Conditions: Schizophrenia
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 995
Healthy volunteers: no

Brief summary:
To evaluate the long-term safety and tolerability of pimavanserin after 52 weeks of adjunctive treatment in subjects with schizophrenia

Detailed description:

Arms:
arm 1: Pimavanserin 34 mg, 20 mg, or 10 mg, + background antipsychotic, taken once daily by mouth

Interventions: intervention 1: Pimavanserin
Intervention descriptions: intervention 1: Pimavanserin 10 mg, tablet, taken as one 10 mg tablets, once daily by mouth, OR Pimavanserin 20 mg, tablet, taken as two 10 mg tablets, once daily by mouth, OR Pimavanserin 34 mg, tablet, taken as two 17 mg tablets, once daily by mouth

Protocol document:
Prot_000.pdf: 
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  
S P O N S O R SI G N A T U R E P A G E  
Title:  A 5 2- Wee k, O pe n - L a bel, E xte nsi o n St u d y of Pi m a v a nseri n f or t he A dj u ncti ve 
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A C A DI A He a d of Cli nic al De vel o p me nt : 
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A C A DI A P har mace uticals I nc.  
 
 
P h o ne: 
 
 
 
 
 
 
 
 
 
 
 
 
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A C A DI A St u d y  Le a d:  
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A C A DI A P har mace uticals G m b H 
  
  
  
 
P h o ne: 
 
 
 
 
 
 
 
 
 
 
 
See a p pe n de d electr o nic si g n at ure 
p a ge  
 
 
Si g nat ure  
 
Date  
P P D
P P D
P P D
P P D
P P D
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Si g nat ure Pa ge f or A C P- 1 0 3- 0 3 5 Pr ot oc ol A me n d me nt 3 ( 2 0 2 0)
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Study: ACP-103-035 
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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 
 
 
 
 
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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 


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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) 


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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).


Study: ACP-103-035 
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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 


Study: ACP-103-035 
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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. 


Study: ACP-103-035 
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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. 


Study: ACP-103-035 
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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 


Study: ACP-103-035 
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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 
 


Study: ACP-103-035 
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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. 

SAP_001.pdf: 
Official Title: A 52-Week, Open-Label, Extension Study of Pimavanserin for the 
Adjunctive Treatment of Schizophrenia 
NCT Number: NCT03121586 
Document Date: 26 January 2024 
 


 
 
STATISTICAL ANALYSIS PLAN 
 
Protocol No.: 
ACP-103-035 
Protocol Title: 
A 52-Week, Open-Label, Extension Study of 
Pimavanserin for the Adjunctive Treatment of 
Schizophrenia 
Drug: 
Pimavanserin 
Sponsor:  
Acadia Pharmaceuticals Inc. 
Version No. and Date 
Version 1.0, January 26, 2024 
 
 
 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc. 


Protocol ACP-103-035 
Version 1.0 
Statistical Analysis Plan 
26 JAN 2024 
 
 
 
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SIGNATURE/APPROVAL PAGE 
AUTHOR 
See appended electronic signature page 
_____________________________________________ 
____________ 
 
Date 
Director, Biostatistics, Biometrics  
Acadia Pharmaceuticals Inc. 
 
 
APPROVERS 
 
See appended electronic signature page 
_____________________________________________ 
____________ 
 M.D. 
Date 
 Clinical Development 
Acadia Pharmaceuticals Inc. 
 
See appended electronic signature page 
_____________________________________________ 
____________ 
 Ph.D. 
Date 
Executive Director, Biostatistics, Biometrics 
Acadia Pharmaceuticals Inc. 
 
 
 
 
PPD
PPD
PPD
PPD


Signature Page for ACP-103-035 Statistical Analysis Plan V1.0
Signature Page for ACP-103-035 Statistical Analysis Plan V1.0
Approve
Biostatistics
27-Jan-2024 00:00:29 GMT+0000
Approve
Clinical
27-Jan-2024 07:52:46 GMT+0000
Approve
Biostatistics
27-Jan-2024 19:20:59 GMT+0000
PPD
PPD
PPD


Protocol ACP-103-035 
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Statistical Analysis Plan 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................................ 4 
LIST OF TABLES .......................................................................................................................... 7 
LIST OF FIGURES ........................................................................................................................ 7 
ABBREVIATIONS ......................................................................................................................... 8 
1 
INTRODUCTION ...................................................................................................... 10 
2 
OBJECTIVES ............................................................................................................. 10 
2.1 
Primary Objective ....................................................................................................... 10 
2.2 
Secondary Objective ................................................................................................... 10 
2.3 
Exploratory Objectives ............................................................................................... 10 
3 
STUDY DESIGN ........................................................................................................ 10 
3.1 
General Study Design ................................................................................................. 10 
3.2 
Schedule of Assessments ............................................................................................ 13 
3.3 
Randomization ............................................................................................................ 17 
3.4 
Blinding....................................................................................................................... 17 
3.5 
Determination of Sample Size .................................................................................... 17 
4 
ANALYSIS SETS ....................................................................................................... 17 
5 
DATA HANDLING CONVENTIONS ....................................................................... 17 
5.1 
General Data Reporting Conventions ......................................................................... 17 
5.2 
Derived Variables ........................................................................................................ 18 
5.2.1 
Clinical Global Impressions Scale – Severity (CGI-S) 
19 
5.2.2 
Clinical Global Impression of Schizophrenia Scale – Severity (CGI-SCH-S) 
19 
5.2.3 
Positive and Negative Syndrome Scale (PANSS) 
19 
5.2.4 
Negative Symptom Assessment-16 (NSA-16) 
22 
5.2.5 
Personal and Social Performance Scale (PSP) 
23 
5.2.6 
Work Readiness Questionnaire (WoRQ) 
23 
5.2.7 
36-Item Short Form Health Survey (SF-36) 
24 
5.2.8 
Drug Attitude Inventory (DAI-10) 
27 
5.2.9 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
28 
5.2.10 
Abnormal Involuntary Movement Scale (AIMS) 
28 
5.2.11 
Barnes Akathisia Scale (BARS) 
29 


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5.2.12 
Simpson Angus Extrapyramidal Side Effect Scale (SAS) 
29 
5.3 
Data Handling Conventions ........................................................................................ 30 
5.4 
Study Day.................................................................................................................... 30 
5.5 
Baseline Definition ..................................................................................................... 30 
5.6 
Analysis Visit Windows .............................................................................................. 30 
5.6.1 
Unscheduled Assessments 
31 
5.6.2 
Multiple Measurements within Visit Windows 
31 
5.7 
Missing or Incomplete Date for Last Dose of Study Drug ......................................... 32 
5.8 
Missing or Incomplete Dates for Concomitant or Post-Treatment Medications ........ 32 
5.9 
Missing or Incomplete Dates for Adverse Events....................................................... 32 
5.10 
Missing Severity Assessment for Adverse Events ...................................................... 32 
5.11 
Missing Relationship to Study Drug for Adverse Events ........................................... 33 
5.12 
Character Values of Clinical Laboratory Variables ..................................................... 33 
5.13 
Duplicate Subjects ...................................................................................................... 33 
6 
SUBJECT DISPOSITION .......................................................................................... 33 
7 
PROTOCOL DEVIATIONS ....................................................................................... 33 
8 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ................... 34 
9 
MEDICAL HISTORY ................................................................................................ 35 
10 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE ............................ 35 
10.1 
Exposure to Study drug ............................................................................................... 36 
10.1.1 
Exposure to open-label pimavanserin 
36 
10.1.2 
Total exposure to pimavanserin across the double-blind and open-label periods 
36 
10.2 
Measurement of Treatment Compliance ..................................................................... 37 
11 
CONCOMITANT AND POST-TREATMENT MEDICATION ................................. 37 
12 
EFFICACY ANALYSES ............................................................................................ 38 
12.1 
Efficacy Variables ....................................................................................................... 38 
12.2 
Adjustment for Covariates .......................................................................................... 38 
12.3 
Handling of Missing Data ........................................................................................... 39 
12.4 
Multiple Comparisons / Multiplicity .......................................................................... 39 
12.5 
Examination of Subgroups .......................................................................................... 39 
13 
METHODS OF EFFICACY ANALYSES .................................................................. 39 
13.1 
Analysis of Continuous Efficacy Endpoints ............................................................... 39 


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13.2 
Categorical Analysis ................................................................................................... 41 
13.2.1 
For All Subjects 
41 
13.2.2 
For Subjects Rolled Over from Study ACP-103-038 and -064 
41 
13.2.3 
For Subjects Rolled Over from Study ACP-103-064 
42 
14 
SAFETY ANALYSES ................................................................................................ 42 
14.1 
Adverse Events ........................................................................................................... 42 
14.2 
Clinical Laboratory Variables ..................................................................................... 43 
14.3 
Vital Signs ................................................................................................................... 48 
14.4 
Electrocardiogram (ECG) ........................................................................................... 49 
14.5 
Physical Examination.................................................................................................. 50 
14.6 
Other Safety Variables ................................................................................................ 51 
14.6.1 
Suicidality 
51 
14.6.2 
Extrapyramidal Symptom Measures 
51 
15 
CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES . 52 
16 
INTERIM ANALYSIS ................................................................................................ 52 
17 
DATA MONITORING/REVIEW COMMITTEE ...................................................... 52 
18 
COMPUTER METHODS .......................................................................................... 52 
19 
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL ...................................... 53 
20 
REFERENCES ........................................................................................................... 54 
21 
APPENDICES ............................................................................................................ 55 
21.1 
Summary of Version Changes ..................................................................................... 55 
 
 
 


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LIST OF TABLES 
Table 1 
Schedule of Events and Assessments .................................................................... 14 
Table 2 
SF-36 Re-Coding Rules for Individual Items ....................................................... 25 
Table 3 
SF-36 Scale Components ...................................................................................... 26 
Table 4 
Analysis Visit Windows ........................................................................................ 31 
Table 5 
Scheduled Assessment Timepoints for Efficacy Endpoints Across Double-
Blind (DB) Studies ACP-103-034, -038 and -064 and Open-Label (OL) Study 
-035 ....................................................................................................................... 40 
Table 6 
Criteria for Potentially Clinically Important Laboratory Values – Hematology 
and Chemistry ....................................................................................................... 47 
Table 7 
Criteria for Potentially Clinically Important Laboratory Values - Urinalysis ....... 48 
Table 8 
Criteria for Potentially Clinically Important Vital Signs ...................................... 49 
Table 9 
Criteria for Potentially Clinically Important ECG Values .................................... 50 
 
LIST OF FIGURES 
Figure 1 
Schematic of Study Design ................................................................................... 12 
 


