A 52-Week Open-label Extension Study of Pimavanserin in Adult and Elderly Subjects With Neuropsychiatric Symptoms Related to Neurodegenerative Disease
Phase: PHASE3
Conditions: Neuropsychiatric Symptoms Related to Neurodegenerative Disease
Sponsor: ACADIA Pharmaceuticals Inc.

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. 
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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 
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Date: 5 March 2021 
 
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Placeholder electronic signature page 

Study: ACP-103-047 
 
Final Version: 1.0 
Protocol Amendment 4 
 
Date: 5 March 2021 
 
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DECLARATION OF INVESTIGATOR 
I confirm that I have read the above protocol. I understand it, and I will work according to the 
moral, ethical, and scientific principles governing clinical research as set out in the principles 
of Good Clinical 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 
 
Final Version: 1.0 
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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 
 
Final Version: 1.0 
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). 

Study: ACP-103-047 
 
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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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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 
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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 
treatment may be included.  

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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. 

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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 
 
Final Version: 1.0 
Protocol Amendment 4 
 
Date: 5 March 2021 
 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc. 
Page 60 of 62 
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 
 

Study: ACP-103-047 
 
Final Version: 1.0 
Protocol Amendment 4 
 
Date: 5 March 2021 
 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc. 
Page 61 of 62 
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®) 

Study: ACP-103-047 
 
Final Version: 1.0 
Protocol Amendment 4 
 
Date: 5 March 2021 
 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc. 
Page 62 of 62 
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)