A 52-Week, Open-Label, Extension Study of Pimavanserin for the Adjunctive Treatment of Schizophrenia
Phase: PHASE3
Conditions: Schizophrenia
Sponsor: ACADIA Pharmaceuticals Inc.

Official Title: A 52-Week, Open-Label, Extension Study of Pimavanserin for the 
Adjunctive Treatment of Schizophrenia 
NCT Number: NCT03121586 
Document Date: 11 August 2020 

 
               Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
 
 Page 1 of 96 
 
 
CLINICAL STUDY PROTOCOL 
 
A 52-Week, Open-Label, Extension Study of Pimavanserin for the 
Adjunctive Treatment of Schizophrenia 
 
Protocol No. ACP-103-035 
Amendment 3 
 
EudraCT Number: 2016-003435-38 
 
Original Protocol Date: 28 September 2016 
Amendment 1 Date: 30 November 2016 
Amendment 2 Date: 31 March 2017 
Amendment 3 Date: 11 August 2020 
 
 
 
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. 

St u d y: A C P -1 0 3 -0 3 5  
Fi nal Versi o n: 1. 0  
Cli nical St u d y Pr ot oc ol A me n d me nt 3   
  
  
  
 
               Date: 1 1 A u g ust 2 0 2 0  
  
C o nfi de ntial a n d Pr o prietar y I nf or mati o n of  A C A DI A P har mace uticals I nc.                   Pa ge 2 of 9 6  
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Study: ACP-103-035 
Final Version: 1.0 
Clinical Study Protocol Amendment 3 
 
 
 
 
               Date: 11 August 2020 
  
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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 the United States (US) Code of Federal Regulations (CFR) 21 CFR parts 50, 54, 
56, 312, and according to applicable local requirements. 
Confidentiality Statement 
The confidential information in this document is provided to you as an Investigator or 
Consultant for review by you, your staff, and the applicable institutional review board/ethics 
committee. Your acceptance of this document constitutes agreement that you will not disclose 
the information contained herein to others without written authorization from the Sponsor. 
Investigator 
 
 
Signature 
 
Date 
 
 
 
Name (printed) 
 
 
 
 
 

Study: ACP-103-035 
Final Version: 1.0 
Clinical Study Protocol Amendment 3 
 
 
 
 
               Date: 11 August 2020 
  
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PROTOCOL SYNOPSIS 
Protocol Number 
ACP-103-035 
EudraCT or 
ClinicalTrials.gov 
Number 
2016-003435-38 
Protocol Title 
A 52-Week, Open-Label, Extension Study of Pimavanserin for the 
Adjunctive Treatment of Schizophrenia 
Name of 
Investigational 
Product 
Pimavanserin (tablets) 
Indication 
Adjunctive treatment of the negative symptoms of schizophrenia 
Phase of 
Development 
3 
Sponsor 
ACADIA Pharmaceuticals Inc. 
3611 Valley Centre Drive, Suite 300 
San Diego, CA 92130  USA  
Primary Objective 
• To evaluate the long-term safety and 
tolerability of pimavanserin after 
52 weeks of adjunctive treatment in 
subjects with schizophrenia 
Safety Endpoints 
• Incidence and severity of treatment-
emergent adverse events (TEAEs), 
serious adverse events (SAEs), and 
withdrawals due to TEAEs 
• Vital sign measurements, weight, 
clinical laboratory assessments, 
physical examination findings, 
electrocardiogram (ECG) parameters, 
the Abnormal Involuntary Movement 
Scale (AIMS) score, the Barnes 
Akathisia Rating Scale (BARS) score, 
and the Simpson-Angus 
Extrapyramidal Side Effects Scale 
(SAS) score 
• Changes from Baseline in vital sign 
measurements, weight, clinical 
laboratory and ECG parameters, the 
AIMS score, the BARS score, and the 
SAS score 
• Suicidality: the incidence of subjects 
with suicidal ideation or suicidal 
behavior during the study as assessed 

Study: ACP-103-035 
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by the Columbia-Suicide Severity 
Rating Scale (C-SSRS) 
Secondary Objective 
• Clinical global assessment of overall 
severity of symptoms 
Secondary Endpoints 
• Change from Baseline in the Clinical 
Global Impression – Severity scale 
(CGI-S) 
• Change from Baseline in the Clinical 
Global Impression of Schizophrenia 
Scale – Severity (CGI-SCH-S) (for 
subjects from Studies ACP-103-038 
and ACP-103-064 only) 
Exploratory Objective 
• To evaluate the continued efficacy of 
pimavanserin treatment with respect 
to: 
o Overall symptoms of schizophrenia 
o Negative symptoms of 
schizophrenia (for subjects from 
Studies ACP-103-038 and ACP-
103-064 only) 
o Personal and social performance 
Exploratory Endpoints 
• Change from Baseline in the Positive 
and Negative Syndrome Scale 
(PANSS) total score, subscores, and 
Marder factor scores 
• Change from Baseline in the Negative 
Symptom Assessment-16 (NSA-16) 
scale total score (for subjects from 
Studies ACP-103-038 and 
ACP-103-064 only) 
• Change from Baseline in the Personal 
and Social Performance Scale (PSP) 
score 
• Change from Baseline in 36-item Short 
Form Health Survey (SF-36) score (for 
subjects from Studies ACP-103-034 
and ACP-103-038 only)  
• Change from Baseline in 10-item Drug 
Attitude Inventory (DAI-10) score (for 
subjects from Studies ACP-103-034 
and ACP-103-038 only)  
• Change from Baseline in Work 
Readiness Questionnaire (WoRQ) total 
score (for subjects from Study 
ACP-103-064 only) 
• Change from Baseline in Work 
Readiness Questionnaire (WoRQ) 
readiness to work question (item 8) 
(for subjects from Study ACP-103-064 
only) 

Study: ACP-103-035 
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Number of Study 
Sites 
Approximately 220 global sites will participate in this study. 
Number of Subjects 
Planned 
The planned sample size for this study is not based on statistical power 
but will depend on the number of subjects who complete Studies 
ACP-103-034, 038, or 064, and who transition into this open-label 
extension study. 
Test Product, Dose, 
and Administration 
The test products are pimavanserin 10 mg and 17 mg tablets. Daily 
doses of pimavanserin to be studied are 10 mg, (provided as 1×10 mg 
pimavanserin tablet; 20 mg (2×10 mg pimavanserin tablets); or 34 mg 
(2×17 mg pimavanserin tablets); delivered by mouth. Seventeen 
(17) mg of the active moiety is dosed as 20 mg of the salt 
pimavanserin tartrate; 10 mg of the active moiety is dosed as 11.8 mg 
of the salt pimavanserin tartrate. 
Study Design 
This protocol describes an open-label extension study to determine the 
long-term safety and tolerability of pimavanserin for the adjunctive 
treatment of schizophrenia. This study will be conducted as a 52-week, 
open-label, fixed- or flexible-dose extension of Studies ACP-103-034, 
038, and 064.  
Subjects who have completed Studies ACP-103-034, 038, or 064, and 
who have shown no significant worsening of symptoms at the end of 
the study as evidenced by the CGI-I in Study ACP-103-034 and by the 
CGI-SCH-I in Studies ACP-103-038 and 064 or who may benefit or 
may continue to benefit from adjunctive pimavanserin treatment based 
on the Investigator’s judgment will be included in this long-term 
extension study. 
Study ACP-103-035 subjects must be consented prior to the 
procedures being performed at Week 6 for Study ACP-103-034 or at 
Week 26 for Studies ACP-103-038 and 064. Procedures performed at 
the End-of-Study (EOS) visits of these three double-blind studies 
(ACP-103-034, 038, or 064 [EOT visit]) will be carried over to the 
ACP-103-035 study to be included as baseline information, and this 
visit will be considered the Baseline Visit (Visit 1) of the ACP-103-035 
study. 
All subjects will receive once daily (QD) doses of pimavanserin over 
52 weeks of treatment. Subjects transitioning from Studies 
ACP-103-034 and 038 will start at a dose of 20 mg pimavanserin for 
the first 2 weeks. After the Week 2 visit, the daily dose can be adjusted 
to 34 mg, 20 mg, or 10 mg pimavanserin throughout the study, based 
on the Investigator’s assessment of clinical response. Dose adjustments 
may be made at scheduled or unscheduled visits (which may occur 
prior to the Week 2 visit). Subjects transitioning from Study 

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ACP-103-064 will start at a dose of 34 mg pimavanserin and remain at 
this dose for the duration of the Treatment Period.  
During the Treatment Period, clinic visits will be conducted at 
Baseline and Weeks 2, 6, 12, 20, 28, 36, 44, and 52, or upon early 
termination (ET) from the study. 
Study drug will be dispensed to the subject to take home at the 
Baseline visit and at each subsequent visit. The subject and their study 
partner/caregiver will be provided instructions for the subject’s first 
dose of study drug the day after the Baseline visit. It is recommended 
that the subject take the study drug at approximately the same time 
each day as a single, oral dose. 
The main antipsychotic, all concomitant antidepressants, anxiolytics, 
and other permitted medications should remain at a stable dose 
throughout the study, if possible. Adjustments in the dose of the main 
antipsychotic after Baseline are discouraged to minimize confounding 
interpretation of the pimavanserin dose changes and to better 
understand the reason for treatment discontinuation. 
A follow-up safety assessment will be conducted by telephone call at 
approximately 4 weeks after the last dose of study drug. 
Study Duration 
The duration of participation for individual subjects will be up to 
approximately 56 weeks. Each subject will participate in a 52-week 
Treatment Period followed by a 4-week safety follow-up period 
(Figure 3–1). 
The study completion date is defined as the date the final subject, 
across all sites, completes their final protocol-defined assessment 
(note: this includes the safety follow-up telephone call). 
Main Criteria for 
Inclusion and 
Exclusion 
To be eligible for this study, subjects must meet all of the inclusion 
criteria and none of the exclusion criteria. 
Inclusion Criteria: 
Procedures: 
1. Able to understand and provide signed informed consent, and 
must be able to sign and date a request for medical records 
and/or subject privacy form, if applicable, according to local 
regulations 
2. Has a caregiver or some other identified responsible person 
(e.g., family member, social worker, caseworker, or nurse) 
considered reliable by the Investigator in providing support to 
the subject to help ensure compliance with study treatment, 
study visits, and protocol procedures and who is also able to 
provide input helpful for completing study rating scales 

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3. Is completing the Week 6 visit in Study ACP-103-034 or the 
Week 26 visit in Study ACP-103-038 or 064 while continuing to 
take his/her assigned dose of blinded study drug and may, in the 
Investigator’s opinion, benefit from continued adjunctive 
treatment with pimavanserin to an antipsychotic 
Medical Status: 
4. If the subject is female, she must not be pregnant or 
breastfeeding. She must also be of non-childbearing potential 
(defined as either surgically sterilized or at least 1 year 
postmenopausal) OR must agree to use TWO clinically 
acceptable methods of contraception, or be abstinent during the 
study and for 41 days 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 study treatments. This option is usually made 
for specific moral, religious, legal, or health reason. If 
heterosexual intercourse does occur, two acceptable methods of 
birth control are required. 
Acceptable methods of contraception include the following: 
a. A barrier method (condom, diaphragm, or cervical cap) 
with spermicide 
b. Hormonal contraception, including oral, injectable, 
transdermal, or implantable methods 
c. Intrauterine device (IUD) 
Only one of the two clinically acceptable methods can be a 
hormonal method. 
All female subjects of childbearing potential must have a 
negative urine human chorionic gonadotropin (hCG) pregnancy 
test at Baseline and at Weeks 2, 6, 12, 20, 28, 36, 44, and 52. 
Note: Specific contraceptive methods are not required for male 
subjects with partners of childbearing potential, but may be used 
as a general precaution. 
5. Continue to be medically stable at enrollment, in the opinion of 
the Investigator 
Medications: 
6. Continues to take a stable dose of an antipsychotic within the 
dose range recommended according to the local Prescribing 
Information 

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7. The main antipsychotic with which the subject is being treated 
must continue to be one of the antipsychotics listed below: 
• Aripiprazole 
• Aripiprazole long-acting injectables 
o Abilify Maintena® 
o Aristada® 
• Asenapine 
• Brexpiprazole 
• Cariprazine 
• Lurasidone 
• Olanzapine 
• Paliperidone extended release (ER) (≤9 mg) 
• Paliperidone palmitate 
o Invega Sustenna® (≤156 mg) 
o Invega Trinza® (≤546 mg) 
o Trevicta® (≤350 mg) 
o Xeplion® (≤100 mg) 
• Risperidone 
• Risperidone long-acting injection 
Exclusion Criteria: 
Procedures: 
1. Subject is judged by the Investigator or the Medical Monitor to 
be inappropriate for the study (e.g., significantly noncompliant 
in Studies ACP-103-034, 038, or 064) 
Medical Status: 
2. A urine drug screen (UDS) result at Baseline that indicates the 
presence of any tested prohibited substance of potential abuse  
• Subjects from Studies 034 and 038 with a result indicating 
the presence of marijuana are permitted, if allowed by local 
regulations, if they agree to abstain from marijuana use 
during the study and the medical monitor approves the 
subject’s participation 
• Subjects from Study 064 with a result indicating the 
presence of marijuana are not permitted in the study 

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3. Is taking a medication or drug or other substance that is 
prohibited according to this protocol, including medications that 
prolong the QT interval, strong cytochrome P450 (CYP) 3A4 
enzyme (CYP3A4) inhibitors and inducers 
4. Known family or personal history or symptoms of long QT 
syndrome or risk factors for torsade de pointes and/or sudden 
death, including symptomatic bradycardia, hypokalemia or 
hypomagnesemia, and the presence of congenital prolongation 
of the QT interval 
5. Has a QRS interval <120 ms and QTcF ≥460 ms OR has a QRS 
interval ≥120 ms and QTcF ≥480 ms at Baseline  
6. Has developed a serious and/or unstable psychiatric, neurologic, 
cardiovascular, respiratory, gastrointestinal, renal, hepatic, 
hematologic, or other medical disorder, including cancer or 
malignancies that, in the judgment of the Investigator, would 
jeopardize the safe participation of the subject in the study 
7. Is breastfeeding or lactating 
8. Has a significant sensitivity or allergic reaction to pimavanserin 
or its excipients 
9. Subject and/or caregiver has any condition that, in the opinion 
of the Investigator, would interfere with the ability to comply 
with study instructions, might confound the interpretation of the 
study results, or put the subject at undue risk 
10. Presence of any change in medical or treatment status which 
may increase the risk associated with taking study medication, 
would interfere with safety assessments, or would confound the 
interpretation of the study results, based on Investigator’s 
judgment 
Neuropsychiatric: 
11. Is at a significant risk of suicide, (e.g., answers “Yes” to suicidal 
ideation question 4 or 5 [current or over last 6 months] or 
answers “Yes” to suicidal behavior questions on the C-SSRS 
[over last 6 months]), in the opinion of the Investigator 
12. Has a significant risk of violent behavior in the opinion of the 
Investigator 
Other: 
13. Is an employee of ACADIA, or has a family member who is an 
employee of ACADIA  

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Sample Size 
Calculations 
The planned sample size for this study is not based on statistical power 
but will depend on the number of subjects who complete Studies 
ACP-103-034, 038, or 064, and who transition into this open-label 
extension study. 
Statistical Methods 
The purpose of this study is to collect safety data from subjects after 
open-label exposure to pimavanserin for a total duration of up to 
52 weeks. Secondary and exploratory objectives include assessment of 
efficacy outcome measures over time. No formal statistical testing will 
be performed for any of the safety or efficacy endpoints. 
All safety and efficacy measures will be summarized using descriptive 
statistics. 
For each continuous measure in safety and efficacy analyses, changes 
from Baseline results will be presented in three ways: 
• Using the Baseline results from Study ACP-103-035 and 
reporting the changes across Study ACP-103-035 timepoints 
• Using the Baseline results from double-blind Studies 
ACP-103-034, 038, or 064, and reporting the changes across 
the timepoints of the double-blind Studies ACP-103-034, 038, 
or 064 as well as the open-label Study ACP-103-035 timepoints 
• Based on the Baseline results before the first dose of 
pimavanserin in either the double-blind or the open-label study, 
changes will be reported across the timepoints using the 
Baseline results from the double-blind Studies ACP-103-034, 
038, or 064 for subjects receiving pimavanserin in the double-
blind studies (up to 78 weeks), and using the Baseline from 
Study ACP-103-035 for subjects receiving placebo in the 
double-blind studies (up to 52 weeks) 
Descriptive Statistics 
For continuous variables, the following summary statistics will be 
provided: number of subjects, mean, standard error of the mean, 
standard deviation, minimum, maximum, and median. For categorical 
variables, summaries will include the number and percentage of 
subjects in each category, using the number of subjects with non-
missing values as the denominator for the percentages (unless 
otherwise specified). 
Analysis Sets 
The Safety Analysis Set includes all subjects who received at least one 
dose of open-label study drug. The Safety Analysis Set will be used for 
all analyses. 

