A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Pimavanserin as Adjunctive Treatment for the Negative Symptoms of Schizophrenia
Phase: PHASE2
Conditions: Schizophrenia
Sponsor: ACADIA Pharmaceuticals Inc.

Official Title: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of Pimavanserin as Adjunctive Treatment for the 
Negative Symptoms of Schizophrenia  
NCT Number: NCT02970305 
Document Date: 31 Mar 2017 

 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
ACADIA Pharmaceuticals Inc. 
 
 
Clinical Study Protocol 
Amendment 3 
 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of Pimavanserin as Adjunctive Treatment 
for the Negative Symptoms of Schizophrenia 
Protocol No. ACP-103-038 
EudraCT Number:  2016-003436-20 
 
Original Protocol Date:  08 September 2016 
Amendment 1 Date:  27 September 2016 
Amendment 2 Date:  28 November 2016 
Amendment 3 Date:  31 March 2017 
 
 
 
 
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. 
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SPONSOR CONTACT 
ACADIA Medical and Clinical Contact: 
 
 
 
 
 
 
 
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PROTOCOL SYNOPSIS 
Sponsor:  ACADIA Pharmaceuticals Inc. 
Name of Study Drug:  Pimavanserin 
Indication:  Adjunctive treatment of the negative symptoms of schizophrenia 
Protocol Title:  A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of Pimavanserin as Adjunctive Treatment for the Negative 
Symptoms of Schizophrenia 
Protocol Number:  ACP-103-038 
EudraCT Number:  2016-003436-20 
Objectives 
Primary Objective: 
• To evaluate the efficacy of pimavanserin compared with placebo 
in the adjunctive treatment of the negative symptoms of 
schizophrenia 
Secondary Objectives: 
• To evaluate the safety and tolerability of pimavanserin compared 
with placebo in the adjunctive treatment of the negative 
symptoms of schizophrenia 
• To characterize the pharmacokinetics (PK) and 
pharmacodynamics (PD) of pimavanserin for the adjunctive 
treatment of the negative symptoms of schizophrenia 
Methodology 
This study will be conducted as a Phase 2, 26-week, randomized, 
double-blind, placebo-controlled, multicenter, multinational outpatient 
study in subjects with schizophrenia who have predominant negative 
symptoms while on adequate treatment with an antipsychotic.  
Schizophrenia is defined by the Diagnostic and Statistical Manual of 
Mental Disorders, Fifth Edition (DSM-5), confirmed by a customized 
module of the Structured Clinical Interview for DSM-5, Clinical Trials 
Version (SCID-5-CT). 
This study will enroll approximately 380 subjects (190 subjects per 
treatment group) with predominant negative symptoms of 
schizophrenia.  On the first day of the randomized treatment phase 
(Baseline), eligible subjects will be randomly assigned to receive 
pimavanserin or placebo daily in a 1:1 ratio, according to a computer-
generated randomization schedule.  The randomization will be stratified 
according to geographic region (North America, Europe, or rest of 
world).  The initial daily dose of study drug is pimavanserin 20 mg or 
matching placebo.  The daily dose of pimavanserin may be increased or 
decreased after the first two weeks of treatment through Week 8 but 
must remain stable thereafter.  The daily dose of the main antipsychotic 
must remain stable and may not be changed from Screening through the 
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duration of the study.  Subjects will participate in the study for up to 
34 weeks, including a Screening Period of up to 4 weeks, a 26-week 
Treatment Period, and a 4-week safety follow-up (telephone call) for 
those subjects who discontinue prematurely from the study or who do 
not enroll in the 52-week, open-label extension study 
(Study ACP-103-035). 
Number of Study 
Sites 
Approximately 70 study sites will participate in the study. 
Number of 
Subjects Planned 
Approximately 380 subjects are planned for enrollment. 
Diagnosis and 
Main Criteria for 
Inclusion and 
Exclusion 
Subjects who fulfill all of the inclusion criteria and none of the 
exclusion criteria are eligible to enter this study. 