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ABBREVIATIONS 
AE 
adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
ATC 
Anatomical Therapeutic Chemical 
BARS 
Barnes Akathisia Rating Scale 
BMI 
body mass index 
CGI-S 
Clinical Global Impression scale – Severity 
CGI-SCH-S 
Clinical Global Impression of Schizophrenia scale – Severity 
COVID-19  
coronavirus disease 2019 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DAI-10 
10-item Drug Attitude Inventory 
DB 
Double-blind 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOS 
End-of-Study 
ET 
Early Termination 
GSD 
Guidance for Site Documentation and Data Management Querying of 
Data Impacted by COVID-19 
MedDRA 
Medical Dictionary for Regulatory Activities 
msec 
milliseconds 
NSA-16 
Negative Symptom Assessment-16 
OL 
Open-label 
PANSS 
Positive and Negative Syndrome Scale 
PCI 
potentially clinically important 
PSP 
Personal and Social Performance scale 
QTcB 
QT interval corrected for heart rate using Bazett’s formula 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Simpson-Angus Extrapyramidal Side Effects Scale 
SAS® 
Statistical Analysis System 
SD 
standard deviation 
SE 
standard error 
SF-36 
36-item Short Form Health Survey 
SOC 
system organ class 


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TEAE   
treatment-emergent adverse event 
WoRQ 
Work Readiness Questionnaire 


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1 INTRODUCTION 
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the statistical 
analyses of safety and efficacy data as described in the study protocol Amendment 3 dated 
11 August 2020. Specifications for tables, figures, and listings are contained in a separate 
document. 
For Argentina, a country-specific protocol amendment (Amendment 3-AR finalized 
27 April 2021) specifies additional pregnancy tests at Week 10, 16, 24, 32, 40 and 48 for all 
female subjects of childbearing potential to be conducted only for subjects enrolled in Argentina.  
2 OBJECTIVES 
2.1 
Primary Objective 
• To evaluate the long-term safety and tolerability of pimavanserin after 52 weeks of 
adjunctive treatment in subjects with schizophrenia 
2.2 
Secondary Objective 
• Clinical global assessment overall severity of symptoms 
2.3 
Exploratory Objectives 
To evaluate the continued efficacy of pimavanserin treatment with respect to: 
• Overall symptoms of schizophrenia 
• Negative symptoms of schizophrenia (for subjects from Study ACP-103-038 and -064 
only) 
• Personal and social performance 
3 STUDY DESIGN 
3.1 
General Study Design 
ACP-103-035 is 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, flexible-dose extension of Studies ACP-103-034, -038, and -064. 
Subjects who have completed Studies ACP-103-034, -038, or -064, and who may continue to 
benefit from adjunctive pimavanserin treatment based on the Investigator’s judgment will be 
included in this long-term extension study.  


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Study ACP-103-035 subjects must be consented prior to the final procedures being performed at 
Week 6 for Studies ACP-103-034 or at Week 26 for Study ACP-103-038 or -064.  Procedures 
performed at the End-of-Study (EOS) visits of these three double blind studies 
(ACP-103-034, -038, or -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. 
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 be conducted by telephone call at 
approximately 4 weeks after the last dose of study drug. 
Figure 1 illustrates the study design. 


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Figure 1 
Schematic of Study Design 
 
  
 
 
 
 
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 
EOS/ET 
4-week follow-up 
(telephone call) 


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


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Table 1 
Schedule of Events and Assessments 
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)h 
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-Si
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 eventsj
X
X
X
X
X
X
X
X
X
X
Dispense study drug
X
Xk
Xk
Xk
Xk
Xk
Xk
Xk
Study drug accountability
X
X
X
X
X
X
X
X
 
Footnotes for Table 1 on next page. 
 


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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 
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 
Urine pregnancy tests will be completed at all visits for all female subjects of childbearing potential. Additionally, home urine pregnancy tests should be 
performed at Weeks 10, 16, 24, 32, 40, and 48 for all female subjects of childbearing potential; sites should ascertain the results of these home tests by 
telephone. Any positive urine pregnancy test at home or the site must be followed by a confirmatory serum pregnancy test. 
i 
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. 
j 
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. 
k 
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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3.3 
Randomization 
Not applicable. 
3.4 
Blinding 
Not applicable. 
3.5 
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, and -064 and who 
transition into this open-label extension study. 
4 ANALYSIS SETS 
The Safety Analysis Set will include all subjects who received at least 1 dose of open-label study 
drug. The Safety Analysis Set will be used for all analyses. 
5 DATA HANDLING CONVENTIONS 
All data collected in the study will be listed. 
5.1 
General Data Reporting Conventions 
For continuous variables, the following summary statistics will be provided: number of subjects, 
mean, standard error of the mean (SE), standard deviation (SD), minimum, maximum, and 
median. Unless specified otherwise, means, medians, and confidence intervals (CIs) will be 
presented to one more decimal place than the raw data, and the standard deviations and standard 
errors will be presented to 2 more decimal places than the raw data. Unless otherwise specified, 
the maximum number of decimal places is 4 and values will be truncated to 4 decimal places in 
situations where there are more than 4 decimal places. Wherever possible data will be decimal 
aligned. 
For categorical variables, summaries will include the number and percentage of subjects in each 
category. For demographic and baseline characteristics, the number of subjects and the 
percentage of subjects with missing data will be summarized (if applicable), and the denominator 
for percentages will be the total number of subjects in the given treatment group. Categories with 
zero counts will not have zero percentages displayed. Percentages will be presented to 1 decimal 
place. 


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Values that are collected with “<” or “>” signs will generally be analysed as the numerical value 
without the sign in tables and figures. In listings, these data will be reported as collected with the 
sign. 
No hypothesis testing is planned. Descriptive summaries of all safety and efficacy endpoints will 
be provided.  
All safety endpoints will be summarized for the overall Safety Analysis Set by treatment groups 
includes PIM 34 mg and PIM Flexible dose. Treatment group of “PIM 34 mg” will include 
subject rolled over from Study 064 and subjects rolled over from Studies 034 or 038 who 
changed from the initial dose of 20 to 34 mg and stayed on 34 mg through the end of study (only 
one dose change). Treatment group of “PIM Flexible dose” will include subject rolled over from 
Studies 034 or 038. In addition, an “All PIM” group will include all subjects who received 
pimavanserin at any dose level in Study 035. 
In addition, safety summaries by cohorts based on the antecedent study (ACP-103-034 or 
ACP-103-038/-064) and treatment group according to the original double–blinded treatment in 
the antecedent study (placebo or pimavanserin) will also be provided.  
For efficacy endpoints, summaries by cohorts based on the antecedent study (ACP-103-
034, -038, and -064) and treatment group according to the original double–blinded treatment in 
the antecedent study (placebo or pimavanserin) will be provided. 
For each continuous measure in safety and efficacy analyses, change from Baseline results will 
be presented in two ways: 
1. Main analysis: using the Baseline from Study ACP-103-035 and reporting the changes 
across Study ACP-103-035 timepoints 
2. Exploratory analysis: using the Baseline from the antecedent study (ACP-103-034, -038, 
and -064), and reporting the changes across the timepoints of both the double-blind 
antecedent study and the open-label Study ACP-103-035. 
The analysis using the Baseline from the first dose of pimavanserin in either the double-blind or 
the open-label study is included in the two methods outlined above: for the cohort of subjects 
who received placebo in the antecedent double-blind study, method 1 results represent the 
changes from the first dose of pimavanserin; for the cohort of subjects who received 
pimavanserin in the antecedent double-blind study, method 2 results represent the changes from 
the first dose of pimavanserin.    
5.2 
Derived Variables 
In general, the assessment scale total scores and subscores will be derived within the analysis 
datasets. In the event that total scores and/or subscores are also collected on the electronic case 


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report form (eCRF), the derived values will be used for all analyses. Both the raw and derived 
scores will be presented in listings. 
5.2.1 
Clinical Global Impressions Scale – Severity (CGI-S)  
The CGI-S is assessed at Baseline, Weeks 2, 6, 12, 20, 28, 36, 44 and Week 52/ET visits. 
Subjects rolled over from all antecedent studies will be administered the CGI-S scale. 
The CGI-S is a clinician-rated, 7-point scale that is designed to rate the severity of the subject's 
illness, in this case schizophrenia, at the time of assessment, making use of the clinician’s 
judgment and past experience with subjects who have the same disorder. The 7-point scores are: 
1 = normal, not ill; 2 = minimally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 
6 = severely ill; 7 = among the most severely ill. Higher scores denote more severe 
schizophrenia. The licensed version used in this study is a blend of Guy’s (Guy W; Early Clinical 
Drug Evaluation Unit Assessment Manual for Psychopharmacology; US Department of Health, 
Education, and Welfare; National Institute of Mental Health; 1976) and Haro’s (Haro JM; The 
Clinical Global Impression-schizophrenia scale: a simple instrument to measure the diversity of 
symptoms present in schizophrenia; 2003) versions. 
Missing CGI-S scores will not be imputed. 
5.2.2 
Clinical Global Impression of Schizophrenia Scale – Severity (CGI-SCH-S) 
The CGI-SCH-S is assessed at Baseline, Weeks 2, 6, 12, 20, 28, 36, 44 and Week 52/ET visits. 
Only subjects rolled over from antecedent Study ACP-103-038 and ACP-103-064  will be 
administered the CGI-SCH-S scale and only the negative symptoms will be assessed for this 
scale. 
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. For purpose of this study, 
only the negative symptoms are evaluated. The 7-point scores are: 1 = normal, not ill; 
2 = minimally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; 7 = among 
the most severely ill. Higher scores denote more severe negative symptoms in schizophrenia. 
Missing CGI-SCH-S scores will not be imputed. 
5.2.3 
Positive and Negative Syndrome Scale (PANSS) 
The PANSS is assessed at Baseline, Weeks 12, 28 and Week 52/ET visits. Subjects rolled over 
from all antecedent studies will be administered the PANSS scale. 
The PANSS is a 30-item scale used to evaluate the presence, absence, and severity of 
schizophrenia symptoms. Items are scored over the past week (7 days) on the following 7-point 
scale: 1 = absent; 2 = minimal; 3 = mild; 4 = moderate; 5 = moderate-severe; 6 = severe; 


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7 = extreme. The PANSS total score can range from a minimum of 30 to a maximum of 210, 
with higher scores denoting more severe symptoms. 
The following are the 3 PANSS subscales and the PANSS items that define each subscale: 
• Positive Scale: 7 Items (minimum = 7, maximum = 49) 
o P1 
Delusions 
o P2 
Conceptual disorganization 
o P3 
Hallucinatory behavior 
o P4 
Excitement 
o P5 
Grandiosity 
o P6 
Suspiciousness/persecution 
o P7 
Hostility 
• Negative Scale: 7 Items (minimum = 7, maximum = 49) 
o N1 
Blunted affect 
o N2 
Emotional withdrawal 
o N3 
Poor rapport 
o N4 
Passive/apathetic social withdrawal 
o N5 
Difficulty in abstract thinking 
o N6 
Lack of spontaneity and flow of conversation 
o N7 
Stereotyped thinking 
• General Psychopathology Scale: 16 Items (minimum = 16, maximum = 112) 
o G1 
Somatic concern 
o G2 
Anxiety 
o G3 
Guilt feelings 
o G4 
Tension 
o G5 
Mannerisms and posturing 
o G6 
Depression 
o G7 
Motor retardation 
o G8 
Uncooperativeness 
o G9 
Unusual thought content 
o G10 
Disorientation 
o G11 
Poor attention 
o G12 
Lack of judgment and insight 
o G13 
Disturbance of volition 
o G14 
Poor impulse control 
o G15 
Preoccupation 
o G16 
Active social avoidance 
 