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Primary Analysis 
Safety results will be summarized using descriptive statistics. Adverse 
events will be classified into standard terminology using the Medical 
Dictionary for Regulatory Activities (MedDRA). Treatment-emergent 
adverse events (TEAEs), TEAEs leading to discontinuation, TEAEs 
related to study drug, AEs by maximum severity, fatal TEAEs, SAEs, 
and SAEs related to study drug will be reported. Other TEAEs of 
special interest may also be summarized. 
Descriptive statistics for ECGs, vital signs and body weight, physical 
examinations, clinical laboratory parameters, the AIMS score, the 
BARS score, and the SAS score, 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 International 
Conference on Harmonisation (ICH) guidelines. 
Descriptive statistics for the C-SSRS, including the incidence of 
subjects with suicidal ideation or suicidal behavior during the study, 
will be tabulated. 
Subgroup Analyses 
Selected analyses will be performed in subgroups defined in the 
statistical analysis plan (SAP). 
Interim Analyses 
Interim analyses may be conducted prior to study completion if 
required for regulatory reporting. 
Date 
11 August 2020 
 

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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE .............................................................................................. 2 
DECLARATION OF INVESTIGATOR................................................................................... 4 
PROTOCOL SYNOPSIS .......................................................................................................... 5 
TABLE OF CONTENTS......................................................................................................... 14 
LIST OF TABLES ................................................................................................................... 19 
LIST OF FIGURES ................................................................................................................. 20 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................ 21 
1 
BACKGROUND INFORMATION ........................................................................... 23 
1.1 
Investigational Drug ................................................................................................... 23 
1.2 
Previous Clinical Experience ..................................................................................... 24 
1.3 
Study Rationale .......................................................................................................... 28 
2 
STUDY OBJECTIVES AND ENDPOINTS ............................................................. 29 
2.1 
Study Objectives......................................................................................................... 29 
2.1.1 
Primary Objective....................................................................................................... 29 
2.1.2 
Secondary Objective................................................................................................... 29 
2.1.3 
Exploratory Objectives ............................................................................................... 29 
2.2 
Study Endpoints ......................................................................................................... 29 
2.2.1 
Safety Endpoints......................................................................................................... 29 
2.2.2 
Efficacy Endpoints ..................................................................................................... 30 
2.2.2.1 Secondary Endpoints .................................................................................................. 30 
2.2.2.2 Exploratory Endpoints ................................................................................................ 30 
3 
STUDY DESCRIPTION ............................................................................................ 30 
3.1 
Overview of Study Design ......................................................................................... 30 
4 
STUDY ELIGIBILITY AND WITHDRAWAL CRITERIA .................................... 33 
4.1 
Inclusion Criteria ........................................................................................................ 33 
4.2 
Exclusion Criteria ....................................................................................................... 35 
4.3 
Subject Withdrawal of Consent .................................................................................. 36 
4.4 
Subject or Study Discontinuation ............................................................................... 36 
4.4.1 
Guidance for Investigators on Suicidality, Symptom Worsening, and Relapse ......... 37 
4.4.2 
Handling of Subject Discontinuation During the Treatment Period .......................... 38 
4.5 
Subject Lost to Follow-up .......................................................................................... 38 

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4.6 
Prior and Concomitant Therapy ................................................................................. 39 
4.6.1 
Prior Medication ......................................................................................................... 39 
4.6.2 
Concomitant Medication ............................................................................................ 39 
4.6.2.1 Permitted, Restricted, and Prohibited Medications .................................................... 39 
5 
INVESTIGATIONAL PRODUCT ............................................................................ 42 
5.1 
Investigational Product Description ........................................................................... 42 
5.1.1 
Formulation, Appearance, Packaging, and Labeling .................................................. 42 
5.1.2 
Product Storage and Stability ..................................................................................... 42 
5.1.3 
Dosing and Administration ......................................................................................... 43 
5.1.3.1 Dose Modification ...................................................................................................... 44 
5.1.4 
Method of Assigning Subjects to Treatment Groups.................................................. 44 
5.1.5 
Blinding ...................................................................................................................... 44 
5.1.6 
Study Drug Compliance ............................................................................................. 44 
5.2 
Overdose ..................................................................................................................... 44 
5.3 
Investigational Product Accountability Procedures ................................................... 45 
6 
STUDY PROCEDURES ............................................................................................ 45 
6.1 
Remote Assessments or Visits .................................................................................... 46 
6.2 
Safety Scales............................................................................................................... 46 
6.2.1 
Abnormal Involuntary Movement Scale .................................................................... 46 
6.2.2 
Barnes Akathisia Rating Scale ................................................................................... 46 
6.2.3 
Simpson-Angus Extrapyramidal Side Effects Scale .................................................. 47 
6.2.4 
Columbia-Suicide Severity Rating Scale ................................................................... 47 
6.3 
Safety Measures ......................................................................................................... 47 
6.3.1 
Medical and Psychiatric History ................................................................................ 47 
6.3.2 
Physical Examination ................................................................................................. 47 
6.3.3 
Vital Sign Measurements............................................................................................ 48 
6.3.4 
Weight......................................................................................................................... 48 
6.3.5 
Electrocardiograms ..................................................................................................... 48 
6.4 
Laboratory Procedures/Evaluations ........................................................................... 48 
6.4.1 
Clinical Laboratory Evaluations ................................................................................. 48 
6.4.1.1 Hematology ................................................................................................................ 48 
6.4.1.2 Serum Chemistry ........................................................................................................ 49 
6.4.1.3 Urinalyses ................................................................................................................... 49 
6.4.2 
Clinically Significant Abnormalities .......................................................................... 49 
6.5 
Efficacy Scales ........................................................................................................... 50 
6.5.1 
Clinical Global Impressions – Severity ...................................................................... 50 

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6.5.2 
Clinical Global Impression of Schizophrenia Scale – Severity ................................. 50 
6.5.3 
Positive and Negative Syndrome Scale ...................................................................... 50 
6.5.4 
Informant Questionnaire for the Positive and Negative Syndrome Scale .................. 50 
6.5.5 
Negative Symptom Assessment-16 ............................................................................ 51 
6.5.6 
Personal and Social Performance Scale ..................................................................... 51 
6.5.7 
36-Item Short Form Health Survey ............................................................................ 51 
6.5.8 
10-Item Drug Attitude Inventory ................................................................................ 51 
6.5.9 
Work Readiness Questionnaire................................................................................... 52 
6.6 
Study Schedule ........................................................................................................... 52 
6.6.1 
Treatment Period ........................................................................................................ 52 
6.6.1.1 Baseline Visit (Visit 1)................................................................................................ 52 
6.6.1.2 Weeks 2, 6, 12, 20, 28, 36, and 44 (Visits 2, 3, 4, 5, 6, 7, and 8) ............................... 53 
6.6.1.3 Week 52 (End-of-Treatment/Early Termination Visit) ............................................... 54 
6.6.2 
Follow-up Period (Week 56) ...................................................................................... 55 
6.6.3 
Unscheduled Visit(s) .................................................................................................. 55 
6.6.4 
Schedule of Events and Assessments ......................................................................... 55 
7 
ADVERSE EVENTS ................................................................................................. 59 
7.1 
Specification of Safety Parameters............................................................................. 59 
7.1.1 
Definition of Adverse Event ....................................................................................... 59 
7.1.2 
Definition of Serious Adverse Event .......................................................................... 59 
7.2 
Classification of an Adverse Event ............................................................................ 61 
7.2.1 
Severity of Event ........................................................................................................ 61 
7.2.2 
Relationship to Study Drug ........................................................................................ 61 
7.2.2.1 Duration ...................................................................................................................... 61 
7.2.2.2 Frequency ................................................................................................................... 62 
7.2.2.3 Action Taken with Study Drug ................................................................................... 62 
7.2.2.4 Therapy ....................................................................................................................... 62 
7.2.2.5 Outcome ..................................................................................................................... 62 
7.2.2.6 Seriousness ................................................................................................................. 62 
7.2.3 
Definition of Unexpectedness .................................................................................... 62 
7.3 
Time Period and Frequency for Event Assessment and Follow-up ........................... 63 
7.4 
Reporting Procedures ................................................................................................. 63 
7.4.1 
Adverse Event Reporting ........................................................................................... 63 
7.4.2 
Serious Adverse Event Reporting............................................................................... 63 
7.4.3 
Reporting of Pregnancy .............................................................................................. 64 
7.4.3.1 Reporting Paternal Drug Exposure............................................................................. 64 
7.4.4 
Reporting of Overdose ............................................................................................... 65 

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7.5 
Safety Oversight ......................................................................................................... 65 
8 
CLINICAL MONITORING....................................................................................... 65 
9 
STATISTICAL CONSIDERATIONS ....................................................................... 65 
9.1 
General Statistical Methods........................................................................................ 65 
9.2 
Determination of Sample Size .................................................................................... 66 
9.3 
Handling of Dropouts and Missing Data .................................................................... 66 
9.4 
Subgroup Analyses ..................................................................................................... 66 
9.5 
Study Subjects ............................................................................................................ 66 
9.5.1 
Subject Populations for Analysis ................................................................................ 66 
9.5.2 
Subject Accountability and Subject Disposition ........................................................ 67 
9.5.3 
Demographic and Baseline Characteristics ................................................................ 67 
9.6 
Interim Analyses ......................................................................................................... 67 
9.7 
Safety Analyses .......................................................................................................... 67 
9.7.1 
Exposure to Study Drug ............................................................................................. 67 
9.7.2 
Adverse Events ........................................................................................................... 67 
9.7.3 
Clinical Laboratory Values ......................................................................................... 67 
9.7.4 
Vital Signs and Body Weight ..................................................................................... 68 
9.7.5 
Electrocardiogram ...................................................................................................... 68 
9.7.6 
Physical Examinations ............................................................................................... 68 
9.7.7 
Columbia Suicide Severity Rating ............................................................................. 68 
9.7.8 
Extrapyramidal Symptom Measures .......................................................................... 68 
9.8 
Efficacy Analyses ....................................................................................................... 68 
10 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS
 .................................................................................................................................... 68 
10.1 
Data Collection and Management Responsibilities.................................................... 68 
10.2 
Source Documentation ............................................................................................... 69 
10.3 
Case Report Forms ..................................................................................................... 69 
10.4 
Confidentiality ............................................................................................................ 69 
10.5 
Study Records Retention ............................................................................................ 70 
10.6 
Protocol Exceptions and Deviations........................................................................... 70 
10.7 
Protocol Amendments ................................................................................................ 70 
11 
QUALITY ASSURANCE AND QUALITY CONTROL ................................... 71 
11.1 
Risk Management ....................................................................................................... 71 
11.2 
Quality Control and Quality Assurance...................................................................... 71 

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12 
ETHICS/PROTECTION OF HUMAN SUBJECTS ............................................ 72 
12.1 
Ethical Standard ......................................................................................................... 72 
12.2 
Institutional Review Board/Ethics Committee ........................................................... 72 
12.3 
Informed Consent Process .......................................................................................... 73 
12.3.1 Consent and Other Informational Documents Provided to Subjects .......................... 73 
12.3.2 Consent Procedures and Documentation .................................................................... 73 
12.3.2.1 Remote Consent Procedures and Documentation ...................................................... 73 
13 
PUBLICATION PLAN .............................................................................................. 74 
14 
CONFLICT OF INTEREST POLICY ....................................................................... 74 
14.1 
Finance, Insurance, and Indemnity............................................................................. 74 
15 
LITERATURE REFERENCES ................................................................................. 75 
16 
APPENDICES ............................................................................................................ 78 
Appendix A. 
Prohibited and Restricted Medications ........................................................... 78 
Appendix B.  Prohibited and Restricted Concomitant Medications: Inhibitors and Inducers 
of Cytochrome P450 Enzyme 3A4 .................................................................. 82 
Appendix C. 
Abnormal Involuntary Movement Scale (AIMS) ........................................... 84 
Appendix D. 
Barnes Akathisia Rating Scale (BARS) .......................................................... 85 
Appendix E. 
Simpson-Angus Extrapyramidal Side Effects Scale (SAS) ............................ 86 
Appendix F. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ....................................... 87 
Appendix G. 
Clinical Global Impression – Severity (CGI-S) Scale .................................... 88 
Appendix H. 
Clinical Global Impression of Schizophrenia Scale – Severity (CGI-SCH-S) ... 
 
 ........................................................................................................................ 89 
Appendix I. 
Structured Clinical Interview – Positive and Negative Syndrome Scale 
(PANSS) ........................................................................................................... 90 
Appendix J. 
Informant Questionnaire for the Positive and Negative Syndrome Scale (IQ-
PANSS) ............................................................................................................ 91 
Appendix K. 
Negative Symptom Assessment-16 (NSA-16) – Long Form ......................... 92 
Appendix L. 
Personal and Social Performance Scale (PSP) ............................................... 93 
Appendix M. 36-Item Short Form Health Survey (SF-36) ................................................... 94 
Appendix N. 
10-Item Drug Attitude Inventory (DAI-10) .................................................... 95 
Appendix O. 
Work Readiness Questionnaire (WoRQ) ........................................................ 96 

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LIST OF TABLES 
Table 5–1 
Treatment Administration Schedule for Protocol ACP-103-035 (Subjects from 
ACP-103-034 and 038) .................................................................................... 43 
Table 6–1 
Schedule of Events and Assessments............................................................... 56 

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LIST OF FIGURES 
Figure 3–1 
Schematic of Study Design for ACP-103-035 ................................................. 32 
 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
5-HT 
5-hydroxytryptamine (serotonin) 
5-HT2A 
5-hydroxytryptamine (serotonin) 2A 
5-HT2C 
5-hydroxytryptamine (serotonin) 2C 
AE 
adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
BARS 
Barnes Akathisia Rating Scale 
CFR 
Code of Federal Regulations 
CGI-I 
Clinical Global Impression – Improvement scale 
CGI-S 
Clinical Global Impression – Severity scale 
CGI-SCH-I 
Clinical Global Impression of Schizophrenia Scale – Improvement 
CGI-SCH-S 
Clinical Global Impression of Schizophrenia Scale – Severity 
CI 
confidence interval 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP 
cytochrome P450 
CYP3A4 
CYP 3A4 enzyme 
DAI-10 
10-item Drug Attitude Inventory 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOS 
End of Study 
EOT 
End of Treatment 
ER 
extended release 
ET 
Early Termination 
EU GDPR 
European Union General Data Protection Regulation 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IQ-PANSS 
Informant Questionnaire for the Positive and Negative Syndrome Scale 
IR 
immediate release 
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
ms 
millisecond 

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Abbreviation 
Definition 
NSA-16 
Negative Symptom Assessment – 16 scale 
PANSS 
Positive and Negative Syndrome Scale 
PSP 
Personal and Social Performance Scale 
QRS interval 
QRS interval of ECG 
QT interval 
QT interval for heart rate of ECG 
QTc interval 
corrected QT interval 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
QTcLD 
QT interval corrected for heart rate using the population specified linear 
derived method 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Simpson-Angus Extrapyramidal Side Effects Scale 
SAS® 
Statistical Analysis System 
SF-36 
36-item Short Form Health Survey 
TEAE 
treatment-emergent adverse event 
UDS 
urine drug screen 
US 
United States 
WoRQ 
Work Readiness Questionnaire 

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1 BACKGROUND INFORMATION 
Schizophrenia is a chronic and debilitating disease that affects approximately 2.4 million 
adults in the United States. The lifetime prevalence is about 1% worldwide (McGrath et al. 
2008). The onset of symptoms generally occurs among people 16 to 30 years of age. Positive 
symptoms of psychosis are necessary to establish a diagnosis; however, other symptom 
clusters, including negative, cognitive, and general psychopathology symptoms, are also 
highly prevalent and contribute significantly to the disability and functional impairment of 
people with the disease. Throughout life the course of the symptoms fluctuate, with acute 
exacerbations being treated and followed by maintenance periods until a relapse occurs. The 
chronic nature of schizophrenia and enduring positive and negative symptoms pose a 
significant need for safe and effective long-term treatment. 
According to the World Health Organization, schizophrenia is included as one of the seven 
most disabling diseases in adults aged between 20 and 45 years, surpassing diabetes, 
cardiovascular disease, and HIV-AIDS (Ebdrup et al. 2011). Indeed, 40% to 80% of patients 
with schizophrenia have a reduced capability for learning and working, performing self-care, 
and maintaining interpersonal relationships and general living skills (Ebdrup et al. 2011).  
Schizophrenia is characterized by positive symptoms, negative symptoms, and cognitive 
impairment. Comorbid sleep disorders may also present in this disease. Negative symptoms 
of schizophrenia include blunted affect, alogia, avolition, asociality, and anhedonia)  
(Alphs et al. 1989; Andreasen 1982; Kay et al. 1987; Kirkpatrick et al. 1989). In contrast to 
positive symptoms, negative symptoms are relatively enduring, constant, and more predictive 
of psychosocial impairment (Tamminga et al. 1998; Peralta et al. 2000). Persistent negative 
symptoms are present in more than 25% of patients with a first episode of psychosis 
(Hovington et al. 2012). 
1.1 
Investigational Drug 
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), and is a novel small molecule designed to specifically block 
serotoninergic neurotransmission mediated by the 5-hydroxytryptamine (5-HT [serotonin]) 
2A (5-HT2A) receptor. At higher doses pimavanserin may block 5HT2C receptors (Vanover et 
al. 2006). 
Pimavanserin shows no appreciable activity at dopaminergic, adrenergic, histaminergic, or 
muscarinic receptors. Activity at these receptors has been implicated in a range of 
dose-limiting side effects associated with existing antipsychotic drugs including cognitive 
dulling (Saeedi et al. 2006; Mehta et al. 2004; Peretti et al. 1997) and an increased risk of 

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mortality in elderly patients with dementia (Wang et al. 2005). On the basis of its novel 
receptor binding profile, adjunctive pimavanserin may be effective in treating schizophrenia 
and may have added benefits in regard to overall tolerability relative to other antipsychotic 
agents. 
In April 2016, pimavanserin was approved in the United States for the treatment of 
hallucinations and delusions associated with Parkinson’s disease psychosis. 
1.2 
Previous Clinical Experience 
The clinical efficacy and safety of pimavanserin has been evaluated in a total of 21 completed 
studies. Approximately 1300 subjects have been exposed to pimavanserin, including 
645 subjects with Parkinson’s disease, 177 subjects with schizophrenia and 346 healthy 
volunteers. Total patient exposure in Parkinson’s disease psychosis exceeds 900 person-years, 
with 172 subjects receiving treatment for at least 2 years, and 279 subjects receiving 
treatment for at least 1 year. The longest single exposure is in a subject with over 10 years of 
continuous treatment with pimavanserin. 
Pimavanserin is considered to be generally safe and well tolerated. In single and multiple 
dose studies in healthy volunteers, the highest doses administered were 255 mg and 136 mg, 
respectively. Across all clinical studies of pimavanserin, the most frequently reported adverse 
events (AEs) were in the central nervous system (CNS), gastrointestinal, and psychiatric 
systems. Most AEs were mild to moderate in intensity. The most common CNS treatment-
emergent adverse events (TEAEs) included dizziness (including postural), headache, and 
somnolence (drowsiness). Common gastrointestinal disturbances included dyspepsia, nausea, 
constipation, and vomiting; severe nausea and vomiting were dose limiting in a few cases. 
Reported psychiatric conditions included such events as agitation, insomnia, and confusional 
state. 
A Phase 2 study (ACP-103-007) was conducted in subjects with schizophrenia experiencing 
haloperidol-induced akathisia. Sixteen subjects received 51 mg/day of pimavanserin in 
addition to their regular dosage of haloperidol (≤20 mg/day) and 18 subjects received placebo 
in addition to their haloperidol dose (≤20 mg/day) for a 5-day Treatment Period. The primary 
efficacy measure was the change from baseline in the Barnes Akathisia Rating Scale (BARS), 
Part 4 (global clinical assessment of akathisia score). The results of this study supported the 
potential for efficacy of pimavanserin in the reduction of haloperidol-induced akathisia. This 
effect was most prominent at Day 3. Pharmacokinetic results indicated that coadministration 
of pimavanserin at 51 mg once daily did not affect haloperidol concentrations. 
The antipsychotic efficacy of pimavanserin was evaluated in a Phase 2 study (ACP-103-008) 
conducted in subjects with schizophrenia (Meltzer et al. 2012). The primary objective of this 