Inclusion Criteria: 
1. Male or female, ≥18 and ≤55 years of age at the time of 
Screening 
2. Able to understand and provide signed informed consent 
3. Able to sign and date a request for medical records and/or subject 
privacy form if applicable according to local regulations 
4. In the Investigator’s opinion, is able to understand the nature of 
the trial, follow protocol requirements, be willing to comply with 
study drug administration, and discontinue prohibited 
concomitant medications 
5. 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 
6. Able to complete subject-reported outcome measures, can be 
reliably rated on assessment scales, and is willing to participate 
in audio recording of assessment scales and in an unrecorded 
telemedicine interview 
7. Diagnosis of schizophrenia according to Diagnostic and 
Statistical Manual of Mental Disorders – Fifth Edition (DSM-5) 
criteria (confirmed using a customized module of the Structured 
Clinical Interview for DSM-5, Clinical Trials Version 
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[SCID-5-CT]) 
8. Diagnosis of schizophrenia made ≥1 year prior to randomization 
9. Score ≥20 on the sum of the 7 PANSS Marder negative factor 
items at Screening and Baseline 
AND 
Score ≥4 on at least 3, or ≥5 on at least 2, of the 7 PANSS 
Marder negative factor items 
10. Score ≤22 on the sum of the 8 PANSS Marder positive factor 
items 
AND 
PANSS score where no more than two of the following items 
have a score of 4 and none of the following items has a score ≥5 
at both Screening and Baseline (see Appendix G): 
• P1 (delusions) 
• P3 (hallucinatory behavior) 
• P6 (suspiciousness/persecution) 
11. A Clinical Global Impression of Schizophrenia Scale – Severity 
(CGI-SCH-S) for the negative symptoms of schizophrenia score 
≥4 (moderately ill or worse) at Screening and Baseline 
12. Has been treated with an adequate dose of an antipsychotic 
within the dose range recommended according to the local 
Prescribing Information for at least 8 weeks prior to Screening 
and remaining at the same dose during the Screening Period  
13. The antipsychotic with which the subject is being treated must be 
one of the antipsychotics listed below: 
• Aripiprazole 
– Aripiprazole long-acting injectables 
– Abilify Maintena® 
• Aristada® 
• Asenapine 
• Brexpiprazole 
• Cariprazine 
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• Lurasidone 
• Olanzapine 
• Risperidone 
• Risperidone long-acting injection 
14. If taking an oral antipsychotic, no dose change within 4 weeks 
prior to Screening or during the Screening Period 
15. If taking a long-acting injectable antipsychotic, no dose change 
within 16 weeks prior to Screening or during the Screening 
Period 
16. If taking an antidepressant medication or an anxiolytic 
medication, no dose change within 4 weeks of Screening or 
during the Screening Period (see also Appendix A for 
restrictions/prohibitions during the study) 
17. Must be medically stable and has been medically stable for at 
least 12 weeks prior to Screening, in the opinion of the 
Investigator 
18. If female, must 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 (e.g., oral, intrauterine device [IUD], diaphragm 
plus spermicide, injectable, transdermal, or implantable 
contraception) 
• All female subjects must have a negative serum human 
chorionic gonadotropin (hCG) pregnancy test at Screening 
and a negative urine pregnancy test at Baseline 
Exclusion Criteria: 
1. Based on the SCID-5-CT, has a current comorbid psychiatric 
disorder other than schizophrenia (e.g., bipolar disorder, 
obsessive compulsive disorder, substance abuse) or a disorder 
that would interfere with the ability to complete study 
assessments (e.g., intellectual disability) 
2. Score ≥2 for two or more movements or a score of 3 or 4 for any 
single movement on the Abnormal Involuntary Movement scale 
(AIMS) 
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3. Total score ≥2 on the Barnes Akathisia Rating scale (BARS) 
4. Total score ≥5 on the Simpson-Angus Extrapyramidal Side 
Effects Scale (SAS) 
5. Calgary Depression Scale for Schizophrenia (CDSS) score ≥9 at 
both Screening and Baseline 
6. Is at a significant risk of suicide, or is a danger to self or others, 
in the opinion of the Investigator  
7. Has a significant risk of violent behavior in the opinion of the 
Investigator 
8. Has met DSM-5 criteria for substance use disorders within the 
last 6 months prior to randomization (other than caffeine and/or 
nicotine) 
9. A urine drug screen result at Screening or Baseline that indicates 
the presence of any tested prohibited substance of potential 
abuse, except marijuana 
• Subjects with a result indicating the presence of marijuana 
are permitted if they agree to abstain from marijuana use 
during the study and the medical monitor approves the 
subject’s participation 
10. Subject was treated with 2 or more antipsychotics, for any 
indication, within 8 weeks prior to Screening 
11. Laboratory testing confirms the absence of the identified 
antipsychotic 
12. 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 (see Appendix A and 
Appendix B) 
13. Known family or personal history or symptoms of long QT 
syndrome 
14. Has a QRS interval <120 ms and QTcF ≥460 ms OR 
has a QRS interval ≥120 ms and QTcF ≥480 ms at Screening or 
Baseline  
15. Current evidence, or history within the previous 12 weeks prior 
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to Screening, of 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 
16. Has moderate to severe congestive heart failure (New York Heart 
Association [NYHA] class III and class IV) 
17. Has a history of myocardial infarction within 6 months prior to 
enrollment 
18. Has a history of uncontrolled diabetes mellitus (DM), Type 1 or 2 
DM requiring insulin treatment, or glycosylated hemoglobin 
(HbA1c) >7% at Screening 