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The following are the 5 Marder factors and the PANSS items that define each factor: 
• Negative Symptoms: 7 Items (minimum = 7, maximum = 49) 
o N1 
Blunted affect 
o N2 
Emotional withdrawal 
o N3 
Poor rapport 
o N4 
Passive/apathetic social withdrawal 
o N6 
Lack of spontaneity and flow of conversation 
o G7 
Motor retardation 
o G16 
Active social avoidance 
• Positive Symptoms: 8 Items (minimum = 8, maximum = 56) 
o P1 
Delusions 
o P3 
Hallucinatory behavior 
o P5 
Grandiosity 
o P6 
Suspiciousness/persecution 
o N7 
Stereotyped thinking 
o G1 
Somatic concern 
o G9 
Unusual thought content 
o G12 
Lack of judgment and insight 
• Disorganized Thought: 7 Items (minimum = 7, maximum = 49) 
o P2 
Conceptual disorganization 
o N5 
Difficulty in abstract thinking 
o G5 
Mannerisms and posturing 
o G10 
Disorientation 
o G11 
Poor attention 
o G13 
Disturbance of volition 
o G15 
Preoccupation 
• Uncontrolled Hostility/Excitement: 4 Items (minimum = 4, maximum = 28) 
o P4 
Excitement 
o P7 
Hostility 
o G8 
Uncooperativeness 
o G14 
Poor impulse control 
• Anxiety/Depression: 4 Items (minimum = 4, maximum = 28) 
o G2 
Anxiety 
o G3 
Guilt feelings 
o G4 
Tension 
o G6 
Depression 
For each of the subscales (positive, negative, or general), if more than 1 item score is missing, 
then that particular subscale score and the PANSS total score will be missing. When there is only 
1 item missing for a subscale, then the missing single item will be imputed using the average of 
the non-missing item scores for that subscale, subject and timepoint, rounded to the nearest 
integer. After the missing item(s) is imputed within the subscale(s), then the PANSS total score 
and Marder factor scores will be computed without further imputation. A Marder factor score 


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will be missing if any item score is missing for that factor, after the imputations within the 
subscales were applied. 
5.2.4 
Negative Symptom Assessment-16 (NSA-16) 
The NSA-16 is assessed at Baseline, Week 28 and Week 52/ET visits. Only subjects rolled over 
from antecedent Study ACP-103-038 and ACP-103-064 will be administered the NSA-16 scale. 
The NSA-16 is a semi-structured interview and a validated scale containing 16 items for 
evaluating negative symptoms of schizophrenia. Negative symptoms represent the reduction or 
absence of emotional expression and volitional behaviors normally present in a healthy person. 
Items are scored based on behaviors during the interview (items 1 to 4, 6, 7, 9, 11, 15, 16) or 
previous 7 days (items 5, 8, 10, 12 to 14) on a 6-point scale from 1 to 6 (a score of 9 indicates the 
item is not ratable and therefore is equivalent to missing). The NSA-16 total score can range 
from a minimum of 16 to a maximum of 96, with higher scores denoting more severe negative 
symptoms in schizophrenia. The “normal” (score = 1) reference is based on the comparison to a 
young person in their twenties without schizophrenia. It is not: (1) the same person at another 
point in time; (2) a healthy person of similar age, living under similar circumstances; or 
(3) another hospitalized person. 
The NSA-16 includes 5 domains:   
• Communication: 4 Items (minimum = 4, maximum = 24) 
o Item 1  
Prolonged time to respond 
o Item 2  
Restricted speech quantity 
o Item 3  
Impoverished speech content 
o Item 4  
Inarticulate speech 
• Emotion/affect: 3 Items (minimum = 3, maximum = 18) 
o Item 5  
Emotion: Reduced range 
o Item 6  
Affect: Reduced modulation of intensity 
o Item 7  
Affect: Reduced display on demand 
• Social involvement: 3 Items (minimum = 3, maximum = 18) 
o Item 8  
Reduced social drive 
o Item 9  
Poor rapport with interviewer 
o Item 10 
Interest in emotional and physical intimacy 


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• Motivation: 4 Items (minimum = 4, maximum = 24) 
o Item 11 
Poor grooming and hygiene 
o Item 12 
Reduced sense of purpose 
o Item 13 
Reduced hobbies and interest 
o Item 14 
Reduced daily activity 
• Retardation: 2 Items (minimum = 2, maximum = 12) 
o Item 15 
Reduced expressive gestures 
o Item 16 
Slowed movements 
 
When calculating the domain score, if any item score is missing in a domain, then that particular 
domain score will be missing. When calculating the NSA-16 total score, if there are no more 
than 3 missing items then the total score will be imputed by replacing each missing item with the 
mean (rounded to the nearest integer) of the non-missing values for that subject and timepoint. If 
there are 4 or more missing items then the total score will be missing.  
Additionally, there is a global negative symptoms rating which assesses the overall severity on a 
7-point scale from 1 to 7, with higher scores denoting more severe negative symptoms in 
schizophrenia. Missing global negative symptoms rating scores will not be imputed. 
5.2.5 
Personal and Social Performance Scale (PSP) 
The PSP is assessed at Baseline, Weeks 12, 28 and Week 52/ET visits. Subjects rolled over from 
all antecedent studies will be administered the PSP scale. 
The PSP is a validated 100-point (1 to100) single-item rating scale to assess the psychosocial 
functioning of subjects with schizophrenia. Ratings are based on four main areas: (a) socially 
useful activities, including work and study; (b) personal and social relationships, (c) self-care; 
and (d) disturbing and aggressive behaviors. The time period assessed is “past month” and does 
not take into account suicidal risk and behavior. Higher scores denote better psychosocial 
functioning: scores of 71-100 reflect only mild difficulties; 31-70 reflect manifest disabilities of 
various degrees; 1-30 reflect functioning so poor that intensive support or supervision is needed. 
Missing PSP scores will not be imputed. 
5.2.6 
Work Readiness Questionnaire (WoRQ) 
The WoRQ is assessed at Baseline, Weeks 12, 28 and Week 52/ET visits. Only subjects rolled 
over from antecedent Study ACP-103-064 will be administered the WoRQ. 
The WoRQ 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 


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calculated by adding scores for the 7 statements. Lower scores denote better work readiness. If 
more than 1 score is missing, then the total score will be missing. If there is only 1 missing item 
score, the total score will be calculated by the arithmetic mean of non-missing items for that 
subject and timepoint multiplied by 7, rounded to the nearest integer. 
5.2.7 
36-Item Short Form Health Survey (SF-36) 
The SF-36 is assessed at Baseline, Weeks 12, 28 and Week 52/ET visits. Subjects rolled over 
from all antecedent studies will be administered the SF-36 scale. 
The SF-36 is a 36-item survey that measures the overall health status of a subject. The SF-36 
assesses eight health concepts during the past 4 weeks: physical functioning, bodily pain, role 
limitations due to physical health problems, role limitations due to personal or emotional 
problems, emotional well-being, social functioning, energy/fatigue, and general health 
perceptions. It also includes a single item that provides an indication of perceived change in 
health compared to one year ago. In Study ACP-103-035, the RAND 36-Item Health Survey 
(Version 1.0) is used. 
Scoring the SF-36 is a 2-step process. First, pre-coded numeric values are re-coded per the 
scoring key given in Table 2  Note that all items are scored so that a high score defines a more 
favorable health state and less disability. In addition, each item is scored on a 0 to 100 range so 
that the lowest and highest possible scores are 0 and 100, respectively. Scores represent the 
percentage of total possible score achieved, with higher scores denoting higher level of 
functioning. In step 2, items in the same scale are averaged together to create the 8 scale scores. 
Table 3 lists the items averaged together to create each scale. Items that are left blank (missing 
data) are not taken into account when calculating the scale scores. Hence, scale scores represent 
the average for all items in the scale that the respondent answered. 


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Table 2 
SF-36 Re-Coding Rules for Individual Items 
Item Number 
Original Response Category1 
Re-Coded Value 
2, 20, 34, 36 
1 
100 
2 
75 
3 
50 
4 
25 
5 
0 
3, 4, 5, 6, 7, 8, 9, 10, 11, 12 
1 
0 
2 
50 
3 
100 
13, 14, 15, 16, 17, 18, 19 
1 
0 
2 
100 
23, 26, 27, 30 
1 
100 
2 
80 
3 
60 
4 
40 
5 
20 
6 
0 
24, 25, 28, 29, 31 
1 
0 
2 
20 
3 
40 
4 
60 
5 
80 
6 
100 
32, 33, 35 
1 
0 
2 
25 
3 
50 
4 
75 
5 
100 
1 
1 
100 
2 
85 
3 
60 
4 
25 
5 
0 
21 
1 
100 
2 
88 
3 
64 
4 
42 
5 
24 
6 
0 


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Table 2 
SF-36 Re-Coding Rules for Individual Items (Continued) 
Item Number 
Original Response Category1 
Re-Coded Value 
22 
1 (Item 21 = 1 or .) 
100 
1 (Item 21 = 2 to 6) 
80 
2 (Item 21 = .) 
75 
2 (Item 21 ^= .) 
60 
3 (Item 21 = .) 
50 
3 (Item 21 ^= .) 
40 
4 (Item 21 = .) 
25 
4 (Item 21 ^= .) 
20 
5  
0 
1 
Pre-coded response choices as printed in the questionnaire. 
 
Table 3 
SF-36 Scale Components 
Scale 
Items 
PHYFUN10: Physical functioning  
3, 4, 5, 6, 7, 8, 9, 10, 11, 12 
ROLEP4: Role limitations due to physical health 
13, 14, 15, 16 
ROLEE3: Role limitations due to emotional problems 
17, 18, 19 
ENFAT4: Energy/fatigue 
23, 27, 29, 31 
EMOT5: Emotional well-being 
24, 25, 26, 28, 30 
SOCFUN2: Social functioning 
20, 32 
SFPAIN2: Pain 
21, 22 
SFGENH5: General health 
1, 33, 34, 35, 36 
 
To enable meaningful comparisons across scales, the 8 scale scores are converted to norm-based 
z-scores based on 1998 General Population statistics: 
   PF_Z = (PHYFUN10 - 82.96845) / 23.83795 ; 
   RP_Z = (ROLEP4 - 77.93107) / 35.34865 ; 
   RE_Z = (ROLEE3 - 83.10276) / 31.64149 ; 
   EN_Z = (ENFAT4 - 56.99917) / 21.12677 ; 
   EM_Z = (EMOT5 - 75.21913) / 17.60698 ; 
   SF_Z = (SOCFUN2 - 83.56494) / 23.02758 ; 
   BP_Z = (SFPAIN2 - 70.22865) / 23.35310 ; 
   GH_Z = (SFGENH5 - 70.10060) / 21.35900 ; 
   