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6-week study was to determine whether a combination of pimavanserin (17 mg once daily) 
with either low-dose haloperidol (2 mg once daily) or low-dose risperidone (2 mg; 1 mg 
twice daily) administered to subjects with schizophrenia would demonstrate antipsychotic 
efficacy, as measured by the Positive and Negative Syndrome Scale (PANSS). 
It was observed that pimavanserin 17 mg plus 2 mg risperidone was significantly more 
efficacious than 2 mg risperidone plus placebo (p≤0.01 starting at Day 15, intent-to-treat 
[ITT] last observation carried forward [LOCF]) and similar in efficacy to a standard dose 
(6 mg) of risperidone (treatment differences not statistically significant). Efficacy advantages 
of the pimavanserin plus risperidone group over the 2 mg risperidone plus placebo group 
were demonstrated in the PANSS total score (p=0.007), PANSS negative symptom score 
(p=0.018), PANSS ≥20% (p=0.001) and ≥50% (p=0.039) responder analysis, and the CGI-S 
score (p=0.008) at endpoint (ACP-103-008). Additionally, discontinuations due to lack of 
efficacy were notably lower in the pimavanserin plus risperidone group (4%) versus the 2 mg 
risperidone plus placebo group (17%). 
No statistical efficacy advantage was demonstrated for pimavanserin plus 2 mg haloperidol 
compared to 2 mg haloperidol plus placebo. The 2 mg haloperidol plus placebo group 
demonstrated improvement in efficacy that was similar to the 6 mg risperidone plus placebo 
group (mean change from baseline to Day 43, ITT LOCF of -25.1 and -23.2, respectively). 
The 2 mg haloperidol dose was therefore not subtherapeutic, and the model was insufficient 
to allow for a statistical advantage of pimavanserin to be demonstrated. 
Exploratory analyses comparing overall weight gain, subjects with 7% weight gain, prolactin 
increase, serum glucose increase, and akathisia (as measured by the BARS) all showed fewer 
events or improvement in the pimavanserin plus 2 mg risperidone group compared to the 
6 mg risperidone arm; the differences were statistically significant on the first four measures 
(p=0.050, p=0.031, p<0.001 and p=0.024, respectively).    
Overall, safety results demonstrated that pimavanserin was generally safe and well-tolerated 
in subjects with schizophrenia. There were no meaningful differences in the TEAE profile, 
clinically relevant changes or trends observed in laboratory data, vital signs, 
electrocardiograms (ECGs), or physical examinations associated with pimavanserin when 
combined with either 2 mg haloperidol or 2 mg risperidone. 
Study ACP-103-020, a Phase 3 study evaluating the efficacy, tolerability and safety of 34 mg 
pimavanserin versus placebo in 199 subjects with Parkinson’s disease psychosis provided the 
primary evidence of efficacy of pimavanserin in the treatment of Parkinson’s disease 
psychosis. Clinically meaningful and statistically significant improvement over placebo was 
demonstrated on the primary and secondary measures of psychosis over a 6-week Treatment 

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Period. Subgroup analyses showed consistent trends regardless of subjects’ age, sex or 
baseline Mini-Mental State Examination (MMSE) status. In addition, clinical benefits were 
observed in all exploratory efficacy measures with significant improvements in nighttime 
sleep, daytime wakefulness, and caregiver burden. The improvements observed in psychotic 
symptoms did not come at the expense of motoric control (Cummings et al. 2014).  
The Phase 3 ENHANCE study (ACP-103-034) was a global six-week, randomized, 
double-blind, placebo-controlled, multicenter, outpatient study designed to examine the 
efficacy and safety of adjunctive use of pimavanserin in patients with schizophrenia who had 
not achieved an adequate response to their current antipsychotic treatment. A total of 
396 subjects were randomized (1:1) to receive either pimavanserin, orally, once daily, in a 
flexible dosing regimen as an adjunctive treatment with a background antipsychotic or 
placebo, orally, once daily, with a background antipsychotic. The starting daily dose of 20 mg 
of pimavanserin or matching placebo at baseline could be adjusted to 34 mg or 10 mg during 
the first three weeks of treatment. The majority of subjects completed the study at the highest 
dose-level (55%). Baseline characteristics were similar across two treatment arms. The most 
prevalent background antipsychotics in the study included risperidone (39.1%), olanzapine 
(35.7%), and aripiprazole (21.3%). The average age of subjects in the study was 37.2 years. 
The primary objective was to evaluate the efficacy of adjunctive pimavanserin versus 
placebo. The primary efficacy measure was the 6-week change from Baseline in PANSS total 
score, the key secondary measure was CGI-S, and other secondary and exploratory measures 
included change from baseline in PANSS factor subscores, and Marder factor scores.  
A consistent improvement of symptoms was observed in the pimavanserin group, but 
improvement on the primary endpoint, the PANSS total score, was not statistically significant 
(p=0.0940) relative to placebo at Week 6. Analysis of the key secondary endpoint, CGI-S 
score, showed improvement consistent with the primary result (unadjusted p=0.0543). 
Secondary and exploratory analyses showed an effect on negative symptoms: PANSS 
negative symptoms subscore (unadjusted p=0.0474) and PANSS Marder Negative Factor 
score (unadjusted p=0.0362). 
Study completion was achieved by 88% of pimavanserin and 96% of placebo subjects. 
Pimavanserin was well tolerated, with a treatment-emergent adverse event (TEAE) rate 
(39.9%) similar to that for placebo (36.4%), and few subjects in either group discontinuing 
due to a TEAE (pimavanserin 2.5%, placebo 0%). Serious adverse events were reported in 
1% of subjects in each arm. Use of adjunctive pimavanserin did not result in clinically 
significant differences from placebo in vital signs, body weight, metabolic syndrome, or 
extrapyramidal symptoms. 

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The Phase 2 ADVANCE study (ACP-103-038) was a 26-week, randomized, double-blind, 
placebo-controlled, multicenter, international study designed to examine the efficacy and 
safety of pimavanserin in patients with schizophrenia who have predominant negative 
symptoms while on a stable background antipsychotic therapy. A total of 403 subjects were 
randomized to receive once-daily pimavanserin (n=201) or placebo (n=202) as an adjunct 
treatment to their ongoing antipsychotic in a flexible dosing regimen. The starting daily dose 
of 20 mg of pimavanserin at baseline could have been adjusted to 34 mg or 10 mg during the 
first eight weeks of treatment. 53.8% of subjects who were randomized to receive 
pimavanserin completed the trial on 34 mg, 44.7% on 20 mg, and 1.5% on 10 mg. The 
primary endpoint of the study was the change from baseline to Week 26 on the Negative 
Symptom Assessment-16 (NSA-16) total score. 
Baseline characteristics were similar across two treatment arms. The most prevalent 
background antipsychotics in the study included risperidone (38.5%), aripiprazole (32.5%), 
and olanzapine (28.0%). The average age of subjects in the study was 37.2 years. 
Pimavanserin demonstrated a statistically significant improvement on the study’s primary 
endpoint, the change from baseline to Week 26 on the NSA-16 total score, compared to 
placebo (-10.4 vs. -8.5; p=0.043; effect size=0.21). A greater improvement in the NSA-16 
total score compared to placebo was observed in the 53.8% of subjects (n=107) who received 
the highest pimavanserin dose of 34 mg (-11.6 vs. -8.5; unadjusted p=0.0065, effect 
size=0.34). 
In the study, pimavanserin was well-tolerated with high completion rates of approximately 
86% in both the pimavanserin and placebo treatment groups and similar rates of adverse 
events between pimavanserin (39.8%) and placebo (35.1%). Additionally, no clinically 
significant differences in vital signs, weight, metabolic syndrome or extrapyramidal 
symptoms were observed in the pimavanserin group compared to placebo. Serious adverse 
events were reported in 2.0% of subjects on pimavanserin and 0.5% of subjects on placebo, 
and discontinuations due to adverse events were also low, 5.0% for pimavanserin and 3.0% 
for placebo. 
Clinical and nonclinical safety pharmacology studies of pimavanserin suggest a potential risk 
for QT prolongation. The magnitude of effect in humans has been assessed in a thorough 
QT study with doses of pimavanserin ranging from 17 to 68 mg. In the Phase 3 Parkinson’s 
disease psychosis program with a dose of 34 mg, an average prolongation of approximately 
5 to 8 milliseconds (ms) was observed. Pimavanserin also carries a boxed warning related to 
increased mortality in elderly patients with dementia-related psychosis. It is not approved for 
the treatment of patients with dementia-related psychosis unrelated to the hallucinations and 
delusions associated with Parkinson’s disease psychosis. 

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Additional information is provided in the Pimavanserin Investigator’s Brochure and in the 
US Package Insert for NUPLAZID® (pimavanserin) tablets for oral use. 
1.3 
Study Rationale 
Schizophrenia is a chronic disease that generally requires life-long treatment. While positive 
symptoms may vary in intensity and recurrence and often lead to relapses, negative 
symptoms are generally persistent and have a greater impact on functioning. Available 
antipsychotics or augmentation strategies are not completely efficacious in controlling 
schizophrenia and carry a number of side effects that increase overall health risk and reduce 
patients’ compliance. There are no approved adjunctive treatments for schizophrenia; 
therefore, an active therapeutic intervention is needed that could effectively manage 
psychotic symptoms and improve negative symptoms without increasing the risk for 
metabolic, cardiovascular or extrapyramidal side effects and overall mortality in this patient 
population.  
Like all of the atypical antipsychotics, pimavanserin shows high potency and efficacy as a 
competitive antagonist and inverse agonist at the 5-HT2A receptor. Importantly for its 
potential use in schizophrenia, pimavanserin has no affinity or functional activity at 
D2 receptors. Thus, pimavanserin may offer antipsychotic benefit in this subject population 
with an acceptable risk profile. In patients with acute schizophrenia pimavanserin has been 
shown to potentiate a subeffective dose of the atypical APD risperidone producing a more 
rapid onset of action than standard-dose risperidone or an equally effective dose of 
haloperidol, while producing fewer side effects (Meltzer et al. 2012). 
ACADIA Pharmaceuticals Inc. (ACADIA) has conducted two double-blind, 
placebo-controlled studies to assess the efficacy and safety of pimavanserin in the adjunctive 
treatment of schizophrenia including a dedicated study for the treatment of negative 
symptoms. Study ACP-103-034 evaluated the efficacy and safety of pimavanserin in the 
adjunctive treatment of schizophrenia, and Study ACP-103-038 evaluated the efficacy and 
safety of pimavanserin in the adjunctive treatment of the negative symptoms of 
schizophrenia. A further double-blind placebo-controlled study, ACP-103-064, will evaluate 
the efficacy and safety of a fixed dose of pimavanserin (34 mg) in the adjunctive treatment of 
the negative symptoms of schizophrenia. 
While the focus of these double-blind studies is to assess the efficacy of selected doses of 
pimavanserin added to the main antipsychotic versus placebo, evaluate the overall clinical 
benefit in various symptom domains and functioning, and obtain short-term safety and 
tolerability data, the purpose of this open-label extension is to obtain additional long-term 
information on the safety and tolerability of pimavanserin. Exploratory information about the 

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sustained efficacy of pimavanserin as adjunctive treatment will also be collected in the 
efficacy assessments throughout the study. 
Examining pimavanserin long-term safety, tolerability, and efficacy is, therefore, of critical 
importance to eventually help clinicians make an informed decision on pharmacotherapy for 
patients. 
2 STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Study Objectives 
2.1.1 
Primary Objective 
• To evaluate the long-term safety and tolerability of pimavanserin after 52 weeks of 
adjunctive treatment in subjects with schizophrenia 
2.1.2 
Secondary Objective 
• Clinical global assessment overall severity of symptoms 
2.1.3 
Exploratory Objectives 
To evaluate the continued efficacy of pimavanserin treatment with respect to: 
• Overall symptoms of schizophrenia 
• Negative symptoms of schizophrenia (for subjects from Studies ACP-103-038 and 064 
only) 
• Personal and social performance 
2.2 
Study Endpoints 
2.2.1 
Safety Endpoints 
• Incidence and severity of treatment-emergent adverse events (TEAEs), serious adverse 
events (SAEs), and withdrawals due to TEAEs 
• Vital sign measurements, weight, clinical laboratory assessments, physical examination 
findings, electrocardiogram (ECG) parameters, the Abnormal Involuntary Movement 
Scale (AIMS) score, the Barnes Akathisia Rating Scale (BARS) score, and the 
Simpson-Angus Extrapyramidal Side Effects Scale (SAS) score 
• Changes from Baseline in vital sign measurements, weight, clinical laboratory and 
ECG parameters, the AIMS score, the BARS score, and the SAS score 
• Suicidality: the incidence of subjects with suicidal ideation or suicidal behavior during 
the study as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS)  

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2.2.2 
Efficacy Endpoints 
2.2.2.1 
Secondary Endpoints 
• Change from Baseline in the Clinical Global Impression – Severity scale (CGI-S) 
• Change from Baseline in the Clinical Global Impression of Schizophrenia Scale – 
Severity (CGI-SCH-S) (for subjects from Studies ACP-103-038 and 064 only) 
2.2.2.2 
Exploratory Endpoints 
• Change from Baseline in the Positive and Negative Syndrome Scale (PANSS) total score, 
subscores, and Marder factor scores 
• Change from Baseline in the Negative Symptom Assessment-16 (NSA-16) scale total 
score (for subjects from Study ACP-103-038 and 064 only) 
• Change from Baseline in the Personal and Social Performance Scale (PSP) score 
• Change from Baseline in 36-item Short Form Health Survey (SF-36) score (for subjects 
from ACP-103-034 and 038 only) 
• Change from Baseline in 10-item Drug Attitude Inventory (DAI-10) score (for subjects 
from ACP-103-034 and 038 only) 
• Change from Baseline in Work Readiness Questionnaire (WoRQ) total score (for subjects 
from Study ACP-103-064 only) 
• Change from Baseline in Work Readiness Questionnaire (WoRQ) readiness to work 
question (item 8) (for subjects from Study ACP-103-064 only) 
3 STUDY DESCRIPTION 
3.1 
Overview of Study Design 
This protocol describes an open-label extension study to determine the long-term safety and 
tolerability of pimavanserin for the adjunctive treatment of schizophrenia. This study will be 
conducted as a 52-week, open-label, fixed- or flexible-dose extension of Studies 
ACP-103-034, 038, and 064.  
Subjects who have completed Studies ACP-103-034, 038, or 064, and who have shown no 
significant worsening of symptoms at the end of the study as evidenced by the CGI-I in Study 
ACP-103-034 and by the CGI-SCH-I in Studies ACP-103-038 and 064 or who may benefit or 
continue to benefit from adjunctive pimavanserin treatment based on the Investigator’s 
judgment will be included in this long-term extension study.  
Study ACP-103-035 subjects must be consented prior to the final procedures being 
performed at Week 6 for Study ACP-103-034 or at Week 26 for Studies ACP-103-038 and 

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064. Procedures performed at the End-of-Study (EOS) visits of these three double-blind 
studies (ACP-103-034, 038, or 064 [EOT visit]) will be carried over to the ACP-103-035 
study to be included as baseline information, and this visit will be considered the Baseline 
visit (Visit 1) of the ACP-103-035 study. 
All subjects will receive once daily (QD) doses of pimavanserin over 52 weeks of treatment. 
Subjects transitioning from Studies ACP-103-034 and 038 will start at a dose of 20 mg 
pimavanserin for the first 2 weeks. After the Week 2 visit, the daily dose can be adjusted to 
34 mg, 20 mg, or 10 mg pimavanserin throughout the study, based on the Investigator’s 
assessment of clinical response. Dose adjustments may be made at scheduled or unscheduled 
visits (which may occur prior to the Week 2 visit). Subjects transitioning from the 
ACP-103-064 study will start at a dose of 34 mg and remain at 34 mg for the duration of the 
Treatment Period. During the Treatment Period, clinic visits will be conducted at Baseline 
and Weeks 2, 6, 12, 20, 28, 36, 44, and 52, or upon early termination (ET) from the study. 
Study drug will be dispensed to the subject to take home at the Baseline visit and at each 
subsequent visit. The subject and their study partner/caregiver will be provided instructions 
for subject’s first dose of study drug on the day after the Baseline visit. It is recommended 
that the subject take the study drug at approximately the same time each day as a single, oral 
dose. The main antipsychotic, all concomitant antidepressants, anxiolytics, and other 
permitted medications should remain at a stable dose throughout the study, if possible. 
Adjustments in the dose of the main antipsychotic after Baseline are discouraged to minimize 
confounding interpretation of the pimavanserin dose changes and to better understand the 
reason for treatment discontinuation. 
In addition to the EOT or ET visit performed at time of study completion or premature 
discontinuation, a follow-up safety assessment will also be conducted by telephone call at 
approximately 4 weeks after the last dose of study drug. Figure 3–1 illustrates the study 
design. 
The study completion date is defined as the date the final subject, across all sites, completes 
their final protocol-defined assessment (note: this includes the safety follow-up telephone 
call).