19. Has a clinically significant thyroid function test result at 
Screening 
20. Has clinically significant laboratory abnormalities that in the 
judgment of the Investigator or Medical Monitor would 
jeopardize the safe participation of the subject in the study 
21. Known to be positive for hepatitis C virus (HCV) or human 
immunodeficiency virus (HIV) 
22. Has a body mass index (BMI) <19 or ≥35 at Screening 
23. Has a history of neuroleptic malignant syndrome 
24. Is breastfeeding or lactating 
25. Has a significant sensitivity or allergic reaction to pimavanserin 
or its excipients 
26. Has previously been randomized in any prior clinical study with 
pimavanserin, and/or received any other investigational (either 
approved or unapproved) drug within 30 days or 5 half-lives 
(whichever is longer) prior to Screening 
27. Has any condition that, in the opinion of the Investigator, would 
interfere with the ability to comply with study instructions, or 
that might confound the interpretation of the study results or put 
the subject at undue risk 
28. Is an employee of ACADIA, or has a family member who is an 
employee of ACADIA 
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29. Has participated in >2 pharmaceutical clinical research studies 
within the previous 2 years 
30. Subject is judged by the Investigator or the Medical Monitor to 
be inappropriate for the study 
31. Subject has had a social hospitalization, defined as admission to 
the hospital as a result of inadequate family support or care at the 
subject’s primary residence, during the 8 weeks prior to 
screening 
Test Product, 
Dose, and Mode of 
Administration 
The test products are pimavanserin 10 mg and 17 mg tablets or 
matching placebo.  Daily doses of pimavanserin to be studied are 10 mg 
(provided as 1 × 10 mg pimavanserin tablet and 1 × matching placebo); 
20 mg (2 × 10 mg pimavanserin tablets); or 34 mg (2 × 17 mg 
pimavanserin tablets); or matching placebo (2 × placebo 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 
Planned Duration 
of Treatment 
The duration of participation for individual subjects will be up to 
approximately 34 weeks.  Each subject will participate in a Screening 
Period of up to 4 weeks, a 26-week Treatment Period, and a 4 week 
safety follow-up (telephone call) for those subjects who discontinue 
prematurely from the study or who do not enroll in the 52-week, open-
label extension study (Study ACP-103-035). 
Efficacy 
Assessments and 
Endpoints 
Primary Efficacy Endpoint: 
• Change from Baseline to Week 26 in the Negative Symptom 
Assessment-16 (NSA-16) total score 
Secondary Endpoints 
Key Secondary Endpoint: 
• Change from Baseline to Week 26 in the Personal and Social 
Performance Scale (PSP) score 
Other Secondary Endpoints: 
• Change from Baseline to Week 26 in the CGI-SCH-S of negative 
symptoms score 
• Clinical Global Impression of Schizophrenia Scale – 
Improvement (CGI-SCH-I) of negative symptoms score at 
Week 26 
• Change from Baseline to Week 26 in the Positive and Negative 
Syndrome Scale (PANSS) total score 
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• Change from Baseline to Week 26 in PANSS subscores 
• Change from Baseline to Week 26 in Brief Assessment of 
Cognition in Schizophrenia (BACS) score 
• Change from Baseline to Week 26 in 10-item Drug Attitude 
Inventory (DAI-10) score 
• Change from Baseline to Week 26 in Karolinska Sleepiness Scale 
(KSS) score 
Exploratory Endpoints: 
• Change from Baseline to Week 26 in PANSS Marder factor 
scores 
• Change from Baseline to Week 26 in Calgary Depression Scale 
for Schizophrenia (CDSS) score 
• Change from Baseline to Week 26 in 36-item Short Form Health 
Survey (SF-36) score 
Confirmation of 
Main 
Antipsychotic 
At Screening, a blood sample will be collected to confirm the presence 
or absence of the identified main antipsychotic. 
Safety and 
Tolerability 
Assessments 
Safety will be evaluated by analyses of adverse events, vital signs, 
ECGs, physical examination results, and clinical laboratory tests 
(including urinalysis), and the Abnormal Involuntary Movement 
Scale(AIMS), the Barnes Akathisia Rating Scale (BARS), the Simpson-
Angus Extrapyramidal Side Effects Scale (SAS), and the Columbia 
Suicide Severity Rating Scale (C-SSRS). 
An independent Data and Safety Monitoring Board (DSMB) will 
review safety information on a regular basis throughout the study. 
Pharmacokinetic 
Assessments and 
Endpoints 
At each predefined timepoint, PK samples will be obtained for 
measurement of concentrations of pimavanserin, its metabolite AC-279, 
and the main antipsychotic.  When possible, an additional PK sample 
will be collected from subjects who experience a serious adverse event 
(SAE) or an adverse event (AE) leading to discontinuation, as soon as 
possible after the occurrence of that event. 
For all PK samples (scheduled and unscheduled), the dates and times of 
administration of the last 3 doses of both study drug and the main 
antipsychotic should be recorded.  For samples collected from subjects 
who experience an SAE or an AE leading to discontinuation, the date 
and time of the last dose prior to the SAE or AE should also be 
recorded. 
Pimavanserin plasma concentration data will remain blinded until the 
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unblinding of the clinical database at the end of the study. 
Pharmacokinetic Endpoints: 
• Plasma concentration of pimavanserin, AC-279, and the main 
antipsychotic 
• Pimavanserin pharmacokinetic parameters using a population 
pharmacokinetic approach 
• PK/PD using appropriate PK/PD analysis methods 
Pharmacogenomic 
Assessments 
A blood sample will be collected at Baseline or later from consenting 
subjects for potential future pharmacogenomics analyses (where local 
regulations permit). 
Data for genetic analyses will be anonymized, as is the customary 
approach according to Good Clinical Practice (GCP). 