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In addition, physical and mental health composite scores will also be computed using the 
individual-scale z-scores:    
Physical health composite scores AGPHYS_Z 
= (PF_Z * 0.42402) + (RP_Z * 0.35119) + (BP_Z * 0.31754) + 
              (GH_Z * 0.24954) + (EM_Z * -.22069) + (RE_Z * -.19206) + 
              (SF_Z * -.00753) + (EN_Z * 0.02877); 
Mental health composite scores AGMENT_Z 
= (PF_Z * -.22999) + (RP_Z * -.12329) + (BP_Z * -.09731) + 
              (GH_Z * -.01571) + (EM_Z * 0.48581) + (RE_Z * 0.43407) + 
              (SF_Z * 0.26876) + (EN_Z * 0.23534); 
The 2 composite scores will not be calculated if any individual scale score is missing. 
Finally, the z-scores will be transformed to t-scores for data 
summaries_Exploratory_Efficacy_Analyses. 
   AGPHYS_T = 50 + (AGPHYS_Z * 10); 
   AGMENT_T = 50 + (AGMENT_Z * 10); 
   PF_T = 50 + (PF_Z * 10) ; 
   RP_T = 50 + (RP_Z * 10) ; 
   RE_T = 50 + (RE_Z * 10) ; 
   EN_T = 50 + (EN_Z * 10) ; 
   EM_T = 50 + (EM_Z * 10) ; 
   SF_T = 50 + (SF_Z * 10) ; 
   BP_T = 50 + (BP_Z * 10) ; 
   GH_T = 50 + (GH_Z * 10) ; 
5.2.8 
Drug Attitude Inventory (DAI-10) 
The DAI-10 is assessed at Baseline, Weeks 12, 28 and Week 52/ET visits. Subjects rolled over 
from all antecedent studies will be administered the DAI-10 scale. 
The DAI-10 contains 6 items (1, 3, 4, 7, 9, and 10) that a subject who is fully adherent to the 
prescribed medication would answer as "True" and 4 items (2, 5, 6, and 8) that a subject who is 
fully adherent to the prescribed medication would answer as "False."  A correct answer is scored 
+1 and an incorrect answer is scored -1. The total score is the sum of pluses and minuses, which
can range from -10 to 10 in increments of 2. A positive total score indicates a positive subjective
response (adherent) and a negative total score indicates a negative subjective response (non-
adherent). Higher scores denote better adherence.
Missing DAI-10 item scores will not be imputed. The total score will be missing if any item 
score is missing. 


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5.2.9 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is assessed at Baseline, Weeks 2, 6, 12, 20, 28, 36, 44 and Week 52/ET visits. 
C-SSRS is a safety assessment and subjects rolled over from all antecedent studies will be 
assessed. 
The C-SSRS monitors changes in suicidal thinking and behavior over time, in order to determine 
risk. Four constructs are measured: the severity of ideation, the intensity of ideation, behavior, 
and lethality. 
The C-SSRS version assessing information since the last visit will be completed at all visits 
(including the Baseline visit). The C-SSRS results for each subject should be reviewed by the 
Investigator at each visit. If at any time the C-SSRS results for a given subject reveal potential 
suicidality, then the Investigator should assess the clinical significance of such results. If a 
clinically significant risk of suicidality is identified for a subject, then the Investigator should 
discontinue the subject and implement appropriate treatment. 
There are 5 questions about suicidal ideation, representing 5 types of suicidal ideation: wish to be 
dead; non-specific active suicidal thoughts; active suicidal ideation with any methods (not plan) 
without intent to act; active suicidal ideation with some intent to act, without specific plan; active 
suicidal ideation with specific plan and intent. If a subject answers “yes” to any of these 
5 questions, this subject will be counted as having suicidal ideation. 
There are 5 questions about suicidal behavior, representing 5 types of suicidal behavior: 
preparatory acts or behavior; aborted attempt; interrupted attempt; actual attempt; suicide. If a 
subject answers “yes” to any of these 5 questions, this subject will be counted as having suicidal 
behavior. 
Missing C-SSRS item scores will not be imputed. 
5.2.10 Abnormal Involuntary Movement Scale (AIMS) 
The AIMS is assessed at Baseline, Weeks 2, 12, 28, 44 and Week 52/ET visits. AIMS is a safety 
assessment and subjects rolled over from all antecedent studies will be assessed. 
The AIMS is a rating scale that was designed to measure involuntary movements known as 
tardive dyskinesia. The AIMS has a total of 12 items rating involuntary movements of various 
areas of the subject's body.  
• Items 1 to 7 assess the severity of dyskinesia (orofacial, extremity and truncal movements) 
are rated on a 5-point scale of severity: 0 (none), 1 (minimal; may be extreme normal), 
2 (mild), 3 (moderate), and 4 (severe).  


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•
Items 8 and 9 assess the overall severity and incapacitation, and are also rated on a 5-point
scale of severity: 0 (none, normal), 1 (minimal), 2 (mild), 3 (moderate), and 4 (severe).
•
Item 10 assesses the subject’s level of awareness of the movements with associated distress
and is rated on a 5-point scale: 0 (no awareness), 1 (aware, no distress), 2 (aware, mild
distress), 3 (aware, moderate distress), and 4 (aware, severe distress).
•
Items 11 and 12 refer to dental status and the responses are yes (scored as 1) or no (scored as
0).
The AIMS total score is the sum of the 12 item scores which can range from 0 to 42, with higher 
scores denoting more severe dyskinesia symptoms. 
Missing AIMS item scores will not be imputed. The total score will be missing if any item score 
is missing. 
5.2.11 Barnes Akathisia Scale (BARS)  
The BARS is assessed at Baseline, Weeks 2, 12, 28, 44 and Week 52/ET visits. BARS is a safety 
assessment and subjects rolled over from all antecedent studies will be assessed. 
The BARS is a 4-item, physician-administered scale that assesses the severity of drug-
induced akathisia. Items 1 to 3 assess the objective presence and frequency of akathisia, the 
subjective awareness of restlessness, and the subjective distress related to restlessness. These 
3 items are rated on a 4-point scale from 0 to 3 and the total score is the sum of these 3 item 
scores, which can range from 0 to 9. Additionally, there is a global clinical assessment of 
akathisia which is rated on a 6-point scale from 0 to 5. For total or global clinical assessment 
scores, higher scores denote more severe akathisia symptoms. 
Missing BARS item scores will not be imputed. The total score will be missing if any non-global 
item score is missing. 
5.2.12 Simpson Angus Extrapyramidal Side Effect Scale (SAS) 
The SAS is assessed at Baseline, Weeks 2, 12, 28, 44 and Week 52/ET visits. SAS is a safety 
assessment and subjects rolled over from all antecedent studies will be assessed. 
The SAS is a 10-item physician-administered scale commonly used for the assessment of 
parkinsonian movement disorder related to psychiatric drug treatment. One item on the SAS 
measures gait/hypokinesia; 6 items measure rigidity (arm-dropping, shoulder shaking, elbow 
rigidity, wrist rigidity or fixation of position, head rotation, and akathisia); and 3 items measure 
glabella tap, tremor, and salivation, respectively. The grade of severity of each item is rated using 
a 5-point scale from 0 to 4. The SAS total score is the sum of the 10 items, which can range from 
0 to 40, with higher scores denoting more severe parkinsonian symptoms. 


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Missing SAS item scores will not be imputed. The total score will be missing if any item score is 
missing. 
5.3 
Data Handling Conventions 
• 1 year = 365.25 days. Year is calculated as (days/365.25) and will be rounded to 
1 digit after the decimal point (tenths) for presentation purposes. 
• 1 month = 30.4375 days. Month is calculated as (days/30.4375) and will be rounded 
to 1 digit after the decimal point (tenths) for presentation purposes. 
• 1 pound = 0.454 kg and 1 kg = 2.2 pounds. 
• 1 inch = 2.54 cm and 1 cm = 0.3937 inches. 
• Body mass index (BMI) calculated as [weight (kg)/height (m)2] 
5.4 
Study Day 
If the date of assessment occurs on or after the first open-label dose date, then study day will be 
calculated as (date of assessment – date of first open-label dose) + 1. If the date of assessment 
occurs prior to the first open-label dose date, then study day will be calculated as (date of 
assessment – date of first open-label dose). There is no study day 0. 
5.5 
Baseline Definition 
The open-label Baseline assessment will be defined as the last non-missing assessment, 
including those from repeated and unscheduled measurements, before or on the first open-label 
dose date. Exceptions to this definition will be handled on a case by case basis.  
5.6 
Analysis Visit Windows  
Efficacy and safety assessments will be summarized by analysis visit as presented in Table 4 
below. 


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Table 4 
Analysis Visit Windows 
Open-label (OL) Analysis 
Visit Name 
Target Study Day1 
Study Day Interval 
OL Baseline  
1  
≤1 (based on the first OL dose 
date) 
 
OL Week 2 
15 
2 to 28 
OL Week 6 
43 
29 to 63 
OL Week 12 
85 
64 to 112 
OL Week 20 
141 
113 to 168 
OL Week 28 
197 
169 to 224 
OL Week 36 
253 
225 to 280 
OL Week 44 
309 
281 to 336 
OL Week 52 
365 
≥ 3372   
1 
If the assessment date ≥ first OL dose date, study day = assessment date - first OL dose date + 1, 
otherwise study day = assessment date – first OL dose. Study day 1 is the first OL dose date. 
2 
Efficacy assessment collected more than seven days after the last OL dosing date will be excluded from the 
efficacy analyses. 
 
5.6.1 
Unscheduled Assessments 
Both scheduled and unscheduled assessments, including early termination visits, will be 
considered for planned timepoint summaries. All assessments will be presented in data listings. 
5.6.2 
Multiple Measurements within Visit Windows 
If more than one assessment falls within a given window then the assessment closest to the target 
study day will be selected for the by-visit summaries. If two assessments are equidistant from the 
target day then the chronologically last assessment will be used for summary. Exceptions may be 
made for incomplete assessments, in which case, more complete assessments may be given 
priority.  Details are provided in a separate programming conventions document. 
For safety summaries where the most extreme values should be selected, e.g. overall post-
baseline minimum, overall post-baseline maximum, and potentially clinically important values 
for overall post-Baseline summaries, all non-missing post-Baseline values should be considered, 
regardless of whether the value is selected for the by-visit summaries. All results will be 
presented in data listings. 
When ECG is collected in triplicate, the average of the triplicate will be considered as one 
assessment for the analyses. 


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5.7 
Missing or Incomplete Date for Last Dose of Study Drug 
In the Safety Analysis Set, if the last dose date of study drug is missing for a subject who 
completed or early terminated from the study, then the date of the end-of-study/early termination 
visit will be used in the calculation of treatment duration. For the incomplete last dose date of the 
study drug, the imputation algorithms will be detailed in the analysis dataset specification 
document. The missing or incomplete dates will be displayed in the data listings as reported on 
the eCRF rather than the imputed dates. 
For the data summarization before final database lock, if a subject is still ongoing, then this 
subject’s last dose date will be imputed using the database extract date.  
5.8 
Missing or Incomplete Dates for Concomitant or Post-Treatment Medications 
Missing or incomplete medication start or end dates will be imputed for the purpose of 
determining whether the medications are taken concomitantly (see Section 11 for definition). 
When the chronological order of medication use relative to the study drug treatment period is 
unclear due to missing or incomplete date(s), the medication will be considered as concomitant. 
The imputation algorithms will be detailed in the analysis dataset specification document. The 
missing or incomplete dates will be displayed in the data listings as reported on the eCRF rather 
than the imputed dates. 
5.9 
Missing or Incomplete Dates for Adverse Events  
Missing or incomplete adverse event (AE) start dates will be imputed for the purpose of 
determining whether the AEs are treatment-emergent (see Section 14.1 for definition). When the 
chronological order of an AE onset relative to the study drug treatment period is unclear due to 
missing or incomplete date(s), the AE will be considered as treatment-emergent. The imputation 
algorithms will be detailed in the analysis dataset specification document. The missing or 
incomplete dates will be displayed in the data listings as reported on the eCRF rather than the 
imputed dates. 
5.10 Missing Severity Assessment for Adverse Events 
If the severity is missing for a treatment-emergent AE, a severity of “Severe” will be assigned. 
The imputed values for severity assessment will be used for incidence summaries, and the actual 
values will be presented in data listings. 