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Figure 3–1 
Schematic of Study Design for ACP-103-035 
  
 
 
 
 
 
a  
For subjects from Study ACP-103-064 only  
b  
For subjects from Studies ACP-103-034 and 038 only 
 
 
 
Eligible subjects who 
completed double-blind studies 
ACP-103-034, 038, or 064, and 
who may, in the opinion of the 
Investigator, continue to benefit 
from adjunctive pimavanserin 
treatment 
Open-Label Treatment Period 
52 weeks 
Stable dose of main antipsychotic + fixeda or flexibleb dose of 
pimavanserin 
Follow-up Period 
4 weeks 
EOT/ET 
4-week follow-up 
(telephone call) 

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4 STUDY ELIGIBILITY AND WITHDRAWAL CRITERIA 
Subjects must meet all of the inclusion and none of the exclusion criteria (Sections 4.1 and 
4.2, respectively) to be eligible for participation 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 study, it is discovered that the subject did not meet all eligibility 
criteria, she or he will be discontinued, unless the discontinuation presents an unacceptable 
medical risk. The justification to allow the subject to continue in the study will be made by 
the Sponsor, with medical input from the Investigator, and will be documented. If allowed to 
remain in the study, 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. 
4.1 
Inclusion Criteria 
A subject must meet all of the following inclusion criteria to be eligible for participation in 
the study: 
Procedures: 
1. Able to understand and provide signed informed consent, and must be able to sign and 
date a request for medical records and/or subject privacy form, if applicable, according 
to local regulations 
2. Has a caregiver or some other identified responsible person (e.g., family member, 
social worker, caseworker, or nurse) considered reliable by the Investigator in 
providing support to the subject to help ensure compliance with study treatment, study 
visits, and protocol procedures and who is also able to provide input helpful for 
completing study rating scales 
3. Is completing the Week 6 visit in Study ACP-103-034 or the Week 26 visit in Studies 
ACP-103-038 or 064 while continuing to take his/her assigned dose of blinded study 
drug and may, in the Investigator’s opinion, benefit from continued adjunctive 
treatment with pimavanserin to an antipsychotic 
Medical Status: 
4. If the subject is female, she must not be pregnant or breastfeeding. She must also be of 
non-childbearing potential (defined as either surgically sterilized or at least 1 year 
postmenopausal) OR must agree to use TWO clinically acceptable methods of 
contraception, or be abstinent during the study and for 41 days 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 specific moral, religious, legal, or health 

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reason. If heterosexual intercourse does occur, two acceptable methods of birth control 
are required. 
Acceptable method of contraception include the following: 
a. A barrier method (condom, diaphragm, or cervical cap) with spermicide 
b. Hormonal contraception, including oral, injectable, transdermal, or implantable 
methods 
c. Intrauterine device (IUD)  
Only one of the two clinically acceptable methods can be a hormonal method. 
All female subjects of childbearing potential must have a negative urine human 
chorionic gonadotropin (hCG) pregnancy test at Baseline and at Weeks 2, 6, 12, 20, 
28, 36, 44, and 52. 
Note: Specific contraceptive methods are not required for male subjects with partners 
of childbearing potential, but may be used as a general precaution. 
5. Continue to be medically stable at enrollment, in the opinion of the Investigator 
Medications: 
6. Continues to take a stable dose of an antipsychotic within the dose range 
recommended according to the local Prescribing Information  
7. The main antipsychotic with which the subject is being treated must continue to be 
one of the antipsychotics listed below: 
• Aripiprazole 
• Aripiprazole long-acting injectables 
o Abilify Maintena® 
o Aristada® 
• Asenapine 
• Brexpiprazole 
• Cariprazine 
• Lurasidone 
• Olanzapine 
• Paliperidone extended release (ER) (≤9 mg) 
• Paliperidone palmitate 
o Invega Sustenna® (≤156 mg) 

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o Invega Trinza® (≤546 mg) 
o Trevicta® (≤350 mg) 
o Xeplion® (≤100 mg) 
• Risperidone 
• Risperidone long-acting injection 
4.2 
Exclusion Criteria 
A subject must meet none of the following exclusion criteria: 
Procedures: 
1. Subject is judged by the Investigator or the Medical Monitor to be inappropriate for 
the study (e.g., significantly noncompliant in Studies ACP-103-034, 038, or 064) 
Medical Status: 
2. A urine drug screen (UDS) result at Baseline that indicates the presence of any tested 
prohibited substance of potential abuse 
• Subjects from Studies 034 and 038 with a result indicating the presence of 
marijuana are permitted, if allowed by local regulations, if they agree to abstain 
from marijuana use during the study and the medical monitor approves the 
subject’s participation 
• Subjects from Study 064 with a result indicating the presence of marijuana are not 
permitted in the study 
3. Is taking a medication or drug or other substance that is prohibited according to this 
protocol, including medications that prolong the QT interval, strong cytochrome P450 
(CYP) 3A4 enzyme (CYP3A4) inhibitors and inducers 
4. Known family or personal history or symptoms of long QT syndrome or risk factors 
for torsade de pointes and/or sudden death, including symptomatic bradycardia, 
hypokalemia or hypomagnesemia, and the presence of congenital prolongation of the 
QT interval 
5. Has a QRS interval <120 ms and QTcF ≥460 ms OR 
has a QRS interval ≥120 ms and QTcF ≥480 ms at Baseline 
6. Has developed a serious and/or unstable psychiatric, neurologic, cardiovascular, 
respiratory, gastrointestinal, renal, hepatic, hematologic, or other medical disorder, 
including cancer or malignancies that, in the judgment of the Investigator, would 
jeopardize the safe participation of the subject in the study 
7. Is breastfeeding or lactating 

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8. Has a significant sensitivity or allergic reaction to pimavanserin or its excipients 
9. Subject and/or caregiver has any condition that, in the opinion of the Investigator, 
would interfere with the ability to comply with study instructions, might confound the 
interpretation of the study results, or put the subject at undue risk 
10. Presence of any change in medical or treatment status which may increase the risk 
associated with taking study medication, would interfere with safety assessments, or 
would confound the interpretation of the study results, based on Investigator’s 
judgment 
Neuropsychiatric: 
11. Is at a significant risk of suicide, (e.g., answers “Yes” to suicidal ideation question 
4 or 5 [current or over last 6 months] or answers “Yes” to suicidal behavior questions 
on the C-SSRS [over last 6 months)], in the opinion of the Investigator 
12. Has a significant risk of violent behavior in the opinion of the Investigator 
Other: 
13. Is an employee of ACADIA, or has a family member who is an employee of ACADIA 
4.3 
Subject Withdrawal of Consent 
In accordance with the Declaration of Helsinki and other applicable regulations, a subject has 
the right to withdraw from the study at any time, and for any reason, without prejudice to his 
or her future medical care. 
Should a subject (or legally acceptable representative) request or decide to withdraw consent, 
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 Week 52 
(End-of-Treatment/Early Termination [EOT/ET]) visit as outlined in Table 6–1. 
Every reasonable effort will be made to complete the 4-week safety follow-up telephone call 
for all subjects who withdraw prematurely. All information will be reported on the applicable 
pages of the electronic case report form (eCRF). 
4.4 
Subject or Study Discontinuation 
Subjects may be discontinued or withdrawn from the study for a number of reasons, 
including, but not limited to, those listed below: 
• Subject voluntarily withdraws consent 
• Female subject becomes pregnant 

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• Investigator determines that continuation in the study would be detrimental to a subject’s 
well-being (e.g., safety or tolerability concerns due to an adverse event; a clinically 
significant risk of suicidality is identified for a subject or a subject’s clinical symptoms 
significantly worsen or relapse which in the opinion of the Investigator required the 
subject to be withdrawn) 
• Subject has a confirmed ECG measurement of QTcF interval >500 ms or a change from 
baseline in the QTcF interval >60 ms concurrently with a QTcF interval >470 ms 
• Subject fails to comply with protocol requirements 
• Subject is lost to follow-up 
• At the discretion of the Sponsor 
A subject is considered to have completed planned participation in the study if all treatment 
visits including the safety follow-up telephone call have been completed. Following 
completion of the study or for those subjects who discontinue prematurely, the Investigator 
must ensure that the subject is appropriately transitioned to standard of care treatment and/or 
followed for additional care per the Investigator or physician’s clinical judgement. 
A single documented social hospitalization (see Section 7.1.2) for a maximum duration of 
2 weeks may be allowed over the course of the study provided that the subject has the 
opportunity to engage in social and functional activities, as required for PSP assessment. 
The Sponsor reserves the right to discontinue the study at any time for any reason. Such 
reasons may be any of, but not limited to, the following: 
• Occurrence of AEs unknown to date in respect of their nature, severity, and duration or 
the unexpected incidence of known AEs 
• Medical, ethical, or business reasons affecting the continued performance of the study 
Regulatory authorities also have the right to terminate the conduct of the study in their region 
for any reason. 
The Sponsor reserves the right to stop a site from further participation due to issues of 
quality, conduct or unresponsiveness. 
4.4.1 
Guidance for Investigators on Suicidality, Symptom Worsening, and Relapse 
The decision to withdraw a subject due to suicidality, symptom worsening, or relapse is a 
clinical judgment made by the Investigator. Below are some potential signs of suicidality, 
symptom worsening, or relapse that Investigators may choose to use to inform this decision: 
• Subject answers “Yes” to suicidal ideation question 4 or 5 (since previous visit) or 
answers “Yes” to suicidal behavior questions on the C-SSRS 

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• An increase in the level of psychiatric care required by the subject (e.g., significant 
crisis intervention needed to avert hospitalization or clinically notable increases in the 
frequency or intensity of subject contact required to maintain outpatient status) 
• Deliberate self-injury, suicidal, or homicidal ideation that is clinically significant as 
determined by the Investigator, or violent behavior resulting in clinically significant 
injury to another person or property damage 
• Increase in main antipsychotic dose of more than 25% of the current stable dose or 
addition or dose increase of another psychotropic medication to prevent symptom 
exacerbation, including additional antipsychotics, mood stabilizers, or 
benzodiazepines (see Appendix A and Appendix B for medications and changes to 
medications that are prohibited and will result in the subject being withdrawn from 
the study) 
• Substantial clinical deterioration, as indicated by a score of 6 (“much worse”) or 
7 (“very much worse”) on the CGI-SCH-I of negative symptoms scale 
4.4.2 
Handling of Subject Discontinuation During the Treatment Period 
Unless the subject has withdrawn consent to be contacted for this study, every reasonable 
effort should be made to complete Visit 9/ET and the safety follow-up visit (as outlined in 
Table 6–1) if a subject discontinues prematurely during the treatment period of the study for 
any reason. All information will be reported on the applicable pages of the electronic case 
report form (eCRF). 
If a subject is discontinued from the study because of an AE, every reasonable attempt should 
be made to follow and appropriately treat the subject until the AE resolves or until the 
Investigator deems the AE to be chronic or stable. For subjects who continue to be followed 
for safety, SAEs should continue to be reported as described in Section 7.4.2. All SAEs will 
continue to be followed and appropriately treated until such events have resolved or the 
Investigator deems them to be chronic or stable. 
4.5 
Subject Lost to Follow-up 
A subject will be considered lost to follow-up if they fail to attend a scheduled visit 
(including the safety follow-up visit) and are unable to be contacted by the study site.  
Every reasonable effort should be made to contact the subject and will include a minimum of 
3 documented phone calls (each performed at different times of the day) and, if necessary, a 
certified letter to the subject’s last known mailing address or local equivalent methods. All 
contact attempts are to be documented in the source documents. 

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4.6 
Prior and Concomitant Therapy 
4.6.1 
Prior Medication 
Prior medication is defined as any medication taken before the date of the first dose of study 
drug. 
4.6.2 
Concomitant Medication 
Concomitant medication is defined as any medication taken on or after the date of the first 
dose of study drug. 
All ongoing concomitant medications will be captured from the preceding double-blind 
studies (ACP-103-034, 038, and 064) and will be recorded from Baseline through the 
EOT/ET visit. 
In order to ensure that appropriate concomitant therapy is administered, it is essential that 
subjects be instructed not to take any medication without prior consultation with the 
Investigator (unless the subject is receiving treatment for a medical emergency). 
The Investigator may prescribe appropriate medication to treat AEs.   
4.6.2.1 
Permitted, Restricted, and Prohibited Medications 
Prohibitions and restrictions for concomitant medications should be followed between the 
initial Baseline visit and Visit 9/EOT/ET as specified in Appendix A and Appendix B. These 
appendices do not constitute an exhaustive list and any questions regarding prohibited and 
restricted medications should be discussed with the Medical Monitor or designee. 
Medications that can prolong QT interval are prohibited (or restricted if approved by the 
Medical Monitor) as specified in Appendix A.  
Permitted concomitant medications should remain at a stable dose throughout the study.  
If a subject is on a medication restricted by the protocol, the medication should be adjusted if 
it is determined by the Investigator to be clinically appropriate (e.g., if the subject's 
symptoms are not well-controlled or if the subject cannot tolerate the current medication) in 
consultation with the treating physician. 
Subjects who require current treatment with a prohibited medication will be withdrawn from 
the study. 
Subjects who have taken a prohibited medication during the study will be withdrawn from 
the study unless: 
• the prohibited medication has been discontinued, AND 
• withdrawal from the study presents an unacceptable medical risk to the subject 

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The justification to allow the subject who has taken a prohibited medication to continue in 
the trial will be made by the Sponsor/Medical Monitor, with medical input from the 
Investigator, and will be documented. If a subject is allowed to remain in the trial, this will be 
reported as a major protocol deviation and not a waiver. 
4.6.2.1.1 
Rationale for Including Paliperidone Extended Release (≤9 mg/day) 
Formulations as Allowed Antipsychotics 
As part of Study ACP-103-035 Protocol Amendment 3, paliperidone (9-OH-risperidone, the 
main active metabolite of risperidone) extended release (ER) drug formulations have been 
added as allowed antipsychotics with a maximum dose of 9 mg/day (or equivalents for depot 
formulations). 
Data from clinical studies conducted by both ACADIA and others support the inclusion of 
paliperidone ER (≤9 mg/day) as an allowed antipsychotic:  
ACADIA Studies 
Review of data from recently completed and ongoing ACADIA studies in patients with 
schizophrenia, in which pimavanserin was used as adjunctive treatment with various 
antipsychotics, showed no evidence of significant QTc prolongation when pimavanserin was 
used with oral risperidone or risperidone long-acting injection, relative to that observed when 
pimavanserin was used with aripiprazole or olanzapine. 
Specifically, 
• in Study ACP-103-034 (6 weeks of double-blind adjunctive treatment; 73 subjects 
treated with risperidone, 37 subjects with aripiprazole, and 69 subjects with 
olanzapine), there were no postbaseline QTcF values ≥481 ms, and one subject in 
each of the risperidone and aripiprazole groups had a change from baseline to 
postbaseline maximum of >60 ms. More subjects had a change from baseline to 
postbaseline maximum of 31 to 60 ms in the risperidone plus adjunctive placebo 
group than in the risperidone plus adjunctive pimavanserin group. 
• in Study ACP-103-038 (26 weeks of double-blind adjunctive treatment; 83 subjects 
treated with risperidone, 60 subjects with aripiprazole, and 47 subjects with 
olanzapine), one subject treated with aripiprazole had a postbaseline QTcF maximum 
of 481 to 500 ms, and one subject treated with aripiprazole had a change from 
baseline to postbaseline maximum of >60 ms. Of note, more subjects had a change 
from baseline to postbaseline maximum between 31 to 60 ms in each of the groups 
treated with aripiprazole or olanzapine than in the group treated with risperidone. 

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• in Study ACP-103-035 (currently ongoing; 52 weeks of open-label adjunctive 
treatment; exposure ranges from 52 to 78 weeks in those subjects who have 
completed the study; 253 subjects on risperidone, 171 subjects on aripiprazole, and 
214 subjects on olanzapine), one subject treated with aripiprazole had a postbaseline 
QTcF maximum of 481 to 500 ms, and one subject in each of the groups treated with 
aripiprazole and risperidone had a double-blind baseline to post double-blind baseline 
maximum of >60 ms. Similar proportions of subjects had changes from double-blind 
baseline to post double-blind baseline maximum between 31 to 60 ms across 
treatments. 
In these studies, subjects received doses of risperidone from 1 mg once daily to 6 mg three 
times daily, with over 85% of subjects on a dose of >4 mg/day. Of note, 6 weeks of treatment 
with approximately 5 mg oral risperidone (Riedel et al. 2005) resulted in similar exposure to 
paliperidone as compared with 12 mg paliperidone ER.  
Invega® Study 
In a thorough QT study testing various doses of immediate release (IR) oral formulation of 
paliperidone, a 4 mg dose with peak plasma concentration at steady state (Cmax,ss) of 
35 ng/mL showed an increased placebo-subtracted QTcLD of 6.8 ms (90% CI: 3.6, 10.1). In 
the same study, an 8 mg paliperidone IR dose showed a mean placebo-subtracted increase 
from Baseline in QTcLD of 12.3 ms (90% CI: 8.9, 15.6). The mean Cmax,ss for this 8 mg dose 
of paliperidone IR was more than twice the exposure observed with the maximum 12 mg 
dose of paliperidone ER recommended by the manufacturer (113 ng/mL and 45 ng/mL, 
respectively). None of the subjects had a change exceeding 60 ms or a QTcLD exceeding 
500 ms at any time during this study (Janssen Pharmaceuticals Inc. 2019).  
Study Precautions 
In light of these findings, study precautions include a maximum dose of 9 mg paliperidone 
ER (i.e., a similar plasma concentration to a 4 mg dose of the IR oral formulation of 
paliperidone) and eligibility review in the parent study (ACP-103-064) of each potential 
subject taking into account medical history and ECG data (i.e., a QRS interval <120 ms and a 
QTcF ≥460 ms, OR a QRS interval ≥120 ms and a QTcF ≥480 ms, at Screening or Baseline is 
exclusionary). Subjects on high doses of paliperidone ER (12 and 18 mg) and paliperidone 
palmitate will be excluded. In addition, ongoing study safety data monitoring will include 
regular data and safety monitoring board (DSMB) reviews and discontinuing subjects who 
have a QTcF interval >500 ms, or an increase of >60 ms from Baseline concurrently with a 
QTcF interval >470 ms. 