Sample Size 
Calculations 
The planned sample size is 380 (190 subjects per treatment group). 
Assuming the true difference in the mean change in the NSA-16 total 
score from Baseline to Week 26 is 4.5 points between the pimavanserin 
group and the placebo group, and the common standard deviation is 
12.8 points, 171 evaluable subjects per treatment group will provide 
90% power to detect a difference between the pimavanserin group and 
the placebo group at a significance level of 0.05, using a 2-sided t-test. 
Adjusting for a potential non-evaluable rate of up to 10%, 
approximately 380 subjects (190 subjects per treatment group) will be 
enrolled. 
Statistical 
Methods 
The safety analysis set includes all randomized subjects who received at 
least one dose of study drug (pimavanserin or placebo).  Subjects will 
be analyzed based on the treatment that they actually received.  
The safety analysis set will be used for all safety analyses. 
The full analysis set includes all randomized subjects who received at 
least one dose of blinded study drug and who have both a baseline value 
and at least one post-baseline value for the NSA-16 total score.  
Subjects will be analyzed based on their randomized treatment.  The full 
analysis set will be used for the analysis of all efficacy endpoints. 
The per-protocol (PP) analysis set will be defined prior to unblinding 
the study for the final analysis.  Subjects will be analyzed based on their 
randomized treatment assignment.  The PP analysis set will be used for 
sensitivity analyses of selected efficacy endpoints. 
The PK analysis set includes all subjects in the safety analysis set who 
have sufficient PK data. 
Subgroup Analysis 
Selected analyses will be performed in subgroups defined by 
geographic region (North America, Europe, or rest of world).  
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Additional subgroup analyses may be specified in the statistical analysis 
plan (SAP). 
Descriptive Statistics 
Continuous measurement results will be reported using the number of 
subjects with data values, mean, standard error of the mean, standard 
deviation, minimum, maximum, and median.  For each categorical 
outcome, the number and percentage of subjects in each category will 
be reported. 
Missing Data 
Handling of missing values will be described in detail in the SAP.  
Sensitivity analyses will be performed to assess the impact of missing 
data, including analyses based on a missing not at random assumption. 
Efficacy Analyses 
All efficacy endpoints will be summarized by treatment group using 
descriptive statistics. 
The NSA-16 total score will be analyzed using mixed model repeated 
measures (MMRM).  The dependent variable will be the change from 
Baseline in the NSA-16 total score.  The independent variables in the 
model will include the following:  treatment group (pimavanserin or 
placebo), visit (Week 2, Week 4, Week 8, Week 14, Week 20, and 
Week 26), the treatment-by-visit interaction, geographic region (North 
America, Europe, or rest of world), the Baseline NSA-16 total score, 
and the Baseline-by-visit interaction.  The treatment comparison will be 
based on the difference in least squares means at Week 26 and will be 
tested at an alpha level of 0.05 (2-sided) using the full analysis set. 
The change from Baseline in the PSP score will be analyzed using an 
MMRM model similar to that described above for the primary endpoint, 
except that the visits will include Week 8 and Week 26, and the Baseline 
PSP score will be included in the model instead of the Baseline NSA-16 
total score.  The treatment comparison will be based on the difference in 
least squares means at Week 26 and will be tested at an alpha level of 
0.05 (two-sided) using the full analysis set. 
A hierarchical testing procedure will be used to control the Type 1 error 
rate across the primary and secondary endpoints.   
Safety Analyses 
Safety results will be summarized by treatment group using descriptive 
statistics.  No formal statistical testing will be performed for any of the 
safety endpoints.  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, TEAEs by 
maximum severity, fatal TEAEs, SAEs, and SAEs related to study drug 
will all be summarized.  Other TEAEs of special interest may also be 
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summarized. 
Descriptive statistics for ECG, vital signs and weight, and clinical 
laboratory parameters, including changes from baseline, will be 
tabulated by timepoint.  Additionally, categorical analyses will be 
conducted on the incidence of subjects with prolonged QTc intervals 
and changes in QTc intervals in accordance with International 
Conference on Harmonisation (ICH) guidelines. 
Pharmacokinetic Analyses 
Plasma concentration data for pimavanserin, its active metabolite (AC-
279), and the main antipsychotic will be listed and summarized using 
descriptive statistics.  Results may be used for other analyses (e.g., 
population PK modeling), which will be presented in a separate report. 
Pharmacokinetic/Pharmacodynamic Analyses 
A population pharmacokinetic/pharmacodynamic (PK/PD) model to 
describe the exposure response relationship between pimavanserin 
plasma concentrations and the relevant efficacy and safety parameters 
will be developed using appropriate PK/PD methods.  Results will be 
presented in a separate report. 