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5.11 Missing Relationship to Study Drug for Adverse Events 
If the relationship to study drug is missing for a treatment-emergent AE, a causality of “Related” 
will be assigned. The imputed values for relationship to study drug will be used for incidence 
summaries, and the actual values will be presented in data listings. 
5.12 Character Values of Clinical Laboratory Variables  
If the reported value of a clinical laboratory variable cannot be used in a summary due to, for 
example, a character string reported for a numeric variable, an appropriately determined coded 
value will be used in the summary. The coding algorithms will be detailed in the analysis dataset 
specification document. The actual values as reported in the database will be presented in data 
listings. 
5.13 Duplicate Subjects  
Duplicate-subject screening will be performed throughout the schizophrenia program to identify 
whether there are individuals who are randomized more than once into the double-blind 
schizophrenia studies ACP-103-034, -038 or -064. Confirmed duplicates will only be included 
for summaries under the subject number and antecedent study to which they were first 
randomized and rolled over from. Data collected under other subject number(s) or antecedent 
study (studies) will be listed but will not be summarized. Case narratives will be provided for 
duplicate subjects. 
6 SUBJECT DISPOSITION 
The number of sites that enrolled at least 1 subject and number of subjects enrolled will be 
summarized by region (North America, Europe, and rest of world) and overall. Enrolled subjects 
are subjects who signed informed consent for Study ACP-103-035 and not recorded as “rollover 
failure” on eCRF. 
For enrolled subjects, number and percentage of subjects in the Safety Analysis Set will be 
summarized. A listing will be provided displaying all subjects excluded from the Safety Analysis 
Set (if any), and will include reason(s) for exclusion.  
The number and percentage of subjects in the Safety Analysis Set who completed the study or 
discontinued (all discontinued and by discontinuation reason) will also be summarized. 
Summaries by region (North America, Europe, and rest of world) will also be presented. 
7 PROTOCOL DEVIATIONS 
Protocol deviations that occurred during the extension study period will be reviewed periodically 
over the course of the study. The review process, definition of the deviation categories, and the 


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classification of a deviation as major or minor are detailed in the Protocol Deviation Project 
Instruction document. Protocol deviations will also be assessed with respect to relationship to 
COVID-19. 
For enrolled subjects, a summary of the number and percentage of subjects with major protocol 
deviations for each deviation category will be presented in three ways: all protocol deviations, 
COVID-19 related protocol deviations, and non-COVID-19 related protocol deviations. 
Three listings of major protocol deviations will be provided: all deviations, COVID-19 related 
protocol deviations and non-COVID-19 related protocol deviations. 
8 DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
Demographics and open-label Baseline characteristics will be summarized for the Safety 
Analysis Set using descriptive statistics. Summaries by region (North America, Europe, and rest 
of world) will also be presented. Variables include age, sex, primary race (subjects of multi-racial 
background can only identify/select one primary race on eCRF, or choose “other” and specify), 
ethnicity, height, weight, body mass index (BMI), region, current smoking status, highest 
education level, marital status, employment status, Baseline PANSS total score, Baseline CGI-S, 
Baseline CGI-SCH-S, Baseline NSA-16 total score and Baseline PSP score. Note that 
CGI-SCH-S and NSA-16 scores are only collected from subjects who rolled over from 
Study ACP-103-038 and -064. 
Age (the eCRF reported age reflects a subject’s age at the open-label Baseline visit date), 
Baseline PANSS total score, Baseline CGI-S, Baseline CGI-SCH-S, Baseline NSA-16 total 
score, Baseline PSP score and Baseline WoRQ score will be presented as both continuous and 
categorical variables. Age categories will be presented as 18 to 35 and >35 years old. Baseline 
PANSS will be presented as <90 (lower symptom severity) or >90 (higher symptom severity). 
Baseline CGI-S and CGI-SCH-S categories will be presented as scores 1 to 7 as well as <4 
(lower disease severity) or >5 (higher disease severity). Baseline NSA-16 will be presented as 
<55 (lower symptom severity) or >55 (higher symptom severity). Baseline PSP will be presented 
by deciles (e.g., scores of 31 to 40, 41 to 50, etc.).  
Schizophrenia disease history will be summarized for Safety Analysis Set using descriptive 
statistics. Variables include:  
• Age (years) at diagnosis of schizophrenia disease 
• Age (years) when received first antipsychotic medication for schizophrenia 
• Duration (years) of schizophrenia disease  


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• Duration of negative symptoms (<1, 1 to 5, or >5 years)  (this information is only 
collected for subjects who rolled over from Study ACP-103-038 and -064) 
• Time (years) since first antipsychotic treatment  
• Treated with clozapine in the past (yes or no) (this information is only collected for 
subjects who rolled over from Study ACP-103-034) 
• Number of hospitalizations for treatment of schizophrenia (0, 1 to 5, 6 to 10, or >10) 
• Current main background antipsychotic medication 
• Duration (months) of current main background antipsychotic medication 
• Had suicidal ideation or behavior at open-label Baseline (yes or no) 
• Had non-suicidal self-injurious behavior at open-label Baseline (yes or no) 
Open-label Baseline visit date will be used as the reference date for calculating the durations 
listed above. 
Additional information will be listed, including the name of first antipsychotic medication and 
the dose and frequency of the current main background antipsychotic medication. For subjects 
who had received clozapine, date of last clozapine dose and the dose level will also be listed. For 
subjects who had been hospitalized before, date of last hospitalization and treatment received in 
the hospital will also be listed.  
9 MEDICAL HISTORY 
Medical and surgical history data will be coded using Medical Dictionary for Regulatory 
activities (MedDRA) version 23.0 or newer. The subject incidence will be summarized for each 
system organ class (SOC) and preferred term for the Safety Analysis Set. A subject will be 
counted only once per SOC or per preferred term for the summary. 
A listing of the SOC, preferred term, body system, verbatim term for the medical history 
condition/event, start and stop dates (when available), and an indicator for whether or not the 
condition is ongoing will be provided. 
10 EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE 
Summaries of exposure and compliance to study drug will be provided for the Safety Analysis 
Set. 


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10.1 Exposure to Study drug  
10.1.1 Exposure to open-label pimavanserin 
For each subject, the duration of exposure to open-label pimavanserin (open-label last dose date 
– open-label first dose date + 1), cumulative dose (first multiply the number of doses taken by 
the dose level for each kit utilized during the open-label study period, then sum the results from 
all kits), and average daily dose (cumulative dose in mg divided by duration of open-label 
exposure in days) will be calculated and summarized. 
Duration of OL pimavanserin exposure will be summarized as both continuous and categorical 
variables. For categorical presentation, the number and percentage of subjects in each of the 
following categories will be presented: <2 weeks (1 to 13 days), 2 to <6 weeks (14 to 41 days), 
6 to <12 weeks (42 to 83 days), 12 to <20 weeks (84 to 139 days), 20 to <28 weeks (140 to 
195 days), 28 to <36 weeks (196 to 251 days), 36 to <44 weeks (252 to 307 days), 44 to 
<52 weeks (308 to 363 days), and >52 weeks (364 days or longer). Kaplan-Meier curves of 
duration on study drug will also be presented. In addition, for subjects from Study ACP-103-034 
and -038, summaries of whether subjects had any dose change (yes vs. no), their highest dose 
level (20 mg or 34 mg), their lowest dose level (10 mg or 20 mg), and their last dose level 
(10 mg, 20 mg, or 34 mg) will also be provided. 
The pimavanserin dose levels are expressed as free base. 
10.1.2 Total exposure to pimavanserin across the double-blind and open-label periods  
For subjects who received pimavanserin in the antecedent studies, the total duration of exposure 
(in days) to pimavanserin will be calculated as the sum of the exposure durations in the double-
blind and open-label periods:  
[(date of last double-blind dose) – (date of first double-blind dose) + 1] + [(date of last open-
label dose) – (date of first open-label dose) + 1]. 
The cumulative dose of pimavanserin will be calculated by first multiplying the number of doses 
taken by the dose level (in mg) for each kit returned to the site during both the double-blind and 
the open-label study periods and then summing the results for all kits. The average daily dose of 
pimavanserin (in mg) will be calculated as the cumulative dose (in mg) divided by total duration 
of exposure (in days). For subjects who received placebo in the antecedent studies, the total 
duration of exposure to pimavanserin, the cumulative dose of pimavanserin, and the average 
daily dose of pimavanserin across the double-blind and open-label periods will be the same as 
the values calculated for the open-label study period alone. Duration of exposure, cumulative 
dose, and average daily dose for pimavanserin across the double-blind and open-label periods 
will be summarized descriptively. 


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Duration of total exposure to pimavanserin will be summarized as both continuous and 
categorical variables. For categorical presentation, the number and percentage of subjects in each 
of the following categories will be presented: <2 weeks (1 to 13 days), 2 to <6 weeks (14 to 
41 days), 6 to <12 weeks (42 to 83 days), 12 to <20 weeks (84 to 139 days), 20 to <28 weeks 
(140 to 195 days), 28 to <36 weeks (196 to 251 days), 36 to <44 weeks (252 to 307 days), 44 to 
<52 weeks (308 to 363 days), 52 to <60 weeks (364 to 419 days), 60 to <68 weeks (420 to 
475 days), 68 to <78 weeks (476 to 545 days), and >78 weeks (546 days or longer). In addition, 
for Study ACP-103-034 and -038, summaries of whether subjects had any dose change (yes vs. 
no), their highest dose level (20 mg or 34 mg), their lowest dose level (10 mg or 20 mg), and 
their last dose level (10 mg, 20 mg, or 34 mg) will also be presented. 
10.2 Measurement of Treatment Compliance 
Study drug dosing compliance (in percentage) for a subject is defined as the total number of 
tablets actually taken divided by the number of tablets expected to be taken and then multiplied 
by 100. The total number of tablets actually taken is calculated by the total number of tablets 
dispensed minus the total number of tablets returned. The number of tablets expected to be taken 
is calculated as the duration of exposure multiplied by 2 (the planned number of tablets taken per 
day). Additional details for handling missing number of tablets returned will be provided in a 
separate specification document. 
Compliance will be summarized as both continuous and categorical variables. For categorical 
presentation, the number and percentage of subjects in each of the following categories will be 
presented: <80%, 80 to 120%, and >120%. 
11 CONCOMITANT AND POST-TREATMENT MEDICATION 
Concomitant medication is defined as any medication with a start date prior to the date of the 
open-label first dose and continuing after the open-label first dose date or with a start date 
between the open-label first dose date and open-label last dose date, inclusive. Any medication 
with a start date after the open-label last dose date will be considered as post-treatment 
medication. Concomitant and post-treatment medications will be summarized separately. 
Medications will be coded using WHO Drug Dictionary 2020March or newer version. For 
concomitant medications, the number and percentage of subjects taking each drug class (ATC 
Level 3) and medication preferred term will be tabulated for Safety Analysis Set. A subject will 
be counted only once per drug class or per medication preferred term for the summary. 
Relationship to COVID-19 will be assessed for selected medications as detailed in the GSD. 
Concomitant and post-treatment medication analyses described above will also be summarized 
and listed by relationship to COVID-19 (Not related to COVID-19 vs. Related to COVID-19). 