St u d y: A C P -1 0 3 -0 3 5  
Fi nal Versi o n: 1. 0  
Cli nical St u d y Pr ot oc ol A me n d me nt 3   
  
  
  
 
               Date: 1 1 A u g ust 2 0 2 0  
C o nfi de ntial a n d Pr o prietar y I nf or mati o n of A C A DI A P har mace uticals I nc.  
Pa g e 4 2  of 9 6  
5  I N V E S TI G A TI O N A L P R O D U C T 
5. 1  
I n vesti g ati o n al Pr o d uct Descri pti o n 
T he i n vesti gati o nal pr o d uct will be pi ma va nseri n 1 0 m g or 1 7 m g ta ble ts. Ta blets will be 
a d mi nistere d orall y as a si n gle d ose o nce dail y. 
Pi ma va nseri n d oses t o be st u die d: 
•  Pi ma va nseri n 1 0 m g ( pr o vi de d as 1 × 1 0 m g ta blet) (s u bjects fr o m St u dies A C P- 1 0 3- 0 3 4 
a n d 0 3 8 o nl y) 
•  Pi ma va nseri n 2 0 m g ( pr o vi de d as 2 × 1 0 m g ta blets) (s u bjec ts fr o m St u dies A C P- 1 0 3- 0 3 4 
a n d 0 3 8 o nl y) 
•  Pi ma va nseri n 3 4 m g ( pr o vi de d as 2 × 1 7 m g ta blets) 
5. 1. 1  
F or m ul ati o n, A p pe ar a nce, P ac k a gi n g, a n d L a beli n g 
Pi ma va nseri n will be pr o vi de d as 1 0 m g a n d 1 7 m g stre n gt h. T he S p o ns or or its desi g nee will 
s u p pl y t he pi ma va nseri n ta blets. 
D uri n g t he Treat me nt Peri o d, st u d y dr u g will be s u p plie d i n b ottles w hic h will c o ntai n 
6 0 ta blets of 1 0 m g pi ma va nseri n or 1 7 m g pi ma v a nseri n. 
Pi ma va nseri n tartrat e is a w hite t o off -w hite p o w d er. Pi ma v a nseri n ta blets i ncl u de t he acti ve 
c o m p o u n d ( pi ma va nseri n) a n d t he f oll o wi n g e x ci pie nts: pre gelati nize d starc h, ma g nesi u m 
stearate, a n d micr ocr ystalli ne cell ul ose, a n d t he ta blet c oati n g is O pa dr y ®  t m 0 7 F 2 8 5 8 8 
w hite. T he dr u g pr o d uct is f or m ulate d wit h sta n dar d p har mace utical e x ci pie nts at 1 0 m g a n d 
1 7 m g stre n gt hs ( 1 1. 8 m g a n d 2 0 m g of pi ma va nseri n tartrate, res pecti vel y), I R ta blets f or 
o nce- dail y or al a d mi nistrati o n.  
Pi ma va nseri n ta blets ar e ma n ufact ur e d u n der c urre nt G o o d Ma n ufact uri n g Practice 
c o m plia nce b y 
 
D uri n g t he treat me nt p eri o d, st u d y dr u g will be distri b ute d i n a q ua ntit y s ufficie nt t o e ns ure 
t he s u bject has a n a de q uate s u p pl y of st u d y dr u g bet wee n st u d y visits. I n a d diti o n t o t he st u d y 
dr u g dis pe nse d at t he site, i n vesti gati o nal pr o d uct ma y be deli vere d directl y t o t he s u bject’s 
place of resi de nce ; relat e d pr oce d ur es will be descri be d i n t he st u d y-s pecifi c p har mac y 
ma n ual.  
5. 1. 2  
Pr o d uct St or a ge a n d St a bilit y  
T he st u d y dr u g m ust be ke pt at 1 5° C t o 3 0° C ( 5 9° F t o 8 6° F) i n a sec ure area wit h restricte d 
access a n d acc or di n g t o l ocal a n d nati o nal re g ulati o ns. Neit her t he I n v esti gat or, n or t he 
p har macist, n or a n y of his or her desi g nees ma y pr o vi de st u d y dr u g t o a n y pers o n n ot 
partici pati n g i n t he st u d y. 
C CI

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5.1.3 
Dosing and Administration 
All subjects will receive once daily (QD) doses of pimavanserin for 52 weeks of treatment. 
For subjects from Studies ACP-103-034 and 038, dosing will start with 20 mg a day for the 
first 2 weeks. Dose adjustment will be allowed thereafter based on the Investigator’s 
assessment of clinical response (see Table 5–1). 
It is recommended that the subject take the study drug at approximately the same time each 
day. Study drug can be taken with or without food consumption. 
Table 5–1 
Treatment Administration Schedule for Protocol ACP-103-035 
(Subjects from ACP-103-034 and 038) 
 
Each daily dose of pimavanserin consists of 1 or 2 individual tablets. If 2 tablets are taken, 
they should be taken together.   
Subjects from Study ACP-103-064 will start at a dose of 34 mg (2×17 mg tablets) and remain 
on 34 mg for the duration of the treatment period. 
Subjects should take the study drug at approximately the same time each day until Week 52 
(EOT/ET). If the dose of study drug is missed, it may be taken within 12 hours; otherwise, 
the missed dose for that day should be skipped. Dosing should be resumed at the usual time 
the next day. Study drug may be taken with or without food consumption. 
Study drug bottles will be dispensed to the subject to take home. 
Subjects will take study drug adjunctively to the main antipsychotic throughout the Treatment 
Period. Adjustments in the dose of the main antipsychotic after Baseline are not encouraged 
to minimize confounding interpretation of the pimavanserin dose changes and to better 
understand the reason for treatment discontinuation. 
Visit Number(s) 
Once Daily Adjunctive Treatment Regimen 
Baseline (Day 1/ Visit 1) 
The starting daily dose of pimavanserin will be 20 mg 
Week 2 Visit (Visit 2) 
through Week 52 Visit 
(Visit 9) 
The daily dose of pimavanserin may be continued at same daily dose as 
Baseline; 
Or, at Investigator discretion, the daily dose of study drug may be increased 
(to further improve symptom relief) to: 
• 
34 mg (2×17 mg tablets) pimavanserin 
Or, at Investigator discretion, decreased (to improve tolerability) to: 
• 
10 mg (1×10 mg tablet) pimavanserin 

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5.1.3.1 
Dose Modification 
For subjects from Studies ACP-103-034 and 038, dose adjustments will be allowed for 
pimavanserin based on clinical response or tolerability. The Investigator may adjust the daily 
dose of pimavanserin to 10 mg, 20 mg, or 34 mg at any visit based on clinical response or 
tolerability (Table 5–1). A dose change at a time other than at a scheduled clinic visit will 
require an unscheduled visit to dispense the appropriate dose of study drug. 
Subjects from Study ACP-103-064 will remain on the 34 mg dose for the duration of the 
treatment period. 
5.1.4 
Method of Assigning Subjects to Treatment Groups 
All subjects will receive open-label pimavanserin. 
Subjects who have signed the Informed Consent Form (ICF) for the extension study and are 
enrolled into the study will be entered into the electronic data capture (EDC) system. Each 
subject will have the same subject identification number in this study as they had in Studies 
ACP-103-034, 038, or 064. The subject identification number consists of a 3-digit site 
number followed by a unique 3-digit number. The subject will keep this same subject 
identification number throughout the study. 
5.1.5 
Blinding 
This study will be conducted as an open-label study. 
5.1.6 
Study Drug Compliance 
The Investigator or designated study center personnel will maintain a log of all study drug 
dispensed and returned during the study. Study drug supplies for each subject will be 
inventoried and accounted for throughout the study to verify the subject’s compliance with 
the dosage regimen. Subjects will be counseled regarding compliance at every visit. Subjects 
who have <80% or >120% compliance may be discontinued from the study. If a subject 
shows significant undercompliance (<80%) between any two scheduled visits, the Medical 
Monitor should be notified to determine if the subject remains eligible for the study and 
whether the incident should be considered a protocol deviation. 
If a subject misses one dose of study drug, he or she should not take an extra dose the next 
day. 
5.2 
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 

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even if toxic effects were not observed (see Section 7.4.4). All events of overdose are to be 
captured as protocol deviations.  
An overdose is considered an AE only if there are symptoms associated with the event. 
5.3 
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 packaging and unused study drug to the Investigator at regularly scheduled clinic 
visits and at the EOT/ET visit. Any study drug supplied is for use in this study only and 
should not be used for any other purpose. 
At appropriate intervals during the study, study drug reconciliation will be performed by the 
Sponsor (or designee) who may return appropriate unused study drug and used and unused 
packaging to the Sponsor’s designee for destruction in accordance with local regulation. 
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. Documentation of study drug destruction will 
be recorded and maintained by both the Sponsor and the Sponsor’s designee. 
6 STUDY PROCEDURES 
Study specific procedures are detailed below. All assessments will be completed according to 
the schedule described in Table 6–1. Every effort should be made to complete the required 
procedures and evaluations at the designated visits and times. It is mandatory that the 
caregiver/responsible person attend every visit with the subject. If a caregiver/responsible 
person misses 2 or more visits, the subject may be discontinued. 
It is required that trained and experienced clinicians administer the safety and efficacy scales 
for this protocol. Training, certification and materials for rating will be provided by the 
Sponsor or its designee. 
For each scale, the time period assessed will be from the time of the last scheduled 
assessment. All Baseline assessments that are referred to in the following sections will be 
carried over from the Week 6 visit of Study ACP-103-034, or from the Week 26 visit of 
Studies ACP-103-038 or 064, where applicable. 
The NSA-16 is only to be administered by site personnel certified as qualified to administer 
the scale. All administrations of the NSA-16 will be audio-recorded for quality control, 
training, and calibration purposes. Personnel will also be trained in the administration of the 

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other efficacy and safety assessment scales prior to administration of assessment scales to 
subjects. Changes in personnel administering scales (e.g., different site personnel 
administering assessments for the same subject at different visits) are strongly discouraged 
and will be monitored by the Sponsor. 
6.1 
Remote Assessments or Visits 
Circumstances may arise (e.g., pandemic, natural disaster, or political upheaval) when on-site 
assessments of efficacy and safety are not possible. In those cases, assessments may be 
performed at the subject’s place of residence by raters either in person, or via video 
technology or telephone where possible. The Investigator must contact the Medical Monitor 
for approval with the plan. Sites must keep a log to identify details of all visits that are 
administered remotely. For some remote efficacy assessments (i.e., NSA-16, PANSS, CGI), 
the vendor will provide additional training to ensure calibration to reduce discrepancy 
between on-site and remote assessments. If a subject is unable to come to the site for lab 
draws and the site is unable to travel to the subject’s place of residence, the subject may visit 
a local lab to obtain all safety labs.  
6.2 
Safety Scales 
The following safety scales will be used to assess abnormal movements (e.g., extrapyramidal 
symptoms) in this study: Abnormal Involuntary Movement Scale (AIMS; see Appendix 
C), Barnes Akathisia Rating Scale (BARS; see Appendix D), and the Simpson-Angus 
Extrapyramidal Side Effects Scale (SAS; see Appendix E). 
In addition, the Columbia-Suicide Severity Rating Scale (C-SSRS; see Appendix F) will be 
used to assess suicidal ideations and behaviors. 
6.2.1 
Abnormal Involuntary Movement Scale 
The AIMS is a 12-item, physician-administered scale that measures involuntary 
movements known as tardive dyskinesia and aids in the early detection of tardive dyskinesia 
(Lane et al. 1985). It assesses severity of dyskinesias (orofacial movements and extremity 
and truncal movements). Additional items assess the overall severity, incapacitation, and the 
subject’s level of awareness of the movements, and associated distress. 
A sample of the AIMS is provided in Appendix C. 
6.2.2 
Barnes Akathisia Rating Scale 
The BARS is a 4-item, physician-administered scale that assesses the severity of drug-
induced akathisia (Barnes 1989). Three items are rated on a 4-point scale and the global 
clinical assessment of akathisia uses a 6-point scale. 

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A sample of the BARS is provided in Appendix D. 
6.2.3 
Simpson-Angus Extrapyramidal Side Effects Scale 
The SAS is a 10-item physician-administered scale commonly used for the assessment of 
Parkinsonian movement disorder related to psychiatric drug treatment (Simpson and Angus 
1970). One item on the SAS measures gait (hypokinesia); six items measure rigidity; and 
three items measure glabella tap, tremor, and salivation, respectively. The grade of severity of 
each item is rated using a 5-point scale and individual scores are combined to obtain a total 
score. 
A sample of the SAS is provided in Appendix E. 
6.2.4 
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 (Since Last Visit version) will be used to assess suicidal ideations and 
behaviors. 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). 
A sample of the C-SSRS is provided in Appendix F. 
6.3 
Safety Measures 
All Baseline assessments that are referred to in the following subsections will be carried over 
from the Week 6 visit of the Study ACP-103-034 and the Week 26 visit of Studies 
ACP-103-038 and 064, where applicable. Additional safety testing may be performed at the 
discretion of the Investigator or designee. 
6.3.1 
Medical and Psychiatric History 
Medical and psychiatric history will be carried over from the preceding double-blind studies 
(Studies ACP-103-034, 038, and 064). 
6.3.2 
Physical Examination 
A complete physical examination will be performed at Baseline (Visit 1) and Week 52 
(EOT/ET visit). Pelvic and/or urogenital examination may be deferred, unless the 
Investigator deems this to be clinically indicated. 

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6.3.3 
Vital Sign Measurements 
Vital signs, including sitting (at least 3 minutes) blood pressure, pulse rate, respiratory rate, 
and temperature, will be performed at Baseline (Visit 1) and at all scheduled visits. Vital 
signs must be measured before study drug is given. 
6.3.4 
Weight 
Weight will be measured at Baseline (Visit 1) and at all scheduled visits. 
6.3.5 
Electrocardiograms 
Single 12-lead ECG recordings will be performed at Baseline and at Weeks 2, 28, and 52. 
A single 12-lead ECG can be performed any time before blood sampling or at least 
30 minutes after blood sampling during clinic visits. The ECG should not be recorded from 
the same arm as the blood draw if taken after blood draw. 
6.4 
Laboratory Procedures/Evaluations 
6.4.1 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations will be analyzed by a central laboratory. Laboratory tests will 
include hematology, serum chemistry (including metabolic parameters, prolactin levels), and 
urinalysis. Blood and urine samples for laboratory evaluations will be collected at Baseline 
and at Weeks 28 and 52 (EOT/ET visit). Additional laboratory studies for a given subject may 
be repeated at any time throughout the Treatment Period, at the discretion of the Investigator. 
If a subject is unable to come to the site for lab draws and the site is unable to travel to the 
subject’s place of residence, the subject may visit a local lab to obtain all safety labs. The 
Investigator must contact the Medical Monitor for approval with the plan. Sites must keep a 
log to identify details of all visits that are administered remotely. 
6.4.1.1 
Hematology 
Hematology tests will include the following: 
• Complete blood count (CBC) including: 
o White blood cell (WBC) count 
o Complete differential (relative and absolute) 
o Hematocrit (Hct), hemoglobin (Hgb), red blood cells (RBC), platelets 
o Reticulocyte count 

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6.4.1.2 
Serum Chemistry 
Serum chemistry tests will include the following: 
• Sodium (Na) , potassium (K), chloride (Cl), phosphorus (P), calcium (Ca), carbon dioxide 
(CO2), blood urea nitrogen (BUN), creatinine (Cr), uric acid 
• Alanine aminotransferase (ALT/SGPT), aspartate aminotransferase (AST/SGOT), 
gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), total bilirubin 
(TBIL), lactate dehydrogenase (LDH), glucose 
• Albumin (ALB), total protein 
• Creatine kinase (CK)/creatine phosphokinase (CPK) 
• Prolactin 
• Lipid panel  
o Total cholesterol, high-density lipoprotein (HDL)-cholesterol, triglycerides, 
low-density lipoprotein (LDL)-cholesterol, cholesterol/HDL ratio, non-HDL 
cholesterol 
It is preferable but not required that subjects be in a fasted state (e.g., fasting for 
approximately 10 hours) before the blood sample for clinical chemistry is obtained.  
6.4.1.3 
Urinalyses 
Urinalysis tests will include the following: 
• Blood, RBCs, WBCs, protein, glucose, ketones, specific gravity, pH 
• Urine drug screen tests may be performed at any time throughout the 52-week 
Treatment Period, at the discretion of the Investigator. Urine drug screen will include 
testing for the following substances: tetrahydrocannabinol (THC), benzodiazepines, 
barbiturates, cocaine, amphetamine, methamphetamine, Ecstasy, opiates, methadone, 
oxycodone, buprenorphine, and phencyclidine. A positive UDS for benzodiazepines 
will be evaluated by the Investigator in the context of allowed anxiolytics. 
• A urine pregnancy test will be performed for all female subjects of childbearing 
potential at Baseline and at each scheduled visit. Baseline pregnancy test results must 
be confirmed to be negative before a subject is administered any study drug. 
6.4.2 
Clinically Significant Abnormalities 
Laboratory abnormalities judged by the Investigator to be clinically significant will be 
repeated as clinically appropriate. Abnormal laboratory test results that are considered to be 
clinically significant by the Investigator must be recorded as an AE. 

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Further details on blood and urine sample collection are specified in the laboratory manual. 
6.5 
Efficacy Scales 
6.5.1 
Clinical Global Impressions – Severity 
The CGI-S is a clinician-rated, 7-point scale that is designed to evaluate positive, negative, 
depressive, cognitive symptoms, and overall severity in schizophrenia (Guy 1976). 
Note: The CGI-S will be administered to subjects from all three antecedent studies. 
A sample CGI-S is provided in Appendix G. 
6.5.2 
Clinical Global Impression of Schizophrenia Scale – Severity  
The CGI-SCH-S is a clinician-rated, 7-point scale that is designed to evaluate positive, 
negative, depressive, cognitive symptoms, and overall severity in schizophrenia (Haro et al. 
2003). 
Note: Only subjects from Studies ACP-103-038 and 064 will be administered the CGI-SCH-
S; for purposes of this study, only the negative symptoms will be assessed. 
A sample CGI-SCH-S is provided in Appendix H. 
6.5.3 
Positive and Negative Syndrome Scale 
The PANSS is a 30-item scale used to evaluate the presence, absence, and severity of 
schizophrenia symptoms (Kay et al. 1988). The 30 items are arranged as 7 positive symptom 
items, 7 negative symptom items, and 16 general psychopathology symptom items. The 
PANSS total score can range from a minimum of 30 to a maximum of 210. 
A sample PANSS is provided in Appendix I. 
6.5.4 
Informant Questionnaire for the Positive and Negative Syndrome Scale 
The Informant Questionnaire for the Positive and Negative Syndrome Scale (IQ-PANSS) is a 
14-item Informant Questionnaire designed to obtain input from the informant on each of the 
items by evaluating the presence, absence, and severity of schizophrenia symptoms as they 
relate to the subject (Opler and Ramirez 2009). Behaviors observed by the informant about 
the subject are captured verbatim in notes below each PANSS item. 
While two PANSS items, Passive/apathetic social withdrawal (N4) and Active social 
avoidance (G16), are scored exclusively based on information obtained from the informant, 
information reported on the other items included in the IQ-PANSS is to be used in 
conjunction with data obtained during the Structured Clinical Interview for the PANSS 
(SCI-PANSS). 