Date 
31 March 2017 
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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ............................................................................................... 2 
SPONSOR CONTACT .............................................................................................................. 3 
PROTOCOL SYNOPSIS ........................................................................................................... 4 
TABLE OF CONTENTS ......................................................................................................... 15 
LIST OF TABLES ................................................................................................................... 20 
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 .......................................................................................................... 26 
2 
STUDY OBJECTIVES AND ENDPOINTS .............................................................. 27 
2.1 
Study Objectives......................................................................................................... 27 
2.1.1 
Primary Objective....................................................................................................... 27 
2.1.2 
Secondary Objectives ................................................................................................. 27 
2.2 
Study Endpoints ......................................................................................................... 27 
2.2.1 
Primary Endpoint ....................................................................................................... 27 
2.2.2 
Secondary Endpoints .................................................................................................. 27 
2.2.2.1 Key Secondary Endpoint ............................................................................................ 27 
2.2.2.2 Other Secondary Endpoints ........................................................................................ 27 
2.2.3 
Exploratory Endpoints ................................................................................................ 28 
2.2.4 
Pharmacokinetic Endpoints ........................................................................................ 28 
2.2.5 
Safety Assessments..................................................................................................... 28 
3 
STUDY DESIGN ....................................................................................................... 28 
3.1 
Overview of Study Design ......................................................................................... 28 
3.2 
Screening Period......................................................................................................... 29 
3.3 
Double-blind Treatment Period .................................................................................. 30 
3.4 
Follow-up ................................................................................................................... 30 
4 
STUDY POPULATION AND WITHDRAWAL CRITERIA .................................... 32 
4.1 
Inclusion Criteria ........................................................................................................ 32 
4.2 
Exclusion Criteria ....................................................................................................... 34 
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4.3 
Withdrawal of Subjects .............................................................................................. 36 
4.4 
Premature Study Termination ..................................................................................... 37 
5 
STUDY TREATMENT .............................................................................................. 38 
5.1 
Description of Study Drugs ........................................................................................ 38 
5.2 
Administration of Study Drug .................................................................................... 38 
5.3 
Overdose ..................................................................................................................... 40 
5.4 
Method of Assigning Subjects to Treatment Groups.................................................. 40 
5.5 
Prior and Concomitant Medications ........................................................................... 40 
5.5.1 
Prior Medications ....................................................................................................... 40 
5.5.2 
Concomitant Medications........................................................................................... 40 
5.5.3 
Prohibited and Restricted Medications....................................................................... 41 
5.6 
Blinding ...................................................................................................................... 41 
5.7 
Study Drug Handling.................................................................................................. 41 
5.7.1 
Study Drug Packaging ................................................................................................ 41 
5.7.2 
Study Drug Storage .................................................................................................... 42 
5.7.3 
Record of Dispensing ................................................................................................. 42 
5.8 
Study Drug Accountability Procedures ...................................................................... 42 
5.9 
Treatment Compliance ............................................................................................... 42 
6 
STUDY PROCEDURES AND SCHEDULE ............................................................ 43 
6.1 
Efficacy Scales ........................................................................................................... 43 
6.1.1 
Negative Symptom Assessment-16 (NSA-16) ........................................................... 43 
6.1.2 
Personal and Social Performance Scale ..................................................................... 43 
6.1.3 
Clinical Global Impression of Schizophrenia Scale – Severity ................................. 43 
6.1.4 
Clinical Global Impression of Schizophrenia Scale – Improvement ......................... 43 
6.1.5 
Positive and Negative Syndrome Scale ...................................................................... 44 
6.1.6 
Informant Questionnaire for the Positive and Negative Syndrome Scale .................. 44 
6.1.7 
Brief Assessment of Cognition in Schizophrenia ....................................................... 44 
6.1.8 
Calgary Depression Scale for Schizophrenia ............................................................. 44 
6.1.9 
36-Item Short Form Health Survey ............................................................................ 45 
6.1.10 10-Item Drug Attitude Inventory ................................................................................ 45 
6.1.11 Karolinska Sleepiness Scale ....................................................................................... 45 
6.2 
Safety Scales............................................................................................................... 45 
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 .................................................. 46 
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6.2.4 
Columbia-Suicide Severity Rating Scale ................................................................... 46 
6.3 
Safety Measures ......................................................................................................... 47 
6.3.1 
Medical and Psychiatric History ................................................................................ 47 
6.3.2 
Medication History ..................................................................................................... 47 
6.3.3 
Physical Examination ................................................................................................. 47 
6.3.4 
Vital Sign Measurements............................................................................................ 47 
6.3.5 
Height and Weight ...................................................................................................... 47 