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12 EFFICACY ANALYSES 
All efficacy analyses will be performed for the Safety Analysis Set. No hypothesis testing is 
planned. Descriptive summaries of all efficacy endpoints will be provided. 
12.1 Efficacy Variables 
Secondary Endpoints 
• Change from Baseline in the Clinical Global Impressions – Severity scale (CGI-S) 
• Change from Baseline in the Clinical Global Impression of Schizophrenia Scale – 
Severity (CGI-SCH-S) (for subjects from Study ACP-103-038 and ACP-103-064 only) 
Exploratory Endpoints 
• Change from Baseline in the Positive and Negative Syndrome Scale (PANSS) total score, 
subscores (positive scale, negative scale, and general psychopathology scale), and Marder 
factor scores (negative symptoms, positive symptoms, disorganized thought, uncontrolled 
hostility/excitement, and anxiety/depression factors) and individual item scores 
See Section 5.2.3 for the PANSS items included in each Marder factor. 
• Change from Baseline in the Negative Symptom Assessment-16 (NSA-16) scale total 
score, domain scores (communication, emotion/affect, social involvement, motivation, or 
retardation), and individual item scores (for subjects from Study 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 ACP-103-034 and ACP-103-038 only) 
See Section 5.2.6 for details 
• Change from Baseline in 10-item Drug Attitude Inventory (DAI-10) score (for subjects 
from Study 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) 
12.2 Adjustment for Covariates 
Not applicable. 


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12.3 Handling of Missing Data 
Any derived scores (i.e. total, domain, or subscale scores) that are missing, after the imputation 
of individual missing items as described in Section 5.2, will not be imputed. 
12.4 Multiple Comparisons / Multiplicity 
No hypothesis testing is planned.  
12.5 Examination of Subgroups 
Summaries for below subgroups will be tabulated for the change from Baseline in the CGI-S and 
CGI-SCH-S scores: 
• region (North America, Europe, or rest of world) 
• age group (18 to 35 or >35 years old) 
• sex (male or female) 
13 METHODS OF EFFICACY ANALYSES 
13.1 Analysis of Continuous Efficacy Endpoints 
Descriptive statistics for all secondary and exploratory efficacy endpoints listed in Section 12.1 
will be tabulated by cohorts based on antecedent study and double-blind treatment group at 
scheduled timepoints. The summaries of the change from Baseline results will be presented by 
cohort at scheduled timepoints in two ways as specified in Section 5.1. The scheduled timepoints 
across the double-blind and the open-label study periods for all efficacy endpoints are presented 
in Table 5 below. 
 
  


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Table 5 
Scheduled Assessment Timepoints for Efficacy Endpoints Across Double-Blind (DB) Studies ACP-103-034, -038 
and -064 and Open-Label (OL) Study -035 
  
CGI-S 
CGI-SCH-S 
PANSS 
NSA-16 
PSP 
SF-36 
DAI-10 
WoRQ 
034 
038 
/064 
034 
038 
/064 
034 
038 
/064 
034 
038 
/064 
034 
038 
/064 
034 
038 
034 
038 
 
064 
DB Baseline 
x 
N/A  
N/A  
x 
x 
x 
N/A  
x 
x 
x 
x 
x 
x 
x 
x 
DB W1 
x 
N/A  
N/A  
  
x 
  
N/A  
  
  
  
  
  
  
  
 
DB W2 
x 
N/A  
N/A  
x 
x 
  
N/A  
x 
  
  
  
  
  
  
 
DB W3 
x 
N/A  
N/A  
  
x 
  
N/A  
  
  
  
  
  
  
  
 
DB W4 
x 
N/A  
N/A  
x 
x 
  
N/A  
x 
  
  
  
  
  
  
 
DB W5 
x 
N/A  
N/A  
  
x 
  
N/A  
  
  
  
  
  
  
  
 
DB W6 
  (034 EOS) 
x 
N/A  
N/A  
  
x 
  
N/A  
  
x 
  
x 
  
x 
  
 
DB W8 
  
N/A  
N/A  
x 
  
  
N/A  
x 
  
x 
  
  
  
  
x 
DB W14 
  
N/A  
N/A  
x 
  
  
N/A  
x 
  
  
  
  
  
  
x 
DB W20 
  
N/A  
N/A  
x 
  
  
N/A  
x 
  
  
  
  
  
  
 
DB W26 
  (038/064 EOS) 
  
x 
N/A  
x 
  
x 
N/A  
x 
  
x 
  
x 
  
x 
x 
OL W2 
x 
x 
N/A  
x 
  
  
N/A  
  
  
  
  
  
  
  
 
OL W6 
x 
x 
N/A  
x 
  
  
N/A  
  
  
  
  
  
  
  
 
OL W12 
x 
x 
N/A  
x 
x 
x 
N/A  
  
x 
x 
x 
x 
x 
x 
x 
OL W20 
x 
x 
N/A  
x 
  
  
N/A  
  
  
  
  
  
  
  
 
OL W28 
x 
x 
N/A  
x 
x 
x 
N/A  
x 
x 
x 
x 
x 
x 
x 
x 
OL W36 
x 
x 
N/A  
x 
  
  
N/A  
  
  
  
  
  
  
  
 
OL W44 
x 
x 
N/A  
x 
  
  
N/A  
  
  
  
  
  
  
  
 
OL W52 
x 
x 
N/A  
x 
x 
x 
N/A  
x 
x 
x 
x 
x 
x 
x 
x 
 
 


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13.2 Categorical Analysis 
13.2.1 For All Subjects  
Two types of responders will be counted by cohort at each scheduled post-Baseline visit: 
• ≥ 20% reduction in the corrected PANSS total score (subtracting 30 points from the raw 
scores; see details below) from Baseline 
• ≥ 30% reduction in the corrected PANSS total score (subtracting 30 points from the raw 
scores; see details below) from Baseline 
Note that since PANSS is an interval scale that lacks a natural zero point, the percent change in 
PANSS total score will be calculated based on corrected scores after subtracting 30 points from 
the raw scores (Leucht et al., 2007; Leucht et al., 2009; Obermeier et al., 2010; Obermeier et al., 
2011). For example, if a subject’s Baseline PANSS total score is 80 and Week 52 PANSS total 
score is 30 (absent of all symptoms), the percent change from Baseline to Week 52 in PANSS 
total score will be calculated as: 
[(30 – 30) – (80 – 30)] ÷ (80 – 30) × 100% = -100%. 
At any given visit, the proportion of responders will be calculated using 2 different methods:  
• Observed cases (subjects with missing PANSS total score are excluded from the 
calculation): number of responders divided by number of subjects with non-missing 
PANSS total score for the given visit and cohort. 
• Missing as failures (subjects with missing PANSS total score are considered as non-
responders in the calculation): number of responders divided by total number of subjects 
in the Safety Analysis Set for the given cohort.  
13.2.2 For Subjects Rolled Over from Study ACP-103-038 and -064 
Multiple responder criteria will be used to define a NSA-16 responder (Schooler et al., 2015): 
• ≥20%, ≥30%, ≥40%, ≥50%, ≥75% and 100% reduction in total score from Baseline 
Note that since NSA-16 is an interval scale that lacks a natural zero point, the percent change in 
NSA-16 total score will be calculated based on corrected scores after subtracting 16 points from 
the raw scores (Leucht et al., 2007; Leucht et al., 2009). For example, if a subject’s Baseline 
NSA-16 total score is 60 and Week 52 NSA-16 total score is 16 (absent of all symptoms), the 
percent change from Baseline to Week 52 in NSA-16 total score will be calculated as: 
[(16 – 16) – (60 – 16)] ÷ (60 – 16) × 100% = -100%. 


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At any given visit, the proportion of responders will be calculated using 2 different methods:  
• Observed cases (subjects with missing NSA-16 total score are excluded from the 
calculation): number of responders divided by number of subjects with non-missing 
NSA-16 total score for the given visit and cohort. 
• Missing as failures (subjects with missing NSA-16 total score are considered as non-
responders in the calculation): number of responders divided by total number of subjects 
in the Safety Analysis Set for the given cohort. 
13.2.3 For Subjects Rolled Over from Study ACP-103-064 
WoRQ readiness to work question (item 8) will also be summarized in shift tables by visit.   
14 SAFETY ANALYSES 
The safety summaries will be presented for the Safety Analysis Set using descriptive statistics. 
Safety variables include AEs, clinical laboratory variables, vital signs, body weight, BMI, 
physical examinations, ECG, C-SSRS, AIMS, BARS, and SAS variables. Safety variables will 
also be summarized by cohorts based on antecedent study and double-blind treatment group. For 
each continuous measure in clinical laboratory variables, vital signs, and electrocardiogram, 
change from Baseline results will be presented in two ways as specified in Section 5.1. 
14.1 Adverse Events  
All Adverse events (AEs) will be coded using MedDRA version 23.0 or newer. 
An AE (classified by preferred term) will be considered a treatment-emergent AE (TEAE) if it 
started on or after the open-label first study dose date and no later than the open-label last study 
dose date + 30 days. 
The event counts and the number and percentage of subjects reporting TEAEs will be tabulated 
by SOC and preferred term; and, by SOC, preferred term, and maximum severity. If more than 
1 AE occurs with the same preferred term for the same subject, the subject will be counted only 
once for that preferred term using the most severe occurrence for the summarization by severity. 
In addition, the event counts and the number and percentage of subjects with TEAEs classified 
by the Investigators as related to the study drug, with most frequently reported TEAEs (preferred 
terms reported by 5% of subjects in the Safety Analysis Set), with treatment-emergent serious 
AEs (TESAEs), with fatal AEs (i.e. events that cause death), and with TEAEs leading to 
discontinuation of study drug will be summarized by SOC and preferred term. The display in 
these tables will be sorted alphabetically by SOC and then by descending subject frequency for 
the preferred terms (based on counts in the Safety Analysis set) within each SOC. 