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The IQ-PANSS will be administered to the caregiver at Baseline, Week 12, Week 28, and 
Week 52 (EOT/ET). 
A sample IQ-PANSS is provided in Appendix J. 
6.5.5 
Negative Symptom Assessment-16 
The NSA-16 is a validated scale that can be completed in approximately 20 to 30 minutes for 
most subjects, but may take longer (i.e., based on effort and/or response of the subject) 
(Axelrod et al. 1993). The NSA-16 assesses five domains of negative symptoms: (1) 
communication, (2) emotion/affect, (3) social involvement, (4) motivation, and (5) 
retardation. 
Note: For purposes of this study, the NSA-16 will be administered only to subjects who 
completed Studies ACP-103-038 and 064. 
A sample NSA-16 is provided in Appendix K. 
6.5.6 
Personal and Social Performance Scale 
The PSP is a validated 100-point single-item rating scale to assess the psychosocial 
functioning of subjects with schizophrenia (Morosini et al. 2000). Ratings are based on the 
assessment of subject functioning across four domains of socially useful activities (e.g., work 
and study, personal and social relationships, self-care, and disturbing and aggressive 
behavior). 
A sample of the PSP is provided in Appendix L. 
6.5.7 
36-Item Short Form Health Survey 
The SF-36 is a 36-item survey that measures the overall health status of a subject (McHorney 
et al. 1994). The SF-36 assesses eight health concepts. The scores are weighted sums of the 
questions in each section. Scores range from 0 to 100 where lower scores indicate greater 
disability, higher scores indicate less disability. In this study, the SF-36 will be administered 
by a trained interviewer. 
Note: The SF-36 will be administered only to subjects who completed Studies ACP-103-034 
and 038. 
A sample of the SF-36 is provided in Appendix M. 
6.5.8 
10-Item Drug Attitude Inventory 
The DAI-10 is a modified version of the original 30-item Drug Attitude Inventory (Hogan et 
al. 1983). It is a true-false questionnaire that assesses attitude, experience, and beliefs about 
antipsychotics in subjects diagnosed with schizophrenia. The items on this questionnaire have 

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been shown to distinguish between subjects who are compliant with their treatment regimen 
and those who are not, primarily through subjective feeling factors (Awad et al. 1993). In this 
study, the DAI-10 will be administered by a trained interviewer. 
Note: The DAI-10 will be administered only to subjects who completed Studies 
ACP-103-034 and 038. 
A sample of the DAI-10 is provided in Appendix N. 
6.5.9 
Work Readiness Questionnaire 
The WoRQ (Potkin et al. 2016) consists of 7 statements that the Investigator rates on a 
4 point scale (“strongly agree” [1 point] to “strongly disagree” [4 points], with “strongly 
agree” being the most indicative of work readiness). Using the ratings of these 7 statements 
as an aid, the Investigator provides a global yes/no judgment about the subject’s readiness to 
work. The WoRQ total score is calculated by adding scores for the 7 statements. 
Note: The WoRQ will be administered only to subjects who completed Study ACP-103-064. 
A sample WoRQ is provided in Appendix O. 
6.6 
Study Schedule 
6.6.1 
Treatment Period 
6.6.1.1 
Baseline Visit (Visit 1) 
Study ACP-103-035 subjects must be consented prior to the final procedures being 
performed at the Week 6 visit of Studies ACP-103-034 or for the Week 26 visit of Studies 
ACP-103-038 and 064. Procedures from the EOT visits of these three double-blind studies 
(ACP-103-034, 038, and 064) will be carried over to the ACP-103-035 study to be included 
as baseline information, and this visit will be considered the Baseline Visit (Visit 1) of the 
ACP-103-035 study. 
At the Baseline visit of Study ACP-103-035, study drug will be dispensed to the subject to 
take home. The subject and their study partner/caregiver will be provided instructions for the 
subject’s first dose of study drug on the day after the Baseline visit. It is recommended that 
the subject take the study drug at approximately the same time each day as a single, oral 
dose. 
Following completion of the following procedures at Baseline, the following safety and 
efficacy assessment scales may be administered in any order. 

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• Complete physical examination 
• Vital signs (pre-dose) (sitting [at least 3 minutes] blood pressure, pulse rate, respiratory 
rate, and temperature) 
• Weight 
• 12-lead ECG (single recording) 
• Verbal confirmation of continued antipsychotic use  
• Clinical laboratory tests (hematology, serum chemistry, prolactin levels, and urinalysis) 
• UDS 
• Urine pregnancy test for all female subjects of childbearing potential 
• AIMS, BARS, and SAS 
• C-SSRS (Since Last Visit version) 
• Clinical Global Impressions – Severity scales: 
o CGI-S  
o CGI-SCH-S of negative symptoms (for Study ACP-103-038 and 064 subjects 
only) 
• PANSS (including the caregiver reported IQ-PANSS) 
• NSA-16 (for Study ACP-103-038 and 064 subjects only) 
• PSP 
• SF-36 and DAI-10 (for Study ACP-103-034 and 038 subjects only) 
• WoRQ (for Study ACP-103-064 subjects only) 
• Assessment of concomitant medications/treatments 
• Assessment of AEs 
• Dispense study drug 
6.6.1.2 
Weeks 2, 6, 12, 20, 28, 36, and 44 (Visits 2, 3, 4, 5, 6, 7, and 8) 
Subjects will have the following procedures completed at each visit (unless otherwise 
indicated): 
• Vital signs (pre-dose) (sitting [at least 3 minutes] blood pressure, pulse rate, respiratory 
rate, and temperature) 
• Weight 
• 12-lead ECG (single recording) (Weeks 2 and 28 only) 
• Verbal confirmation of continued antipsychotic use 

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• Clinical laboratory tests (hematology, serum chemistry, prolactin levels, and urinalysis) 
(Week 28 only) 
• UDS (Week 28 only) 
• Urine pregnancy test for all female subjects of childbearing potential 
• AIMS, BARS, and SAS (Weeks 2, 12, 28, and 44 only) 
• C-SSRS (Since Last Visit version)  
• Clinical Global Impressions – Severity scales: 
o CGI-S  
o CGI-SCH-S of negative symptoms (for Study ACP-103-038 and 064 subjects 
only) 
• PANSS (including the caregiver reported IQ-PANSS) (Weeks 12 and 28 only) 
• NSA-16 (for Study ACP-103-038 and 064 subjects only and only at Week 28) 
• PSP (Weeks 12 and 28 only) 
• SF-36 and DAI-10 (for Study ACP-103-034 and 038 subjects only and only at Weeks 12 
and 28) 
• WoRQ (for Study ACP-103-064 subjects only and only at Weeks 12 and 28) 
• Assessment of concomitant medications/treatments 
• Assessment of AEs 
• Study drug accountability 
• Dispense study drug 
6.6.1.3 
Week 52 (End-of-Treatment/Early Termination Visit) 
Subjects will have the following procedures completed at the EOT/ET visit: 
• Complete physical examination 
• Vital signs (pre-dose) (sitting [at least 3 minutes] blood pressure, pulse rate, respiratory 
rate, and temperature) 
• Weight 
• 12-lead ECG (single recording) 
• Verbal confirmation of continued antipsychotic use 
• Clinical laboratory tests (hematology, serum chemistry, prolactin levels, and urinalysis) 
• UDS 
• Urine pregnancy test for all female subjects of childbearing potential 

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• AIMS, BARS, and SAS 
• C-SSRS (Since Last Visit version) 
• Clinical Global Impressions – Severity scales: 
o CGI-S  
o CGI-SCH-S of negative symptoms (for Study ACP-103-038 and 064 subjects 
only) 
• PANSS (including the caregiver reported IQ-PANSS) 
• NSA-16 (for Study ACP-103-038 and 064 subjects only)  
• PSP 
• SF-36 and DAI-10 (for Study ACP-103-034 and 038 subjects only) 
• WoRQ (for Study ACP-103-064 subjects only) 
• Assessment of concomitant medications/treatments 
• Assessment of AEs 
• Study drug accountability 
Every reasonable effort should be made to complete assessments as outlined above for 
subjects who discontinue prematurely from the study. 
6.6.2 
Follow-up Period (Week 56) 
A 4-week safety follow-up telephone contact is to be completed for subjects who complete 
the study or who discontinue prematurely from the study. Subjects will have the following 
completed via telephone approximately 4 weeks after last dose of study drug: 
• Assessment of concomitant medications/treatments 
• Assessment of AEs 
6.6.3 
Unscheduled Visit(s) 
Unscheduled visits may occur as determined by the Investigator. The following safety 
assessments generally should be recorded at each unscheduled visit: assessment of adverse 
events, assessment of concomitant medications/treatments, measurement of vital signs, and 
completion of the C-SSRS (Since Last Visit version). The Investigator may perform any 
additional safety evaluations deemed by the Investigator to be clinically indicated. 
6.6.4 
 Schedule of Events and Assessments 
The schedule of events and assessments for the study is presented in Table 6–1. 
 

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Table 6–1 
Schedule of Events and Assessments 
Period 
Treatment Period 
Follow-Upa 
Visitb 
1 
2 
3 
4 
5 
6 
7 
8 
9 
(EOT/ET) 
Telephone call 
Day or Week 
Baselinec Week 2 Week 6 Week 12 Week 20 Week 28 Week 36 Week 44 
Week 52 
Week 56 
Allowable visit window (# days) 
0 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
+7 
Informed consentd 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
Physical examinatione 
X 
 
 
 
 
 
 
 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECGf 
X 
X 
 
 
 
X 
 
 
X 
 
Verbal confirmation of continued 
antipsychotic use from double-blind 
studies ACP-103-034, 038, or 064 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical laboratory testsg 
X 
 
 
 
 
X 
 
 
X 
 
Urine pregnancy test (female subjects of 
childbearing potential only) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AIMS, BARS, and SAS 
X 
X 
 
X 
 
X 
 
X 
X 
 
C-SSRS (Since Last Visit version) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CGI-S and/or CGI-SCH-Sh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PANSS and IQ-PANSS 
X 
 
 
X 
 
X 
 
 
X 
 
NSA-16 (for ACP-103-038 and 064 
subjects only) 
X 
 
 
 
 
X 
 
 
X 
 
PSP 
X 
 
 
X 
 
X 
 
 
X 
 
SF-36 and DAI-10 (for ACP-103-034 and 
038 subjects only) 
X 
 
 
X 
 
X 
 
 
X 
 
WoRQ (for ACP-103-064 subjects only) 
X 
 
 
X 
 
X 
 
 
X 
 
Assessment of concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of adverse eventsi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense study drug 
X 
Xj 
Xj 
Xj 
Xj 
Xj 
Xj 
Xj 
 
 
Study drug accountability 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Abbreviations:  AIMS=Abnormal Involuntary Movement Scale; BARS=Barnes Akathisia Rating Scale; CGI-S=Clinical Global Impression – Severity; 
CGI-SCH-S=Clinical Global Impression of Schizophrenia – Severity; C-SSRS=Columbia-Suicide Severity Rating Scale; DAI-10=10-item Drug Attitude 
Inventory; ECG=electrocardiogram; EOS=End of Study; EOT=End of Treatment; ET=Early Termination; IQ-PANSS=Informant Questionnaire for the 

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Positive and Negative Syndrome Scale; NSA-16=Negative Symptom Assessment-16 scale; PANSS=Positive and Negative Syndrome Scale; PSP=Personal 
and Social Performance Scale; SAS=Simpson-Angus Extrapyramidal Side Effects Scale; SF-36=36-item Short Form Health Survey; WoRQ=Work 
Readiness Questionnaire 
a 
For subjects who complete the study or who discontinue prematurely from the study, a safety follow-up telephone call will occur approximately 4 weeks 
after the last dose of study drug. 
b 
Study visits are designated by weeks and have a window, calculated from the Baseline visit, of ±3 days for Visits 2, 3, and 4; ±7 days for Visits 5, 6, 7, 8, and 
9; and +7 for a follow-up telephone call approximately 4 weeks after last dose of study drug. Circumstances may arise (e.g., pandemic, natural disaster, or 
political upheaval) when on-site assessments of efficacy and safety are not possible. In those cases, assessments may be performed at the subject’s place of 
residence by raters either in person, or via video technology or telephone where possible. The Investigator must contact the Medical Monitor for approval 
with the plan. Sites must keep a log to identify details of all visits that are administered remotely. For some remote efficacy assessments (i.e., NSA-16, 
PANSS, CGI), the vendor will provide additional training to ensure calibration to reduce discrepancy between on-site and remote assessments. 
c 
Procedures performed at the EOS visits for Studies ACP-103-034, 038, or EOT visit for 064, will be carried over as baseline information, if applicable. 
d 
Study ACP-103-035 subjects must be consented prior to final procedures being performed at the Week 6 visit for Studies ACP-103-034 or at the Week 26 
visit for Studies ACP-103-038 and 064. The subject’s caregiver must provide written agreement indicating their agreement to participate in the study in the 
caregiver role. 
e 
A complete physical examination should be performed at Baseline and Week 52. Pelvic and/or urogenital examination may be deferred, unless the 
Investigator deems this to be clinically indicated. 
f 
A single 12-lead ECG can be performed any time before blood sampling or at least 30 minutes after blood sampling during clinic visits. The ECG should not 
be recorded from the same arm as the blood draw if taken after blood draw. The subject must rest in a supine position for 5 minutes before the ECG is 
obtained. ECG tracings (paper or electronic) will be reviewed and interpreted by a qualified clinician. ECG tracings and results (ventricular rate, PR, QRS, 
QT, QTcF and QTcB intervals) will be included in the subject's study records. Circumstances may arise (e.g., pandemic, natural disaster, or political 
upheaval) when on-site ECG assessment is not possible. In those cases, ECG assessments may be performed at the subject’s place of residence by study 
staff. The Investigator must contact the Medical Monitor for approval with the plan. Sites must keep a log to identify details of all visits that are 
administered remotely. 
g 
To include hematology, serum chemistry, prolactin levels, and urinalysis (note: UDS and additional laboratory studies [in addition to scheduled timepoints 
shown in the table] for a given subject may be repeated at any time throughout the Treatment Period, at the discretion of the Investigator). It is preferable but 
not required that subjects be in a fasted state (e.g., fasting for approximately 10 hours) before the blood sample for clinical chemistry is obtained. 
Circumstances may arise (e.g., pandemic, natural disaster, or political upheaval) when on-site clinical laboratory tests are not possible. In those cases, clinical 
laboratory tests may be performed at the subject’s place of residence by study staff or a local laboratory. The Investigator must contact the Medical Monitor 
for approval with the plan. Sites must keep a log to identify details of all visits that are administered remotely. 

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h 
The CGI-S will be administered to subjects from all three antecedent studies. The CGI-SCH-S will be administered only to subjects who completed Studies 
ACP-103-038 and 064; for the purposes of this study, only the negative symptoms will be evaluated. 
i 
Adverse events will be recorded in study ACP-103-035 from the first dose of open-label study drug until 30 days after the last dose of study drug. 
j 
Subjects are to return unused study drug and study drug bottles at each subsequent visit; new study drug bottle(s) will be dispensed at each identified visit. In 
addition to the study drug dispensed at the site, investigational product may be delivered directly to the subject’s place of residence; related procedures will 
be described in the study-specific pharmacy manual.  
 

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7 ADVERSE EVENTS 
7.1 
Specification of Safety Parameters 
7.1.1 
Definition of Adverse Event 
An AE is defined as “any untoward medical occurrence in a patient or clinical study 
participant, temporally associated with the use of study drug, whether or not considered 
related to study drug”. 
An AE can therefore be any unfavorable and unintended sign (e.g., an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a drug, without any 
judgment about causality or seriousness. An AE can arise from any use of the drug (e.g., off 
label use, use in combination with another drug) and from any route of administration, 
formulation, or dose, including an overdose. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
drug caused the AE. 
AEs do not include the following: 
• Stable or intermittent chronic conditions (such as myopia requiring eyeglasses) that are 
present prior to Baseline and do not worsen during the study 
• Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion). 
The condition that leads to the procedure is an AE if not present at Baseline. 
• Overdose of concomitant medication without any signs or symptoms unless the subject is 
hospitalized for observation; if an overdose occurs, it will be reported on an overdose 
form. 
• Hospitalization for elective surgery planned prior to study (situation where an untoward 
medical occurrence has not occurred) 
• Pregnancy will not be considered an AE, but if it occurs, it will be reported on a 
pregnancy form 
7.1.2 
Definition of Serious Adverse Event 
In addition to the severity rating, each AE will be classified by the Investigator as “serious” 
or “not serious.” The seriousness of an event will be defined according to the applicable 
regulations and generally refers to the outcome of an event. An SAE is one that meets one or 
more of the following: 
• Is fatal 
• Is immediately life threatening 

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• 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 
• 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. 

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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. 
7.2 
Classification of an Adverse Event 
7.2.1 
Severity of Event 
The severity of each AE will be graded on a 3-point scale and reported in detail as indicated 
on the eCRF: 
• Mild: awareness of sign or symptom but easily tolerated, causing minimal discomfort, 
and not interfering with normal everyday activities 
• Moderate: sufficiently discomforting to interfere with normal everyday activities 
• Severe: incapacitating and/or preventing normal everyday activities 
7.2.2 
Relationship to Study Drug 
The causality of each AE should be assessed and classified by the Investigator as “related” or 
“not related”. An event is considered related if there is a reasonable possibility that the event 
may have been caused by the study drug under investigation (i.e., there are facts, evidence, or 
arguments to suggest possible causation). 
Consider the following when assessing causality: 
• Temporal associations between the agent and the event 
• Response to cessation (de-challenge) or re-challenge 
• Compatibility with known class effect 
• Known effects of concomitant medications 
• Pre-existing risk factors 
• A plausible mechanism 
• Concurrent illnesses 
7.2.2.1 
Duration 
The start and stop dates for AEs will be recorded using the following criteria: 
• Start: Date of the first episode of the AE or date of significant sustained worsening in 
severity 
• Stop: Date when AE either ceased permanently or worsened in severity 

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7.2.2.2 
Frequency 
The frequency of the AE should be indicated according to the following definitions: 
• Single: Experienced once, without recurrence 
• Recurrent: More than one discrete episode with the same severity 
7.2.2.3 
Action Taken with Study Drug 
• Dose reduced: Study drug reduced 
• Dose increased: Study drug increased 
• Dose not changed: No change in study drug 
• Drug interrupted: Study drug temporarily stopped 
• Drug withdrawn: Study drug discontinued permanently 
• Not applicable 
• Unknown 
7.2.2.4 
Therapy 
• None: No new treatment instituted 
• Medication: New treatment initiated as a direct result of AE 
• Other: Other action required 
7.2.2.5 
Outcome 
• Recovered/resolved: Recovered or resolved 
• Recovered/resolved with sequelae: Recovered or resolved with sequelae 
• Not recovered/not resolved: Not recovered or not resolved 
• Fatal: Death related to AE 
• Unknown: Unknown 
7.2.2.6 
Seriousness 
• Not serious 
• Serious (see Section 7.1.2) 
7.2.3 
Definition of Unexpectedness 
An AE, the nature or severity of which is not consistent with the information provided in the 
Reference Safety Information section of the current Pimavanserin Investigator’s Brochure. 