6.3.6 
Electrocardiograms ..................................................................................................... 47 
6.4 
Laboratory Procedures/Evaluations ........................................................................... 47 
6.4.1 
Clinical Laboratory Evaluations ................................................................................. 47 
6.4.2 
Other Assays or Procedures ........................................................................................ 49 
6.4.2.1 Confirmation of Main Antipsychotic ......................................................................... 49 
6.4.2.2 Pharmacokinetic Assessments .................................................................................... 49 
6.4.2.3 Specimen Preparation, Handling, Storage, and Shipment.......................................... 49 
6.4.2.4 Pharmacogenomic Assessment................................................................................... 49 
6.5 
Study Schedule ........................................................................................................... 50 
6.5.1 
Screening Period (Day -28 to Day -7) ........................................................................ 50 
6.5.2 
Treatment Period ........................................................................................................ 51 
6.5.2.1 Baseline Visit (Visit 2/Day 1) ..................................................................................... 51 
6.5.2.2 Weeks 2, 4, 8, 14, and 20 (Visits 3, 4, 5, 6, and 7) ..................................................... 52 
6.5.2.3 Week 26 (End-of-Study/Early Termination Visit) ...................................................... 53 
6.5.3 
Follow-up Period (Week 30) ...................................................................................... 53 
6.5.4 
Unscheduled Visit(s) .................................................................................................. 53 
6.5.5 
Schedule of Events and Assessments ......................................................................... 54 
7 
ASSESSMENTS OF SAFETY .................................................................................. 58 
7.1 
Specification of Safety Parameters............................................................................. 58 
7.1.1 
Definition of Adverse Event ....................................................................................... 58 
7.1.2 
Definition of Serious Adverse Event .......................................................................... 59 
7.2 
Classification of an Adverse Event ............................................................................ 60 
7.2.1 
Severity of Event ........................................................................................................ 60 
7.2.2 
Relationship to Study Drug ........................................................................................ 60 
7.2.2.1 Duration ...................................................................................................................... 61 
7.2.2.2 Frequency ................................................................................................................... 61 
7.2.2.3 Action Taken with Study Drug ................................................................................... 61 
7.2.2.4 Therapy ....................................................................................................................... 61 
7.2.2.5 Outcome ..................................................................................................................... 61 
7.2.2.6 Seriousness ................................................................................................................. 61 
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7.2.3 
Definition of Unexpectedness .................................................................................... 62 
7.3 
Time Period and Frequency for Event Assessment and Follow-up ........................... 62 
7.4 
Reporting Procedures ................................................................................................. 62 
7.4.1 
Adverse Event Reporting ........................................................................................... 62 
7.4.2 
Serious Adverse Event Reporting............................................................................... 62 
7.4.3 
Reporting of Pregnancy .............................................................................................. 63 
7.4.4 
Reporting of Overdose ............................................................................................... 64 
7.5 
Safety Oversight ......................................................................................................... 64 
8 
CLINICAL MONITORING ....................................................................................... 64 
9 
STATISTICAL CONSIDERATIONS ........................................................................ 64 
9.1 
Statistical and Analytical Plans .................................................................................. 64 
9.2 
Statistical Hypotheses................................................................................................. 64 
9.3 
Analysis Datasets ....................................................................................................... 65 
9.4 
Description of Statistical Methods ............................................................................. 65 
9.4.1 
General Approach ....................................................................................................... 65 
9.4.2 
Analysis of the Primary Efficacy Endpoint ................................................................ 66 
9.4.3 
Analysis of the Secondary Endpoints ......................................................................... 66 
9.4.3.1 Key Secondary Endpoint ............................................................................................ 66 
9.4.3.2 Other Secondary Endpoints and Exploratory Endpoints ............................................ 66 
9.4.4 
Safety Analyses .......................................................................................................... 68 
9.4.4.1 Adverse Events ........................................................................................................... 68 
9.4.4.2 Clinical Laboratory Values ......................................................................................... 68 
9.4.4.3 Vital Signs and Body Weight ..................................................................................... 68 
9.4.4.4 Electrocardiogram ...................................................................................................... 68 
9.4.4.5 Physical Examinations ............................................................................................... 68 
9.4.4.6 Columbia Suicide Severity Rating ............................................................................. 69 
9.4.4.7 Extrapyramidal Symptom Measures .......................................................................... 69 
9.4.5 
Confirmation of Main Antipsychotic ......................................................................... 69 
9.4.6 
Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analyses ........................ 69 
9.4.7 
Adherence and Retention Analyses ............................................................................ 69 
9.4.8 
Baseline Descriptive Statistics ................................................................................... 69 
9.4.9 
Planned Interim Analyses ........................................................................................... 70 
9.4.9.1 Safety Review............................................................................................................. 70 
9.4.9.2 Efficacy Review ......................................................................................................... 70 
9.4.10 Additional Subgroup Analyses ................................................................................... 70 
9.4.11 Multiple Comparison/Multiplicity ............................................................................. 70 
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9.4.12 Tabulation of Individual Response Data .................................................................... 70 
