interpretation, will be analyzed using the centrally evaluated data. 
14.4.1 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): 
• Observed: ≤450, 451 to 480, 481 to 500, and >500 
• Change from Baseline: ≤10, 11 to 30, 31 to 60, and >60 
14.4.2 ECG Methods of Analysis 
14.4.2.1 
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. 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 (only for the 
OL study period). 
14.4.2.2 
PCI Values 
Electrocardiogram values will be considered PCI if they meet or exceed the upper limit 
values listed in Table 8. The number and percentage of subjects with PCI values will be 
summarized at scheduled post-Baseline visits and for overall post-Baseline (only for the 
OL study period). 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, visit and cohort, and the 
denominator is the number of subjects with non-missing values for the given parameter, visit 
and cohort. 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 
cohort, and the denominator is the number of subjects with at least 1 post-Baseline value for 
the given parameter and cohort.   
Table 8 
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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14.4.2.3 
Cardiologist Interpretations 
For cardiologist’s interpretations, the number and percentage of subjects with ECG results 
that are classified as normal or abnormal will be summarized at scheduled visits. The overall 
post-baseline worst interpretation (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) will also be 
summarized (only for the OL study period). 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 (only for the OL study period) 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 given cohort. 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 for the given cohort.  
14.4.2.4 
Data Listings 
All data, including machine-read Baseline results, will be listed. A listing of all ECG PCI 
values in study ACP-103-047 will be provided. This listing will include all observations from 
study ACP-103-047 for those subjects and parameters for which at least one PCI value 
(including Baseline) was observed. 
14.5 Physical Examination 
Physical examination is performed at Baseline, Week 28, and Week 52/ET visits. 
Physical examination results (normal, abnormal, and not done) at Baseline, Week 28, and 
Week 52/ET will be summarized in a frequency table by cohort and body system. 
14.6 Other Safety Variables 
14.6.1 ESRS-A 
The ESRS-A is assessed at Baseline, Weeks 2, 4, 8, 12, 16, 28, 40, and Week 52/ET visits. 
The ESRS-A total score and the 4 individual global CGI-S scores will be summarized using 
descriptive statistics at Baseline and scheduled post-Baseline visits. The change from 
Baseline scores will also be summarized at scheduled post-Baseline visits. For each of the 
above endpoints, results will be presented for OL timepoints only using OL Baseline, and 
DB+OL timepoints using the DB Baseline from the antecedent study (see Section 5.2 and 
Table 4). 


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The individual item scores and subscale scores will be listed but not summarized. 
14.6.2 MMSE 
The MMSE is assessed at Baseline, Weeks 2, 4, 8, 12, 16, 28, 40 and Week 52/ET visits.  
The MMSE total score will be summarized using descriptive statistics at Baseline and 
scheduled post-Baseline visits. The change from Baseline scores will also be summarized at 
scheduled post-Baseline visits. The MMSE total score will be presented for OL timepoints 
only using OL Baseline, and DB+OL timepoints using the DB Baseline from the antecedent 
study (see Section 5.2 and Table 4). 
The individual item scores will be listed but not summarized. 
14.6.3 Suicidality 
The C-SSRS will be administered if the subject, in the Investigator’s judgement, is able to 
reliably complete it. Otherwise, the GCAS will be administered and used thereafter in the 
study. 
14.6.3.1 
C-SSRS 
The C-SSRS is assessed (when applicable) at Baseline, Weeks 2, 4, 8, 12, 16, 28, 40 and 
Week 52/ET visits.  
The event counts and the number and percentage of subjects reporting any post-OL 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-OL Baseline 
non-suicidal self-injurious behavior will also be tabulated. 
For calculating the percentages, the denominator will be the number of subjects with an OL 
C-SSRS assessment within each cohort. The above summaries will be presented only for the 
OL study period. 
14.6.3.2 
GCAS 
The GCAS is assessed (when applicable) at Baseline, Weeks 2, 4, 8, 12, 16, 28, 40 and Week 
52/ET visits. 
The overall post-OL Baseline worst suicidality rating will be summarized using the number 
and percentage of subjects within each rating. The number and percentage of subjects 


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reporting any post-OL Baseline rating of 3 or 4 will be tabulated. For calculating percentages, 
the denominator is the number of subjects with an OL GCAS assessment at the given visit 
and within each cohort. The above summaries will be presented only for the OL study period 
and using the clinician ratings. 
Subject and study partner/caregiver ratings will not be summarized but will be included in 
data listings. 
15 CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
Not applicable. 
16 INTERIM ANALYSIS 
One or more interim analyses may be conducted in order to support safety and efficacy 
evaluations for regulatory submissions. 
16.1 Interim Analyses  
The ACP-103-046 database lock for the first interim analysis (IA-1) occurred on December 
13, 2019 (under version 1 of the SAP), and included data from 288 subjects whose last visit 
occurred on or before December 2, 2019. Of these subjects, 231 rolled-over into 
ACP-103-047 and were included in IA-1. A second interim analysis occurred on July 2, 2020 
(for purposes of a 120 day update) and included 504 subjects. Of these, 353 rolled over into 
ACP-103-047 and are to be included in IA-2. The rate of rollovers was lower for IA-2 
because of the temporary suspension of enrollment into ACP-103-047, beginning on 
March 20, 2020, due to COVID-19 disruptions. 
17 DATA MONITORING/REVIEW COMMITTEE 
Safety data are monitored throughout the study and aggregate safety reports are produced and 
reviewed approximately quarterly. Furthermore, selected safety data from this study will be 
presented periodically to the Data and Safety Monitoring Board (DSMB) along with data 
from the ACP-103-046 study to assist with interpretation of benefit versus risk in that study. 
18 COMPUTER METHODS  
Statistical analyses will be performed using Version 9.4 (or newer) of SAS software 
(SAS Institute Inc., Cary, North Carolina) on a suitably qualified and validated environment. 
Validation and quality control of the tables, listings and figures containing the results of the 
statistical analyses will follow appropriate standard operating procedures. 


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19 CHANGES TO ANALYSES SPECIFIED IN PROTOCOL 
None. 


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20 REFERENCES 
1. FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 
Pandemic, March 2020; updated May 14, 2020. 
2. EMA Guidance on the Management of Clinical Trials during the COVID-19 
(Coronavirus) pandemic, March 2020. 
 


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21 APPENDICES 
21.1 Summary of Version Changes   
Version No: 
Document History 
Description of Update 
Author(s) 
Version Date 
1.0 
Original version 
 
26 NOV 2019 
2.0 
Updated to include handling of 
analyses related to COVID-19 
 
15 JUL 2020 
3.0 
In alignment with Protocol 
Amendment 4 changes were 
made to indicate that 
exploratory efficacy data from 
interim analyses conducted in 
this study may also be evaluated 
in order to support regulatory 
submissions. 
 
08 March 2021