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7.3 
Time Period and Frequency for Event Assessment and Follow-up 
Adverse events will be recorded in study ACP-103-035 from the first dose of open-label 
study drug until 30 days after the last dose of study drug. If an AE is ongoing at the end of the 
study safety follow-up period, every reasonable attempt should be made to follow and 
appropriately treat the subject until the AE resolves or until the Investigator deems the AE to 
be chronic or stable. 
In the event that a subject discontinues and has an ongoing AE at the time of discontinuation 
(Section 4.4.2) or is withdrawn from the study because of an AE, the subject should be 
followed and appropriately treated until the AE resolves or until the Investigator deems the 
AE to be chronic or stable. 
7.4 
Reporting Procedures 
7.4.1 
Adverse Event Reporting 
The Investigator must record all observed AEs and all reported AEs. At each visit, the 
Investigator should ask the subject a nonspecific question (e.g., “Have you noticed anything 
different since your last visit?”) to assess whether any AEs have been experienced since the 
last report or visit. 
Note that any use of medication (and specifically any newly prescribed medication) during 
the course of a study may indicate the occurrence of an AE that may need to be recorded on 
both the AE and the concomitant medication page. 
All AEs, serious and not serious, will be recorded on the AE eCRF page using appropriate 
medical terminology. Severity and relationship to study drug will be assessed by the 
Investigator. 
When possible, clinical AEs should be described by diagnosis and not by symptoms 
(e.g., “cold” or “seasonal allergies” instead of “runny nose”). 
All AEs, whether or not related to the study drug, must be fully and completely documented 
on the AE eCRF and in the subject’s notes. 
7.4.2 
Serious Adverse Event Reporting 
The reporting of SAEs by the Sponsor or designee to the regulatory authorities is a regulatory 
requirement. Each regulatory authority has established a timetable for reporting SAEs based 
upon established criteria. 
Serious AEs must be reported within 24 hours of discovery to the Sponsor or its designee; use 
the appropriate form for initial and/or follow-up reporting.  

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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 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. 
When an SAE occurs, Investigators will review all documentation related to the event and 
will complete the paper SAE form with all required information (for initial and/or follow-up 
information) and fax or email (within 24 hours of discovery) to the contact information 
provided on the SAE form. 
Subjects will be followed through the safety follow-up period (i.e., 4 weeks after last dose of 
study drug) for any SAEs and/or other reportable information until such events have resolved 
or the Investigator 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 safety follow-up period (i.e., 4 weeks after last dose of study 
drug) should be reported if in the judgment of the Investigator there is “a reasonable 
possibility” that the event may have been caused by the product. 
SAEs should also be reported to the IRB/EC according to local regulations. 
7.4.3 
Reporting of Pregnancy 
Any female subject who becomes pregnant during the study (with or without AEs) must be 
withdrawn from the study and the pregnancy must be reported on the Pregnancy form within 
24 hours of discovery to the Sponsor or its designee. Any female subject who becomes 
pregnant during the study will be followed through the pregnancy outcome. 
Any AEs that are the consequence of pregnancy and which meet the criteria for serious 
should also be reported via the SAE form. 
7.4.3.1 
Reporting Paternal Drug Exposure 
Paternal drug exposure is defined as a father’s exposure to a medicinal product before or 
during his partner’s pregnancy. Any paternal drug exposure cases must be reported to the 

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Sponsor within 24 hours of discovery via the Pregnancy form. Any AEs that are the 
consequence of paternal drug exposure and which meet the criteria for serious must also be 
reported to the Sponsor within 24 hours of discovery via the SAE form. 
7.4.4 
Reporting of Overdose 
An overdose is a deliberate or inadvertent administration of a treatment at a dose higher than 
the maximum recommended dose per protocol. It must be reported to the Sponsor or 
designee on the Overdose form within 24 hours of discovery. In addition, all events of 
overdose are to be captured as protocol deviations. 
7.5 
Safety Oversight 
A Safety Management Team (SMT), internal to the Sponsor, will regularly monitor all 
aspects of subject safety throughout this study. The SMT will be comprised of qualified 
representatives from Clinical Development, Drug Safety and Pharmacovigilance, and 
Regulatory Affairs, as well as other ad hoc representatives as appropriate. The SMT will meet 
regularly to review all SAEs and will examine aggregate non-serious AEs, clinical laboratory 
data, and other relevant safety data. 
8 CLINICAL MONITORING 
Routine monitoring of study sites is described in Section 11.1. 
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 Good Clinical Practice (GCP), and with applicable 
regulatory requirements. Details of the study site monitoring process are described in a 
separate clinical monitoring plan document. 
9 STATISTICAL CONSIDERATIONS 
Statistical methods will be documented in detail in a statistical analysis plan (SAP) to be 
approved by the Sponsor prior to database lock.  
9.1 
General Statistical Methods 
For continuous variables, the following summary statistics will be provided: number of 
subjects, mean, standard error of the mean, standard deviation, minimum, maximum, and 
median. For categorical variables, summaries will include the number and percentage of 
subjects in each category, using the number of subjects with non-missing values as the 
denominator for the percentages (unless otherwise specified). 

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No hypothesis testing is planned. All safety and efficacy measures will be summarized using 
descriptive statistics. 
For each continuous measure in safety and efficacy analyses, change from Baseline results 
will be presented in three ways: 
• Using the Baseline results from Study ACP-103-035 and reporting the changes across 
Study ACP-103-035 timepoints; 
• Using the Baseline results from double-blind Studies ACP-103-034, 038, or 064, and 
reporting the changes across the timepoints of the double-blind Studies ACP-103-034, 
038, and 064, as well as the open-label Study ACP-103-035 timepoints; 
• Based on the Baseline results before the first dose of pimavanserin in either the double-
blind or the open-label study, changes will be reported across the timepoints using the 
Baseline results from the double-blind Studies ACP-103-034, 038, or 064 for subjects 
receiving pimavanserin in the double-blind studies (up to 78 weeks), and using the 
Baseline results from Study ACP-103-035 for subjects receiving placebo in the 
double-blind studies (up to 52 weeks). 
Unless otherwise specified, all reported p-values will be two-sided. All analyses will be 
performed using SAS® V9.4 (SAS Institute, Inc., Cary, North Carolina) or higher. Validation 
and quality control of the tables, listings and figures containing the results of the statistical 
analyses will follow appropriate standard operating procedures. 
9.2 
Determination of Sample Size 
The planned sample size for this study is not based on statistical power but will depend on 
the number of subjects who complete double-blind Studies ACP-103-034, 038, or 064, and 
who transition into this open-label extension study. 
9.3 
Handling of Dropouts and Missing Data 
Handling of missing values will be described in detail in the SAP. 
9.4 
Subgroup Analyses 
Selected analyses will be performed in subgroups defined in the SAP. 
9.5 
Study Subjects 
9.5.1 
Subject Populations for Analysis  
The Safety Analysis Set includes all subjects who received at least one dose of open-label 
study drug. The Safety Analysis Set will be used for all analyses. 

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9.5.2 
Subject Accountability and Subject Disposition 
Study enrollment by center will be summarized. The number and percentage of subjects 
treated in the study will be presented, together with the number and percentage of subjects 
who completed the study and those who withdrew early. A breakdown of the corresponding 
reasons for early withdrawal from the study will be provided. 
9.5.3 
Demographic and Baseline Characteristics 
Demographics and baseline characteristics will be summarized using descriptive statistics 
and corresponding listings will be provided. 
9.6 
Interim Analyses 
Interim analyses may be conducted prior to study completion if required for regulatory 
reporting. 
9.7 
Safety Analyses 
9.7.1 
Exposure to Study Drug 
For each subject, the duration of exposure to study drug will be calculated as the number of 
days from first dose date to last dose date inclusive. Descriptive statistics will be tabulated. 
A categorical summary will also be provided using categories defined in the SAP. 
In addition, for subjects from Studies ACP-103-034 and 038, the highest dose, lowest dose, 
final dose, and mean daily dose will be determined for each subject and summarized. 
9.7.2 
Adverse Events 
All AEs will be classified into standard terminology using the MedDRA coding dictionary. 
All AEs will be listed and TEAEs will be summarized by system organ class and preferred 
term. Summaries by maximum severity and by relationship to study drug will also be 
provided. Serious adverse events, fatal AEs, and TEAEs leading to discontinuation will also 
be summarized. Other TEAEs of special interest may also be summarized with details 
provided in the SAP. 
9.7.3 
Clinical Laboratory Values 
Clinical laboratory parameters, including changes from Baseline, will be summarized by 
timepoint using descriptive statistics. 
For selected parameters, the number and percentage of subjects with potentially clinically 
important post-baseline laboratory values will be summarized by timepoint as well as across 
all post-baseline timepoints. The criteria for potentially important values will be specified in 
the SAP. 

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9.7.4 
Vital Signs and Body Weight 
Vital sign measurements and body weight, including changes from Baseline, will be 
summarized by timepoint using descriptive statistics. 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. 
9.7.5 
Electrocardiogram 
ECG parameters, including changes from Baseline, will be summarized by timepoint using 
descriptive statistics. 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 and Food and Drug Administration (FDA) E14 Guidance Document. 
9.7.6 
Physical Examinations 
The results of the physical examinations will be tabulated by timepoint. 
9.7.7 
Columbia Suicide Severity Rating 
The incidence of subjects with suicidal ideation or suicidal behavior during the study, as 
assessed using the C-SSRS, will be tabulated. 
9.7.8 
Extrapyramidal Symptom Measures 
Descriptive statistics for AIMS, BARS, and SAS, including changes from Baseline, will be 
tabulated by timepoint. 
9.8 
Efficacy Analyses 
Descriptive statistics for CGI-S, CGI-SCH-S of negative symptoms (for subjects from 
Studies ACP-103-038 and 064 only), PANSS, NSA-16 (for subjects from Studies 
ACP-103-038 and 064 only), PSP, SF-36 (for subjects from Studies 034 and 038 only), 
DAI-10 (for subjects from Studies 034 and 038 only), and WoRQ (for subjects from 
Study ACP-103-064 only), including changes from Baseline, will be tabulated by timepoint. 
10 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
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 or remote access to source documents (such as original medical 

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records). Direct or remote access includes permission to examine, analyze, verify, and 
reproduce any records and reports that are needed for the evaluation of the study either in 
person or through a remote video/electronic medium (such as email). The Investigator must 
ensure the reliability and availability of source documents from which the information on the 
eCRF was derived. 
10.2 Source Documentation 
All study specific medical information obtained at each study visit must be recorded in the 
subject’s record (source documentation) in real time as it is collected, and then entered into a 
validated 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. 
The study monitors will be responsible for reviewing and verifying the data recorded on the 
eCRFs, utilizing the source documentation, and will query discrepant findings. The 
Investigator and site personnel will be responsible for answering all queries. The eCRFs will 
be submitted to the Sponsor or its designee for quality control review and statistical analysis. 
A copy of the final eCRFs will be retained by the Investigator, who must ensure that the copy 
is stored in a secure place. 
10.4 Confidentiality 
The Investigator must ensure that each subject’s anonymity is maintained as described below. 
On the eCRFs, medical records, 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. Data collection and handling should comply 
with the European Union General Data Protection Regulation (EU GDPR), where applicable. 
ACADIA has assigned a Data Protection Officer (DPO) as per the EU GDPR. 

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10.5 Study Records Retention 
Investigators are required to maintain all essential study documentation as per ICH GCP 
guidelines. This includes, but is not limited to, copies of signed, dated and completed eCRFs, 
documentation of eCRF corrections, signed ICFs, audio recordings, subject-related source 
documentation, and adequate records for the receipt and disposition of all study drug. 
Investigators should maintain all essential study documentation, for a period of at least 
2 years following the last approval of marketing application in an ICH region (US, Europe, 
and Japan), or until at least 2 years after the drug investigational program is discontinued, 
unless a longer period is required by applicable law or regulation. Only the Sponsor can 
notify an Investigator or vendor when any records may be discarded. Investigators should 
contact the Sponsor before destroying any files. 
10.6 Protocol Exceptions and Deviations 
No prospective entry criteria protocol deviations are allowed; all subjects must meet all 
eligibility criteria in order to participate in the study. 
Protocol waivers for eligibility will not be granted by the Sponsor under any circumstances. 
If, during the course of a subject’s post-enrollment participation in the trial it is discovered 
that the subject did not meet all eligibility criteria, this will be reported as a major protocol 
deviation and not a waiver. In this situation, the subject 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. All follow-up safety assessments must be completed and 
documented as outlined in the protocol (Section 6.6). 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. 

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11 QUALITY ASSURANCE AND QUALITY CONTROL 
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 
documented activities: 
• Risk Identification: risks to critical trial processes, governing systems, investigational 
product, trial design, data collection, and recording are identified. 
• Risk Evaluation: identified risks are evaluated by considering the following factors: 
(a) likelihood of occurrence, (b) impact on human subject protection and data integrity, 
and (c) detectability of errors. 
• Risk Control: risks that can be avoided, reduced (i.e., mitigated), or 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 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. 

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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, sites participating in 
this study may 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. 
12 ETHICS/PROTECTION OF HUMAN SUBJECTS 
12.1 Ethical Standard 
The study will be conducted in compliance with the protocol, the Declaration of Helsinki, 
ICH GCP, and other applicable regulatory requirements (e.g., Serious Breach reporting, 
urgent safety measures, and European Union General Data Protection Regulation 
[EU GDPR]). 
The study will be performed in accordance with current US Health Insurance Portability and 
Accountability Act (HIPAA) regulations, US FDA GCP Regulations (US CFR 21 parts 50, 
54, 56, and 312), and ICH guidance on GCP (E6) and clinical safety data management (E2A). 
In accordance with Directive 75/318/EEC, as amended by Directive 91/507/EEC, the final 
clinical study report will be signed by an Investigator and/or Coordinating Investigator who 
will be designated prior to the writing of the clinical study report. 
12.2 Institutional Review Board/Ethics Committee 
The Investigator or designee will provide the IRB/EC with all requisite material, including a 
copy of the protocol, informed consent, and any subject information or advertising materials. 
The study will not be initiated until the IRB/EC provides written approval of the protocol and 
the informed consent and until approved documents have been obtained by the Investigator 
and copies received by the Sponsor. All amendments will be sent to the IRB/EC for 
information (minor amendment) or for submission (major amendment) before 
implementation. The Investigator will supply the IRB/EC and the Sponsor with appropriate 
reports on the progress of this study, including any necessary safety updates, in accordance 
with the applicable government regulations and in agreement with policy established by the 
Sponsor. 

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12.3 Informed Consent Process 
Properly executed, written informed consent must be obtained from each subject prior to 
initiating baseline evaluations required by this protocol. The subject’s caregiver must provide 
written agreement. 
The informed consent must, at a minimum, include the elements of consent described in the 
ICH guidance on GCP and the US CFR 21 part 50.25. A copy of the ICF planned for use will 
be reviewed by the Sponsor or designee for acceptability and must be submitted by the 
Investigator or designee together with the protocol, to the appropriate IRB/EC for review and 
approval prior to the start of the study at that investigational site. Consent forms must be in a 
language fully comprehensible to the prospective subject. The Investigator must provide the 
Sponsor or designee with a copy of the IRB/EC letter approving the protocol and the 
ICF before the study drug supplies will be shipped and the study can be initiated. 
The consent form must be revised if new information becomes available during the study that 
may be relevant to the subject’s willingness to continue participation. Any revision must be 
submitted to the appropriate IRB/EC for review and approval in advance of use. 
12.3.1 
Consent and Other Informational Documents Provided to Subjects 
The subject and caregiver must be given a copy of the signed informed consent(s) and the 
original maintained in the designated location at the site. 
12.3.2 
Consent Procedures and Documentation 
It is the Investigator or designee’s responsibility to obtain written informed consent from the 
subject after adequate explanation of the aims, methods, anticipated benefits, and potential 
hazards of the study. The subject must be given ample time to decide about study 
participation and opportunity to inquire about details of the study. The IRB/EC-approved 
consent form must be personally signed dated by the subject and by the person who 
conducted the informed-consent discussion. The Investigator or appropriate site personnel 
must document the details of obtaining informed consent in the subject’s study documents.  
The subject’s caregiver must also indicate their understanding of the study and their role as a 
caregiver to the subject during the study. The subject’s caregiver must provide written 
agreement indicating their agreement to participate in the study in the caregiver role. 
12.3.2.1 
Remote Consent Procedures and Documentation 
Investigators may also need to obtain informed consent from a potential trial participant or 
their caregiver when these individuals are unable to travel to the site where the investigator is 
located due to extenuating circumstances (e.g., pandemic, natural disaster, or political 
upheaval). The consent form may be sent to the subject or the subject’s caregiver by facsimile 

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or e-mail, and the consent interview may then be conducted by telephone when the subject or 
subject’s caregiver can read the consent form during the discussion. After the consent 
discussion, the subject or the subject’s caregiver can sign and date the consent form. Options 
for returning the document to the clinical investigator may include facsimile, scanning the 
consent form and returning it through a secure e-mail account, or posting it to a secure 
internet address. Alternatively, the subject or caregiver may bring the signed and dated 
consent form to his/her next visit to the clinical site, if restrictions on traveling to the clinical 
trial site are alleviated, or mail it to the clinical investigator. The case history for each subject 
must document that informed consent was obtained prior to participation in the trial. In 
addition, the person signing the consent form must receive a copy of the consent form.  
If concerns exist about having subjects mail to the investigator potentially contaminated 
consent documents from the subject’s location, the investigator may employ the procedures 
described above for enrolling patients in isolation through the use of a photographic image of 
the signed consent form transmitted through electronic means.  
The subject or the subject’s caregiver must sign and date the informed consent form before 
the investigator may conduct any study-related procedures involving the subject. Where it is 
not feasible for investigators to receive the signed consent form prior to beginning 
study-related procedures, the investigators should have the subject or caregiver confirm 
verbally during the consent interview that the subject or caregiver has signed and dated the 
form. In addition, the overseeing IRB must review and approve the planned informed consent 
process. 
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 
Alphs LD, Summerfelt A, Lann H, Muller RJ. The negative symptom assessment: a new 
instrument to assess negative symptoms of schizophrenia. Psychopharmacol Bull. 
1989;25(2):159-163. 
Andreasen NC. Negative symptoms in schizophrenia. Definition and reliability. Arch Gen 
Psychiatry. 1982;39(7):784-788. 
Awad AG. Subjective response to neuroleptics in schizophrenia. Schizophr Bull. 
1993;19(3):609-618. 
Axelrod BN, Goldman RS, Alphs LD. Validation of the 16-item Negative Symptom 
Assessment. J Psychiatr Res. 1993;27(3):253–258. 
Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989;154:672-676. 
Cummings J, Isaacson S, Mills R, et al. Pimavanserin for patients with Parkinson's disease 
psychosis: a randomised, placebo-controlled phase 3 trial. Lancet. 2014;383(9916):533-540. 
Ebdrup B, Rasmussen H, Arnt J, Glenthøj B. Serotonin 2A receptor antagonists for treatment 
of schizophrenia. Expert Opin Investig Drugs. 2011;20(9):1211-1223. 
Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for 
Industry and Investigators: Safety Reporting Requirements for INDs and BA/BE Studies. 
Silver Spring, MD: US Department of Health and Human Services; December 2012. 
Guy W. Clinical Global Impressions. In: ECDEU Assessment Manual for 
Psychopharmacology —Revised (DHEW publication number ADM 76–338). Rockville, MD, 
U.S. Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug 
Abuse, and Mental Health Administration, NIMH Psychopharmacology Research Branch, 
Division of Extramural Research Programs, 1976, 218–222. 
Haro JM, Kamath SA, Ochoa S, et al. The Clinical Global Impression – Schizophrenia scale: 
a simple instrument to measure the diversity of symptoms present in schizophrenia. Acta 
Psychiatr Scand. 2003;107(Suppl 416):16-23. 
Hogan TP, Awad AG, Eastwood R. A self-report scale predictive of drug compliance in 
schizophrenics: reliability and discriminative validity. Psychol Med. 1983;13(1):177-183. 
Hovington CL, Bodnar M, Joober R, Malla AK, Lepage M. Identifying persistent negative 
symptoms in first episode psychosis. BMC Psychiatry. 2012;12:224. 
Janssen Pharmaceuticals Inc. INVEGA® [package insert]. Titusville, NJ, January 2019. 