9.5 
Sample Size ................................................................................................................ 70 
9.6 
Measures to Minimize Bias ........................................................................................ 71 
9.6.1 
Enrollment/Randomization/Masking Procedures....................................................... 71 
9.6.2 
Breaking the Study Blind/Subject Code ..................................................................... 71 
10 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ..... 71 
10.1 
Case Report Forms and Data Verification .................................................................. 71 
10.2 
Source Documentation ............................................................................................... 72 
11 
QUALITY ASSURANCE AND QUALITY CONTROL .......................................... 72 
11.1 
Quality Control and Quality Assurance...................................................................... 72 
12 
ETHICS/PROTECTION OF HUMAN SUBJECTS .................................................. 73 
12.1 
Ethical Standard ......................................................................................................... 73 
12.2 
Institutional Review Board/Ethics Committee ........................................................... 73 
12.3 
Informed Consent Process .......................................................................................... 73 
12.3.1 Consent and Other Informational Documents Provided to Subjects .......................... 74 
12.3.2 Consent Procedures and Documentation .................................................................... 74 
12.4 
Subject and Data Confidentiality ............................................................................... 74 
13 
DATA HANDLING AND RECORD KEEPING ....................................................... 75 
13.1 
Data Collection and Management Responsibilities.................................................... 75 
13.2 
Study Records Retention ............................................................................................ 75 
13.3 
Protocol Exceptions and Deviations........................................................................... 75 
13.4 
Protocol Amendments ................................................................................................ 76 
13.5 
Publication and Data Sharing Policy .......................................................................... 76 
14 
CONFLICT OF INTEREST POLICY ....................................................................... 76 
14.1 
Finance, Insurance, and Indemnity............................................................................. 76 
15 
DECLARATION OF INVESTIGATOR .................................................................... 77 
16 
LITERATURE REFERENCES .................................................................................. 78 
17 
APPENDICES ............................................................................................................ 82 
Appendix A Prohibited and Restricted Therapy ................................................................... 82 
Appendix B Prohibited and Restricted Concomitant Medications:  Inhibitors and Inducers 
of Cytochrome P450 Enzyme 3A4 ............................................................................. 85 
Appendix C Negative Symptom Assessment-16 (NSA-16) – Long Form ........................... 87 
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Appendix D Personal and Social Performance Scale (PSP) ................................................. 95 
Appendix E Clinical Global Impression of Schizophrenia Scale – Severity (CGI-SCH-S) . 98 
Appendix F Clinical Global Impression of Schizophrenia Scale – Improvement 
(CGI-SCH-I) ............................................................................................................... 100 
Appendix G Structured Clinical Interview – Positive and Negative Syndrome Scale 
(PANSS) .....................................................................................................................102 
Appendix H Informant Questionnaire for the Positive and Negative Syndrome Scale (IQ-
PANSS) .......................................................................................................................121
Appendix I 10-Item Drug Attitude Inventory (DAI-10) ....................................................... 141 
Appendix J Karolinska Sleepiness Scale (KSS) ................................................................... 143 
Appendix K Calgary Depression Scale for Schizophrenia (CDSS)...................................... 145 
Appendix L 36-Item Short Form Health Survey (SF-36) ..................................................... 148 
Appendix M Abnormal Involuntary Movement Scale (AIMS) ............................................ 154 
Appendix N Barnes Akathisia Rating Scale (BARS) ........................................................... 156 
Appendix O Simpson-Angus Extrapyramidal Side Effects Scale (SAS) ............................. 159 
Appendix P Columbia-Suicide Severity Rating Scale (C-SSRS) ......................................... 162 
LIST OF TABLES 
Table 5–1 
Treatment Administration Schedule for Protocol ACP-103-038 ..................... 39 
Table 6–1 
Schedule of Events and Assessments............................................................... 55 
LIST OF FIGURES 
Figure 3–1 
Schematic of Study Design for ACP-103-038 ................................................. 31 
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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 
AC-279 
N-desmethyl-pimavanserin, major metabolite 
AE 
adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
BACS 
Brief Assessment of Cognition in Schizophrenia 
BARS 
Barnes Akathisia Rating Scale 
CDSS 
Calgary Depression Scale for Schizophrenia 
CFR 
Code of Federal Regulations 
CGI-SCH-I 
Clinical Global Impression of Schizophrenia Scale – Improvement 
CGI-SCH-S 
Clinical Global Impression of Schizophrenia Scale – Severity 
CNS 
central nervous system 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP 
cytochrome P450 
CYP3A4 
CYP 3A4 enzyme 
DAI-10 
10-item Drug Attitude Inventory 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
DSMB 
Data and Safety Monitoring Board 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOS 
End-of-Study 
ET 
Early Termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HbA1c 
glycosylated hemoglobin 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IQ-PANSS 
Informant Questionnaire for the Positive and Negative Syndrome Scale 
IRB 
Institutional Review Board 
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Abbreviation 
Definition 
IRT 
interactive response technology 
KSS 
Karolinska Sleepiness Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model repeated measures 
ms 
millisecond 
NSA-16 
Negative Symptom Assessment – 16  
PANSS 
Positive and Negative Syndrome Scale 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PSP 
Personal and Social Performance Scale 
QRS interval 
QRS interval of ECG 
QT interval 
QT interval for heart rate of ECG 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RBC 
red blood cells 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Simpson-Angus Extrapyramidal Side Effects Scale 
SAS® 
Statistical Analysis System 
SCID-5-CT 
Structured Clinical Interview for DSM-5, Clinical Trials Version 
SF-36 
36-item Short Form Health Survey 
SUSAR 
suspected unexpected serious adverse reactions 
TEAE 
treatment-emergent adverse event 
UDS 
urine drug screen 
US 
United States 
WBC 
white blood cells 
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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., 1988; 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), 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 
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(Saeedi et al., 2006; Mehta et al., 2004; Peretti et al., 1997) and an increased risk of mortality 
in elderly patients with dementia (Wang et al., 2005).  On the basis of its novel receptor 
binding profile, 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 AEs (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. 