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The event counts and the number and percentage of subjects with any TEAEs will also be 
tabulated by preferred term without SOCs. The display in this table will be sorted by descending 
subject frequency based on counts in the Safety Analysis set.  
The relationship of selected AEs to COVID-19 will be assessed as detailed in the GSD. TEAEs 
tabulated by SOC and preferred term will be presented with and without COVID-19 related 
TEAEs. 
An AE listing by subject will display all events, including those which are not treatment-
emergent, and will include the verbatim term in addition to the MedDRA SOC and preferred 
term. This listing will also include all relevant eCRF data associated with the event: e.g. date of 
onset, date resolved, date of the open-label first dose, date of the open-label last dose, dose level 
at AE onset, severity, frequency, outcome, relationship to study drug, action taken with study 
drug, and required therapy. When a date is presented, the study day associated with the date will 
also be displayed. Separate listings will be presented for subjects with SAEs, subjects with AEs 
leading to discontinuation and subjects who died (if any). In these listings, an indicator for 
TEAEs will also be included. Separate listings will be presented for treatment-emergent SAEs, 
related TEAEs, TEAEs leading to discontinuation, fatal TEAEs (if any), and all COVID-19 
related events. 
14.2 Clinical Laboratory Variables 
Clinical laboratory tests are performed at Baseline, Week 28 and Week 52/ET visits. Due to 
various circumstances (e.g., pandemic, natural disaster, or political upheaval), it is possible that 
some test results may be collected from a local laboratory. Local laboratory results and the 
associated normal ranges will be converted to SI units; the local laboratory results, in SI units, 
will then be normalized to central lab ranges to be included in summary data analysis together 
with the central laboratory results. The normalization will be performed using the following scale 
transformation equation: 
𝑠= 𝐿௦+ (𝑥−𝐿௫) 𝑈௦−𝐿௦
𝑈௫−𝐿௫
 
where s is the normalized individual laboratory value to be used for summary; x is the original 
value from the local lab; Lx and Ux are the lower and upper limits from the local lab; Ls and Us 
are the lower and upper limits from the central lab. 


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For labs with only a single upper (or lower) limit, the following scale transformation equation 
will be used: 
𝑠= 𝑥𝑈௦
𝑈௫
 
where s is the normalized individual laboratory value to be used for summary; x is the original 
value from the local lab; Us is the upper (or lower) limit from the central lab; Ux is the upper (or 
lower) limit from the local laboratory. Local laboratory results and normalized results will be 
included in data listings. Only central lab and normalized local lab results will be used for 
summary of change from baseline, shift, and potentially clinically important (PCI) analyses. 
• Hematology tests include the following: 
o Complete blood count (CBC) including: 
− 
White blood cell (WBC) count 
− 
Complete differential (relative and absolute) 
− 
Hematocrit (Hct), hemoglobin (Hgb), red blood cells (RBC), platelets 
− 
Reticulocyte  
• Serum chemistry tests include the following: 
o Sodium (Na), potassium (K), chloride (Cl), phosphorus (P), calcium (Ca), carbon dioxide 
(CO2), blood urea nitrogen (BUN), creatinine (Cr), uric acid 
o Alanine aminotransferase (ALT/SGPT), aspartate aminotransferase (AST/SGOT), 
gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), total bilirubin 
(TBIL), lactate dehydrogenase (LDH), glucose 
o Albumin (ALB), total protein 
o Creatine kinase (CK)/creatine phosphokinase (CPK) 
o Prolactin 
o Lipid panel  
– Total cholesterol, high-density lipoprotein (HDL)-cholesterol, triglycerides, low-
density lipoprotein(LDL)-cholesterol, cholesterol/HDL ratio, non-HDL 
cholesterol 
Note: 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 
• Urinalysis tests include the following: 
o Occult blood, leukocyte esterase, protein, glucose, ketones, specific gravity, pH 
o 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 


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o A urine pregnancy test will be performed for all women 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 
o Additionally, home urine pregnancy tests should be performed at Weeks 10, 16, 24, 32, 
40, and 48 for women of childbearing potential; sites should ascertain the results of these 
home tests by telephone. 
o Any positive urine pregnancy test at home or the site must be followed by a confirmatory 
serum pregnancy test. 
All laboratory test results will be listed. The listings will include date and study day of collection. 
All units will be displayed in Système International [SI] units. Out of range values will be 
flagged in the data listings. 
Clinical laboratory values reported as continuous values for hematology, chemistry and 
urinalysis will be summarized using descriptive statistics at Baseline and scheduled post-
Baseline visits. The change from Baseline values will also be summarized at scheduled post-
Baseline visits. The overall minimum and maximum post-Baseline observed and change from 
Baseline values will also be summarized (for open-label study period only). For hemoglobin, 
hematocrit and uric acid, the above summaries will be presented for each gender as well as for 
both genders combined. For urinalysis with categorical results, the number and percentage of 
subjects will be tabulated by category at Baseline and scheduled post-Baseline visits, and the 
denominator is the number of subjects with non-missing values for the given parameter, visit and 
cohort. 
Laboratory values will also be summarized in shift tables to determine the number and 
percentage of subjects with values classified as below (low), within (normal), or above (high) 
normal ranges at scheduled post-Baseline visits relative to the same classification at the Baseline 
visit. The shifts from Baseline to overall post-Baseline minimum and overall post-Baseline 
maximum will also be presented (for open-label study period only). For the by-visit shift 
summary, the denominator is the number of subjects with non-missing values at Baseline and the 
given visit for the given parameter and cohort. For the summaries of shift from Baseline to the 
overall post-Baseline minimum or maximum, the denominator is the number of subjects with 
non-missing Baseline and at least 1 post-Baseline value for the given parameter and cohort. For 
hemoglobin, hematocrit and uric acid, the shift summaries will be presented for each gender as 
well as for both genders combined. 
Number and percentage of subjects with potentially clinically important (PCI) laboratory values 
at scheduled post-Baseline visits and overall post-Baseline (for open-label study period only) 
will be summarized by Baseline status (all or within normal range) for selected parameters. PCI 
criteria are listed in Table 6 and Table 7. For the overall post-Baseline summaries, all post-


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Baseline values will be considered, including unscheduled and out of window values. Subjects 
with multiple PCI values for a given parameter will be counted only once for that parameter. For 
the by-visit summary, the numerator for the percentage is the number of subjects with a post-
Baseline PCI value for the given parameter, visit and cohort, and the denominator is the number 
of subjects with non-missing values for the given parameter, visit and cohort. For the overall 
post-Baseline summary, the numerator for the percentage is the number of subjects with at least 
1 post-Baseline PCI value for the given parameter and cohort, and the denominator is the number 
of subjects with at least 1 post-Baseline value for the given parameter and cohort. For 
hemoglobin, hematocrit, and uric acid, the count and percentage of subjects with PCI values will 
be presented for each gender as well as for both genders combined.  A listing of all PCI values in 
study ACP-103-035 will be provided. This listing will include all observations from study 
ACP-103-035 for those subjects and parameters for which at least one PCI value (including 
Baseline) was observed. 


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Table 6 
Criteria for Potentially Clinically Important Laboratory Values – Hematology 
and Chemistry 
 
Analyte 
Conventional 
Unit 
Low PCI 
Criteria 
High PCI 
Criteria 
SI Unit 
Low PCI 
Criteria 
High PCI 
Criteria 
Hematology (whole blood) 
Hemoglobin (male) 
g/dL 
<11 
>18 
g/L 
<110 
>180 
Hemoglobin 
(female) 
g/dL 
<10 
>17 
g/L 
<100 
>170 
Hematocrit (male) 
% 
<30 
>55 
L/L 
<0.3 
>0.55 
Hematocrit (female) 
% 
<30 
>50 
L/L 
<0.3 
>0.5 
Leukocyte (White 
Blood Cell Count) 
x 103/uL 
≤2.8 
≥15 
x 109/L 
≤2.8 
≥15 
Neutrophils 
x 103/uL 
≤1.5 
No upper limit 
x 109/L 
≤1.5 
No upper limit 
Platelet Count 
x 103/uL 
≤75 
≥700 
109/L 
≤75 
≥700 
Chemistry (serum or plasma) 
ALT (SGPT) 
U/L 
No lower 
limit  
≥3 X ULN 
U/L 
No lower 
limit  
≥3 X ULN 
AST (SGOT) 
U/L 
No lower 
limit  
≥3 X ULN 
U/L 
No lower 
limit  
≥3 X ULN 
Total Bilirubin 
mg/dL 
No lower 
limit 
≥1.5 ULN 
umol/L 
No lower 
limit 
≥1.5 ULN 
BUN 
mg/dL 
No lower 
limit 
≥30.0 
mmol/L 
No lower 
limit 
≥10.71 
Creatine Kinase 
(CK) 
U/L 
No lower 
limit 
≥3 ULN 
U/L 
No lower 
limit 
≥3 ULN 
Sodium 
mEq/L 
≤125 
≥155 
mmol/L 
≤125 
≥155 
Potassium 
mEq/L 
≤3.0 
≥5.5 
mmol/L 
≤3.0 
≥5.5 
Calcium, total 
mg/dL 
<8.0 
>11.0 
mmol/L 
<2.0 
>2.75 
Lactate 
Dehydrogenase 
(LDH) 
U/L 
No lower 
limit 
≥3 X ULN 
U/L 
No lower 
limit 
≥3 X ULN 
Alkaline 
Phosphatase 
U/L 
No lower 
limit 
≥3 X ULN 
U/L 
No lower 
limit 
≥3 X ULN 
Uric acid (male) 
mg/dL 
No lower 
limit 
≥10.5 
umol/L 
No lower 
limit 
≥624.75 
Uric acid (female) 
mg/dL 
No lower 
limit 
≥8.5 
umol/L 
No lower 
limit 
≥505.75 
Albumin 
g/dL 
≤2.6 
≥6.0 
g/L 
≤26 
≥60 
Total Protein 
g/dL 
≤5.0 
≥10.0 
g/L 
≤50 
≥100 
Chloride 
mEq/L 
≤85 
≥120 
mmol/L 
≤85 
≥120 
Glucose (random) 
mg/dL 
≤45.1 
≥200.0 
mmol/L 
≤2.48 
≥11 
Serum Creatinine 
mg/dL 
Not 
Applicable 
>1.5 ULN 
umol/L 
Not 
Applicable 
>1.5 ULN 
Triglycerides 
mg/dL 
Not 
Applicable 
>300 
mmol/L 
Not 
Applicable 
>3.39 
Gamma-Glutamyl 
Transferase (GGT) 
U/L 
Not 
Applicable 
≥3 ULN 
U/L 
Not 
Applicable 
≥3 ULN 
 


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Table 7 
Criteria for Potentially Clinically Important Laboratory Values - Urinalysis 
Urinalysis (qualitative dipstick) 
Low PCI Criteria 
High PCI Criteria 
Blood (occult blood) 
Not Applicable 
≥+2 
Protein 
Not Applicable 
≥+2 
Glucose 
Not Applicable 
≥+2 
 
The pregnancy results (positive or negative) for female subjects will be presented in a listing. 
14.3 Vital Signs 
Vital signs are assessed at Baseline, Weeks 2, 6, 12, 20, 28, 36, 44 and Week 52/ET visits. 
Vital signs including weight, height (measured at the screening visit of antecedent studies), and 
the derived BMI will be summarized using descriptive statistics at Baseline and all scheduled 
post-Baseline visits. The change from Baseline values will also be summarized at the scheduled 
post-Baseline visits. 
Vital sign values will be considered PCI if they meet both the observed value criteria and the 
change from Baseline criteria listed in Table 8. The number and percentage of subjects with post-
Baseline vital signs that are PCI will be summarized at scheduled post-Baseline visits and for 
overall post-Baseline (for open-label study period only). For the overall post-Baseline 
summaries, all post-Baseline values will be considered, including unscheduled and out of 
window values. Subjects with multiple PCI values for a given parameter will be counted only 
once for that parameter. For the by-visit summary, the numerator for the percentage is the 
number of subjects with a post-Baseline PCI value for the given parameter, visit and cohort, and 
the denominator is the number of subjects with non-missing values for the given parameter, visit 
and cohort. For the overall post-Baseline summary, the numerator for the percentage is the 
number of subjects with at least 1 post-Baseline PCI value for the given parameter and cohort, 
and the denominator is the number of subjects with at least 1 post-Baseline value for the given 
parameter and cohort.  A listing of all PCI values in study ACP-103-035 will be provided. This 
listing will include all observations from study ACP-103-035 for those subjects and parameters 
for which at least one PCI value (including Baseline) was observed. 
 