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Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for 
schizophrenia. Schizophr Bull. 1987;13(2):261-276. 
Kay SR, Opler LA, Lindenmayer JP. Reliability and validity of the positive and negative 
syndrome scale for schizophrenics. Psychiatry Res. 1988;23(1):99-110. 
Kirkpatrick B, Buchanan RW, McKenney PD, Alphs LD, Carpenter WT Jr. The Schedule for 
the Deficit syndrome: an instrument for research in schizophrenia. Psychiatry Res. 
1989;30(2):119-23. 
Lane RD, Glazer WM, Hansen TE, Berman WH, Kramer SI. Assessment of tardive 
dyskinesia using the Abnormal Involuntary Movement Scale. J Nerv Ment Dis. 
1985;173(6):353-357. 
McGrath J, Saha S, Chant D, et al. Schizophrenia: a concise overview of incidence, 
prevalence, and mortality. Epidemiol Rev. 2008;30:67-76. 
McHorney CA, Ware JE, Lu JF, Sherbourne CD. The MOS 36-Item Short-Form Health 
Survey (SF-36®): III. Tests of data quality, scaling assumptions and reliability across diverse 
patient groups. Med Care. 1994;32(1):40-66. 
Mehta M, Manes FM, Magnolfi G, Sahakian BJ, Robbins TW. Impaired set-shifting and 
dissociable effects on tests of spatial working memory following the dopamine D2 receptor 
antagonist sulpride in human volunteers. Psychopharmacology. (Berl). 2004;176(3-4):331-
342. 
Meltzer HY, Helio E, Vanover K, et al. Pimavanserin, a selective serotonin (5-HT)2A-inverse 
agonist, enhances the efficacy and safety of risperidone, 2 mg/day, but does not enhance 
efficacy of haloperidol, 2 mg/day: Comparison with reference dose risperidone, 6 mg/day. 
Schizophr Res. 2012;141(2-3):144-152. 
Morosini PL, Magliano L, Brambilla L, Ugolini S, Pioli R. Development, reliability and 
acceptability of a new version of the DSM-IV Social and Occupational Functioning 
Assessment Scale (SOFAS) to assess routine social functioning. Acta Psychiatr Scand. 
2000;101(4):323-329. 
Nasrallah H, Morosini P, Gagnon DD. Reliability, validity and ability to detect change of the 
Personal and Social Performance scale in patients with stable schizophrenia. Psychiatry Res. 
2008; 161(2): 213-224. 
Opler LA, Ramirez PM. Informant Questionnaire for the Positive and Negative Syndrome 
Scale (IQ-PANSS). North Tonawanda, NY: Multi-Health Systems Publications, Inc. 2009. 

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Peralta V, Cuesta MJ, Martinez-Larrea A, Serrano JF. Differentiating primary from secondary 
negative symptoms in schizophrenia: a study of neuroleptic-naïve patients before and after 
treatment. Am J Psychiatry. 2000;157(9):1461-1466. 
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. 
Potkin SG, Bugarski-Kirola D, Edgar CJ, et al. Psychometric evaluation of the Work 
Readiness Questionnaire in schizophrenia. CNS Spectr. 2016;21:199–206. 
Riedel M, Schwarz MJ, Strassnig M, et al. Risperidone plasma levels, clinical response and 
side-effects. Eur Arch Psychiatry Clin Neurosci. 2005;255(4):261-268. 
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. 
Simpson GM, Angus JW. A rating scale for extrapyramidal side-effects. Acta Psychiatr Scand 
Suppl. 1970;212:11-19. 
Tamminga CA, Buchanan RW, Gold JM. The role of negative symptoms and cognitive 
dysfunction in schizophrenia outcome. Int Clin Psychopharmacol. 1998;13(Suppl 3):S21-
S26. 
Vanover KE, Weiner DM, Makhay M, et al. Pharmacological and behavioral profile of N-(4-
fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl) 
carbamide (2R,3R)-dihydroxybutanedioate (2:1) (ACP-103), a novel 5- 
hydroxytryptamine(2A) receptor inverse agonist. J Pharmacol Exp Ther. 2006;317(2):910-
918. 
Wang PS, Schneeweiss S, Avorn J, et al. Risk of death in elderly users of conventional vs 
atypical antipsychotic medications. N Engl J Med. 2005;353(22):2335-2341. 

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16 APPENDICES 
Appendix A. 
Prohibited and Restricted Medications 
Subjects taking prohibited medications at study entry will not be eligible for the study.  
Subjects who require current treatment with a prohibited medication will be withdrawn from 
the study. 
Subjects who have previously taken a prohibited medication during the study will be 
withdrawn from the study unless:  
• the prohibited medication has been discontinued AND  
• withdrawal from the study presents an unacceptable medical risk to the subject 
The justification to allow the subject to continue in the trial will be made by the 
Sponsor/Medical Monitor with medical input from the Investigator, and will be documented. 
If allowed to remain in the trial, this will be reported as a major protocol deviation and not a 
waiver. 
The table below lists prohibitions and restrictions by medication class, including 
representative medications within class. A prohibited medication is not allowed. A restricted 
medication is allowed only under certain conditions. 
Medication Class 
Examples* 
Prohibitions/Restrictions 
Antipsychotics other than 
pimavanserin 
PROHIBITED 
 
• 
All antipsychotics with the 
exception of those listed in the 
protocol are prohibited 
RESTRICTED 
• 
paliperidone 
 
• 
Paliperidone ER is prohibited at 
a dose >9 mg  
• 
Paliperidone palmitate is 
prohibited at the following 
doses: 
• 
Invega Sustenna® (>156 mg) 
• 
Invega Trinza® (>546 mg) 
• 
Trevicta® (>350 mg) 
• 
Xeplion® (>100 mg) 
Anticholinergics 
• 
benztropine 
• 
biperiden 
• 
trihexiphenidyl 
• 
diphenhydramine 
• 
hydroxyzine 
 
• 
The dose of anticholinergic must 
be unchanged for at least 
4 weeks prior to Baseline, may 
not exceed a dose equivalent of 
4 mg of benztropine, and should 
be expected to remain 
unchanged until the subject’s 
final visit 

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Medication Class 
Examples* 
Prohibitions/Restrictions 
Anticonvulsants and mood 
stabilizers 
• carbamazepine  
• lamotrigine 
• lithium 
• phenytoin 
• valproate 
• 
Must be washed out prior to 
Baseline or for 5 half-lives of 
study drug prior to Baseline 
• 
Prohibited throughout the study 
Anxiolytics 
• benzodiazepines 
• 
Lorazepam in doses up to 4 mg 
per day for a maximum of 7 
consecutive days may be used as 
a rescue medication. 
Reassessment and discussion 
with Medical Monitor is 
required if needed beyond 
7 days. 
o 
If lorazepam is not 
available, another 
benzodiazepine may be 
used at doses equivalent to 
lorazepam 
• 
May not be used within 12 hours 
prior to an assessment visit 
Stimulants 
• methylphenidate 
• 
Prohibited at study entry and 
throughout the study 
Non-stimulant attention 
deficit/hyperactivity 
disorder medications 
• atomoxetine 
• 
Prohibited at study entry and 
throughout the study 
Serotonin antagonists 
• cyproheptadine 
• fluvoxamine 
• mianserin 
• mirtazapine 
• nefazodone 
• trazodone 
• 
Prohibited throughout study 
• 
Must be discontinued at least 
3 weeks prior to Baseline visit 
Antiarrhythmic drugs 
• ajmaline 
• amakalant, semantilide 
• amiodarone 
• bretylium 
• disopyramide 
• dofetilide 
• dronedarone 
• flecainide 
• ibutilide 
• procainamide 
• propafenone 
• quinidine 
• sotalol, d-sotalol 
• 
Prohibited at study entry and 
throughout the study  

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Medication Class 
Examples* 
Prohibitions/Restrictions 
Antimicrobials antifungals, 
and antimalarials 
PROHIBITED 
• clarithromycin 
• erythromycin 
• levofloxacin 
• moxifloxacin 
• pentamidine 
• 
Clarithromycin, erythromycin, 
levofloxacin, moxifloxacin, and 
pentamidine are prohibited at 
study entry and throughout the 
study 
RESTRICTED 
• artenimol/piperaquine 
• azithromycin 
• bedaquiline 
• ciprofloxacin 
• gemifloxacin 
• norfloxacin 
• ofloxacin 
• quinine 
• roxithromycin 
• 
Ciprofloxacin and azithromycin 
are restricted: 
o 
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 Investigator 
• 
Artenimol/piperaquine, 
bedaquiline, gemifloxacin, 
norfloxacin, ofloxacin, quinine, 
roxithromycin are allowed under 
the following conditions: 
• 
The subject has a Baseline ECG 
with a QTcF <425 ms OR 
• 
The subject has a QTcF <450 ms 
at Baseline AND QRS duration 
≥120 ms 
Antidepressants  
(continues on next page) 
PROHIBITED 
• esketamine 
• 
Prohibited at study entry and 
throughout the study 

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Medication Class 
Examples* 
Prohibitions/Restrictions 
 
RESTRICTED 
• amitriptyline 
• clomipramine 
• desipramine 
• imipramine 
• nortriptyline 
• citalopram 
• escitalopram 
• venlafaxine 
 
• 
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 subject is remaining on these 
medications, the dose of the 
permitted antidepressants on the 
left must be unchanged for at 
least 4 weeks prior to Baseline 
and is expected to remain 
unchanged until completion of 
the EOT visit. If the medication 
is being discontinued, it must be 
discontinued at least 2 weeks or 
5 half-lives (whichever is 
longer) prior to the Baseline 
visit. 
o 
Citalopram is restricted to a 
maximum dose of 
20 mg/day. 
o 
Escitalopram is restricted to 
a maximum dose of 
10 mg/day. 
• 
Venlafaxine is restricted to a 
maximum dose of 225 mg/day  
Hypnotics 
• zolpidem (as needed up to 
10 mg/day) 
• zaleplon (as needed up to 
20 g/day) 
• zopiclone (as needed up to 
15 mg/day) 
• eszopiclone (as needed up to 
3 mg/day) 
• 
Restricted to doses and 
equivalents on the left 
• 
Any equivalent short half-life non-
benzodiazepine hypnotic may be 
substituted in countries where the 
above medications are not 
available. Treatment with sedating 
antihistamines (e.g., 
diphenhydramine or similar) may 
be used occasionally, as needed. 
Electroconvulsive therapy 
 
• 
Prohibited throughout the study 
Supportive and 
rehabilitation therapies 
 
• 
Permitted if stable for 4 weeks 
prior to Screening 
*Medications within each class include, but are not limited to, the examples listed in this table. 

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Appendix B. 
Prohibited and Restricted Concomitant Medications: Inhibitors 
and Inducers of Cytochrome P450 Enzyme 3A4 
The information presented here is intended to provide guidance and does not constitute an 
exhaustive list of strong CYP 3A4 enzyme (CYP3A4) inhibitors and inducers. Any questions 
should be discussed with the Medical Monitor or appropriate designee.  
Subjects who require current treatment with a prohibited medication will be withdrawn from 
the study. 
Subjects who have previously taken a prohibited medication during the study will be 
withdrawn from the study unless:  
• the prohibited medication has been discontinued AND  
• withdrawal from the study presents an unacceptable medical risk to the subject 
The justification to allow the subject to continue in the study will be made by the 
Sponsor/Medical Monitor with medical input from the Investigator, and will be documented. 
If allowed to remain in the study, this will be reported as a major protocol deviation and not a 
waiver. 
The metabolism of pimavanserin is affected by strong CYP3A4 inhibitors, resulting in an 
increase in maximum plasma concentration (Cmax) and area under the plasma concentration-
time curve (AUC) of approximately 3-fold.  
Strong inhibitors of CYP3A4 are to be stopped at least 7 days or 5 half-lives prior to 
investigational product administration, whichever is longer. Strong inducers of CYP3A4 are 
to be stopped 30 days or 5 half-lives prior to investigational product administration, 
whichever is longer. Moderate inhibitors and inducers of CYP3A4 are allowed but should be 
used with caution. 
STRONG 
INHIBITORS 
Boceprevir (Victrelis®) 
Clarithromycin (Biaxin®)  
Cobicistat (part of Stribild®) 
Conivaptan (Vaprisol®) 
Fluvoxamine (Luvox®) 
Grapefruit juicea  
Indinavir (Crixivan®)  
Itraconazole (Sporanox®)  
Ketoconazole (Nizoral®)  
Lopinavir and Ritonavir 
(Kaletra®) 
Mibefradil (Posicor®) 
Nefazodone (Serzone®)  
MODERATE 
INHIBITORS 
Amprenavir (Agenerase®) 
Aprepitant (Emend®) 
Atazanavir (Reyataz®) 
Ciprofloxacin (Cipro®) 
Darunavir/ritonavir 
(Prezista®/Ritonavir) 
Diltiazem 
Erythromycin (Erythrocin® 
Lactobionate) 
Fluconazole (Diflucan®) 
Fosamprenavir (Lexiva®) 
Grapefruit juicea 
Imatinib (Gleevec®) 
Verapamil (Calan®) 

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Nelfinavir (Viracept®)  
Posaconazole (Noxafil®) 
Quinupristin (Synercid®) 
Ritonavir (Norvir®, part of 
Viekira Pak™)  
Saquinavir (Invirase®)  
Telaprevir (Incivek®) 
Telithromycin (Ketek®)  
Voriconazole (Vfend®) 
STRONG 
INDUCERS 
Avasimibe 
Carbamazepine (Tegretol®) 
Phenobarbital (Luminal®, 
Solfoton®) 
Phenytoin (Dilantin®)  
Rifampin (Rifadin®, Rifadin 
IV®, Rimactane®) 
St. John's Wort 
MODERATE 
INDUCERS 
Bosentan (Tracleer®) 
Efavirenz (Sustiva®) 
Etravirine (Intelence®) 
Modafinil (Provigil®) 
Nafcillin (Unipen®, Nallpen®) 
a 
The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-
dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain 
preparation was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when another 
preparation was used (e.g., low dose, single strength). (FDA Drug Development and Drug Interactions 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabelin
g/ucm093664.htm#classInhibit). 
 
 

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Appendix C. 
Abnormal Involuntary Movement Scale (AIMS) 
Source: 
Guy W: ECDEU Assessment Manual for Psychopharmacology - Revised (DHEW Publ No 
ADM 76-338), US Department of Health, Education, and Welfare; 1976 

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Appendix D. 
Barnes Akathisia Rating Scale (BARS) 
Source: Barnes, 1989 

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Appendix E. 
Simpson-Angus Extrapyramidal Side Effects Scale (SAS) 
Source: Simpson et al. 1970 

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Appendix F. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Source: 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Since Last Visit Version 
Version 1/14/09 
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; 
Burke, A.; Oquendo, M.; Mann, J. 
The Columbia Suicide History Form, developed by John Mann, MD and Maria Oquendo, 
MD, Conte Center for the Neuroscience of Mental Disorders (CCNMD), New York State 
Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., 
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of 
research instruments. In M.B. First [Ed.] Standardized Evaluation in Clinical Practice, pp. 
103-130, 2003.) 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 
1051 Riverside Drive, New York, New York, 10032; inquiries and training requirements 
contact posnerk@nyspi.columbia.edu 
©2008 The Research Foundation for Mental Hygiene, Inc. 

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Appendix G. 
Clinical Global Impression – Severity (CGI-S) Scale  
Source: Adapted from Guy W. ECDEU Assessment Manual for Psychopharmacology. US 
Department of Health, Education, and Welfare publication (ADM) 76-338. Rockville, MD: 
National Institute of Mental Health; 1976. 

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Appendix H. 
Clinical Global Impression of Schizophrenia Scale – Severity 
(CGI-SCH-S) 
The CGI-SCH-S will be administered only to subjects who completed double-blind Studies 
ACP-103-038 or 064; for the purposes of this study, only the negative symptoms will be 
assessed. 
Source: Adapted from Haro et al. 2003 

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Appendix I. 
Structured Clinical Interview – Positive and Negative Syndrome 
Scale (PANSS) 
Source: 
Structured Clinical Interview – Positive and Negative Syndrome Scale 
Lewis A. Opler, M.D., Ph.D. Stanley R. Kay, Ph.D. J.P. Lindenmayer, M.D., & Abraham 
Fiszbein, M.D. 
MHS 
Multi-Health Systems Inc. Copyright© 1992, 1999, 2005. All rights reserved. PO Box 950, 
North Tonawanda, NY 14120-0950. 
 

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Appendix J. 
Informant Questionnaire for the Positive and Negative Syndrome 
Scale (IQ-PANSS) 
Source: 
Informant Questionnaire for the Positive and Negative Syndrome Scale (IQ-PANSS) 
Lewis A. Opler, M.D., Ph.D., & Paul Michael Ramirez, Ph.D. 
MHS 
Multi-Health Systems Inc. Copyright© 1999. All rights reserved. PO Box 950, North 
Tonawanda, NY 14120-0950. 

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Appendix K. 
Negative Symptom Assessment-16 (NSA-16) – Long Form 
The NSA-16 will be administered only to subjects who completed double-blind Studies 
ACP-103-038 and 064. 
Source: Alphs LD. Negative Symptom Assessment-16 (NSA) Instruction Manual. 2006 

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Appendix L. 
Personal and Social Performance Scale (PSP) 
Source: Nasrallah et al. 2008 

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Appendix M. 
36-Item Short Form Health Survey (SF-36) 
The SF-36 will be administered only to subjects who completed double-blind Studies 
ACP-103-034 and 038. 
Source: McHorney et al. 1994 

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Appendix N. 
10-Item Drug Attitude Inventory (DAI-10) 
The DAI-10 will be administered only to subjects who completed double-blind Studies 
ACP-103-034 and 038. 
Source: Hogan et al. 1983 
 

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Appendix O. 
Work Readiness Questionnaire (WoRQ) 
The WoRQ will be administered only to subjects who completed double-blind Study 
ACP-103-064. 
Source: Potkin et al. 2016.