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Table 8 
Criteria for Potentially Clinically Important Vital Signs 
 
Vital Sign Parameter 
 
Unit 
Criteriaa 
Observed Value 
And/Or 
Change Relative to Baseline 
Systolic blood pressure 
(supine or sitting) 
mmHg 
180 
And 
Increase of ≥20 
90 
And 
Decrease of ≥20 
Diastolic blood pressure 
(supine or sitting) 
mmHg 
105 
And 
Increase of ≥15 
50 
And 
Decrease of ≥15 
Pulse (supine or sitting) 
bpm 
120 
And 
Increase of ≥15 
50 
And 
Decrease of ≥15 
Weight 
kg 
Not Applicable 
Increase of ≥7% 
Decrease of ≥7% 
a 
A post-baseline value is considered as a PCI value if it meets both criteria for observed value and change from 
baseline. 
14.4 Electrocardiogram (ECG) 
In countries outside of Czech Republic, ECG is performed at Baseline, Weeks 2, 28 and 
Week 52/ET visits. At the clinical sites in Czech Republic, ECG is performed at all visits. For 
ECG data summaries, the common scheduled visits across all clinical sites will be used (i.e. 
Baseline, Weeks 2, 28 and Week 52/ET visits). 
All tracings will be evaluated by a central reading laboratory. At the Baseline visit, the machine-
read results will also be recorded. All data, including the machine-read Baseline results, will be 
listed. ECG data summaries will be performed using the centrally evaluated data, including the 
cardiologist’s interpretation. 
Observed values of ECG variables (heart rate, PR interval, RR interval, QRS interval, QT 
interval, and QTc intervals) and the changes from Baseline at scheduled visits will be 
summarized.  
QTc intervals include QTcB (Bazett’s formula) and QTcF (Fridericia’s formula). QTcF will also 
be categorized into the following categories (msec) and the number and percentage of subjects in 
each category will be summarized at scheduled visits and overall post-baseline maximum (for 
open-label study period only): 
• Observed: ≤450, 451 to 480, 481 to 500, and >500 
• Change from Baseline: ≤10, 11 to 30, 31 to 60, and >60 
For cardiologist’s interpretations, the number and percentage of subjects with ECG results that 
are determined as normal or abnormal will be summarized at scheduled visits. The overall post-
baseline worst interpretation (for open-label study period only) will also be summarized (i.e. if a 


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subject has one or more ECG results that is/are considered as abnormal, this subject will be 
counted in the abnormal category). Cardiologist’s interpretations will also be summarized in a 
shift table to determine the number and percentage of subjects with ECG results classified as 
normal or abnormal at scheduled post-Baseline visits relative to the same classification at the 
Baseline visit. The shifts from Baseline to overall post-Baseline worst interpretation (for open-
label study period only) will also be presented. For the by-visit shift summary, the denominator 
is the number of subjects with non-missing cardiologist’s interpretation at Baseline and the given 
visit for the given cohort. For the summaries of shift from Baseline to the overall post-Baseline 
worst interpretation, the denominator is the number of subjects with non-missing Baseline and at 
least 1 post-Baseline cardiologist’s interpretation for the given cohort.  
Electrocardiogram values will be considered PCI if they meet or exceed the upper limit values 
listed in Table 9. The number and percentage of subjects with PCI values will be summarized at 
scheduled post-Baseline visits and for overall post-Baseline (for open-label study period only). 
For the by-visit summary, the numerator for the percentage is the number of subjects with a post-
Baseline PCI value for the given parameter, visit and cohort, and the denominator is the number 
of subjects with non-missing values for the given parameter, visit and cohort. For the overall 
post-Baseline summary, the numerator for the percentage is the number of subjects with at least 
1 post-Baseline PCI value for the given parameter and cohort, and the denominator is the number 
of subjects with at least 1 post-Baseline value for the given parameter and cohort.  A listing of all 
PCI values in study ACP-103-035 will be provided. This listing will include all observations 
from study ACP-103-035 for those subjects and parameters for which at least one PCI value 
(including Baseline) was observed. 
Table 9 
Criteria for Potentially Clinically Important ECG Values 
ECG Parameter 
Unit 
High PCI Criteria 
QRS Interval 
Msec 
120 
PR Interval 
Msec 
220 
QTcB or QTcF 
Msec 
>500 
QTcB or QTcF: change from baseline 
>60 Msec 
 
14.5 Physical Examination 
Physical examination is performed at Baseline and Week 52/ET visits. Note that pelvic and/or 
urogenital examination may be deferred, unless the Investigator deems this to be clinically 
indicated. 
Physical examination results (normal, abnormal, and not done) at Baseline and Week 52 will be 
summarized in a frequency table by body system. 


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14.6 Other Safety Variables 
14.6.1 Suicidality 
The C-SSRS is assessed at Baseline, Weeks 2, 6, 12, 20, 28, 36, 44 and Week 52/ET visits. 
The event counts and the number and percentage of subjects reporting any post-Baseline suicidal 
ideation (wish to be dead; non-specific active suicidal thoughts; active suicidal ideation with any 
methods (not plan) without intent to act; active suicidal ideation with some intent to act, without 
specific plan; active suicidal ideation with specific plan and intent), suicidal behavior 
(preparatory acts or behavior; aborted attempt; interrupted attempt; actual attempt; suicide), or 
suicidality (any suicidal ideation or behavior) will be tabulated. 
The event counts and the number and percentage of subjects reporting any post-Baseline non-
suicidal self-injurious behavior will also be tabulated. 
For calculating the percentages, the denominator will be the number of subjects in the Safety 
Analysis Set within each cohort. 
14.6.2 Extrapyramidal Symptom Measures 
14.6.2.1 
Abnormal Involuntary Movement Scale (AIMS) 
The AIMS is assessed at Baseline, Weeks 2, 12, 28, 44 and Week 52/ET visits. 
The AIMS total score will be summarized using descriptive statistics at Baseline and scheduled 
post-Baseline visits. The change from Baseline scores will also be summarized at scheduled 
post-Baseline visits. 
In addition, the number and percentage of subjects with dyskinesia will be summarized at 
scheduled visits and overall post-Baseline (for open-label study period only). Dyskinesia is 
defined as having a score of 3 or more on any of the first 7 AIMS items or a score of 2 or more 
on any two of the first 7 AIMS items. If there are multiple assessments performed within the 
same time frame, all assessments will be evaluated using the above criteria. The tabulations will 
be presented for subjects who have at least 1 AIMS assessment as well as for a subset of these 
subjects who do not have dyskinesia at Baseline. 
The individual item scores will be listed but not summarized. 
14.6.2.2 
Barnes Akathisia Scale (BARS)  
The BARS is assessed at Baseline, Weeks 2, 12, 28, 44 and Week 52/ET visits. 
The BARS total score and the Global Clinical Assessment of Akathisia score will be summarized 
using descriptive statistics at Baseline and scheduled post-Baseline visits. The change from 
Baseline scores will also be summarized at scheduled post-Baseline visits. 


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In addition, the number and percentage of subjects with akathisia will be summarized at 
scheduled visits and overall post-Baseline (for open-label study period only). Akathisia is 
defined as having a Global Clinical Assessment of Akathisia score ≥2. If there are multiple 
assessments performed within the same time frame, all assessments will be evaluated using the 
above criteria. The tabulations will be presented for subjects who have at least 1 BARS 
assessment as well as for a subset of these subjects who do not have akathisia at Baseline. 
The individual item scores will be listed but not summarized. 
14.6.2.3 
Simpson Angus Scale (SAS) 
The SAS is assessed at Baseline, Weeks 2, 12, 28, 44 and Week 52/ET visits. 
The SAS total score will be summarized using descriptive statistics at Baseline and scheduled 
post-Baseline visits. The change from Baseline scores will also be summarized at scheduled 
post-Baseline visits. 
The number and percentage of subjects with Parkinsonism will be summarized at scheduled 
visits and overall post-Baseline (for open-label study period only). Parkinsonism is defined as 
having a SAS total score >3. If there are multiple assessments performed within the same time 
frame, all assessments will be evaluated using the above criteria. The tabulations will be 
presented for subjects who have at least 1 SAS assessment as well as for a subset of these 
subjects who do not have Parkinsonism at Baseline. 
The individual item scores will be listed but not summarized. 
15 CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
Not applicable. 
16 INTERIM ANALYSIS 
An interim analysis will be conducted prior to study completion. 
17 DATA MONITORING/REVIEW COMMITTEE 
Safety data are monitored throughout the study and aggregate safety reports are produced and 
reviewed approximately quarterly. In addition, safety data from this study will be presented 
periodically to the Data and Safety Monitoring Board (DSMB) for Studies ACP-103-034,  -038 
and -064 to help with the interpretation of benefit versus risk in those studies. 
18 COMPUTER METHODS  
Statistical analyses will be performed using Version 9.4 (or newer) of SAS (SAS® Institute, Inc., 
Cary, North Carolina) on a suitably qualified and validated environment. 


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Validation and quality control of the tables, listings and figures containing the results of the 
statistical analyses will follow appropriate standard operating procedures. 
19 CHANGES TO ANALYSES SPECIFIED IN PROTOCOL 
None. 


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20 REFERENCES 
Leucht S, et al. Defining ‘response’ in antipsychotic drug trials: recommendations for the use of 
scale-derived cutoffs. Neuropsychopharmacology. 2007; 32: 1903-1910. 
Leucht S, et al. Definitions of response and remission in schizophrenia: recommendations for 
their use and their presentation. Acta Psychiatr Scand. 2009; 119 (Suppl. 438): 7-14. 
Obermeier M, et al. Should the PANSS be rescaled? Schizophrenia Bulletin. 2010; 36(3): 
455-460. 
Obermeier M, et al. Is the PANSS used correctly? A systematic review. BMC Psychiatry. 2011; 
11:113. 
Schooler N, et al. Defining therapeutic benefit for people with schizophrenia: focus on negative 
symptoms. Schizophr Res. 2015; 162(1-3): 169-174. 
 
 


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