 
 
 
 
 
 
 
 
. 
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 difference 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). 
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. 
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 
At the National Institute of Mental Health (NIMH)-supported consensus meeting on negative 
symptoms, experts agreed that treatments for persistent and clinically signiﬁcant negative 
symptoms are an unmet therapeutic need (Kirkpatrick et al., 2006).  Atypical antipsychotics 
are currently the standard of treatment for schizophrenia.  While the effectiveness of 
antipsychotics has been established, a good proportion of patients do not achieve full control 
of their symptoms, including negative symptoms. 
Despite the clinical importance of negative symptoms, these symptoms remain inadequately 
addressed by current pharmacology with only limited evidence for minor symptom 
improvement (Blanchard et al., 2011).  Thus, the adequate treatment of negative symptoms 
remains an unmet therapeutic need in this patient population.  There is evidence that 
ritanserin, another selective 5-HT2A/2C inverse agonist/antagonist has efficacy against 
negative symptoms of schizophrenia both as monotherapy (Duinkerke et al., 1993) and when 
added to risperidone (Akhondzadeh et al., 2008).  These data support the use of 5-HT2A 
receptor inverse agonists as adjunctive therapy for psychosis and negative symptoms of 
schizophrenia. 
In light of demonstrated antipsychotic efficacy and a well-defined safety profile, and on the 
basis of preclinical and clinical data suggesting potentiation of antipsychotic efficacy in 
coadministration with currently approved antipsychotics, ACADIA Pharmaceuticals Inc. 
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(ACADIA) is currently planning to pursue a new development program for pimavanserin as 
adjunctive treatment of negative symptoms of schizophrenia. 
2 STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Study Objectives 
2.1.1 
Primary Objective 
• To evaluate the efficacy of pimavanserin compared to placebo in the adjunctive 
treatment of the negative symptoms of schizophrenia 
2.1.2 
Secondary Objectives 
The secondary objectives of the study are: 
• To evaluate the safety and tolerability of pimavanserin compared to placebo in the 
adjunctive treatment of the negative symptoms of schizophrenia 
• To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of 
pimavanserin for the adjunctive treatment of the negative symptoms of schizophrenia 
2.2 
Study Endpoints 
2.2.1 
Primary Endpoint 
• Change from Baseline to Week 26 in the Negative Symptom Assessment-16 (NSA-16) 
total score 
2.2.2 
Secondary Endpoints 
2.2.2.1 
Key Secondary Endpoint 
• Change from Baseline to Week 26 in the Personal and Social Performance Scale (PSP) 
score 
2.2.2.2 
Other Secondary Endpoints 
• Change from Baseline to Week 26 in the Clinical Global Impression of Schizophrenia 
Scale – Severity (CGI-SCH-S) of negative symptoms score 
• Clinical Global Impression of Schizophrenia Scale – Improvement (CGI-SCH-I) of 
negative symptoms score at Week 26 
• Change from Baseline to Week 26 in the Positive and Negative Syndrome Scale 
(PANSS) total score 
• Change from Baseline to Week 26 in PANSS subscores 
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• Change from Baseline to Week 26 in Brief Assessment of Cognition in Schizophrenia 
(BACS) score 
• Change from Baseline to Week 26 in 10-item Drug Attitude Inventory (DAI-10) score 
• Change from Baseline to Week 26 in Karolinska Sleepiness Scale (KSS) score 
2.2.3 
Exploratory Endpoints 
• Change from Baseline to Week 26 in PANSS Marder factor scores 
• Change from Baseline to Week 26 in Calgary Depression Scale for Schizophrenia 
(CDSS) score 
• Change from Baseline to Week 26 in 36-item Short Form Health Survey (SF-36) score 
2.2.4 
Pharmacokinetic Endpoints 
• Plasma concentration of pimavanserin, AC-279, and the main antipsychotic 
• Pimavanserin pharmacokinetic parameters using a population pharmacokinetic 
approach 
• PK/PD using appropriate PK/PD analysis methods 
2.2.5 
Safety Assessments 
Safety will be evaluated by analyses of AEs, vital signs, ECGs, physical examination results, 
and clinical laboratory tests (including urinalysis), and the Abnormal Involuntary Movement 
Scale (AIMS), the Barnes Akathisia Rating Scale (BARS), and the Simpson-Angus 
Extrapyramidal Side Effects Scale (SAS); and the Columbia Suicide Severity Rating Scale 
(C-SSRS) as identified in Table 6–1. 
3 STUDY DESIGN 
3.1 
Overview of Study Design 
This study will be conducted as a Phase 2, 26-week, randomized, double-blind, placebo-
controlled, multicenter, multinational outpatient study in subjects with schizophrenia who 
have predominant negative symptoms while on adequate treatment with an antipsychotic.  
Schizophrenia is defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition (DSM-5), confirmed by a customized module of the Structured Clinical Interview for 
DSM-5, Clinical Trials Version (SCID-5-CT).  Negative symptoms are considered 
predominant when other symptoms of schizophrenia, particularly positive symptoms such as 
delusions and hallucinations, are relatively mild and well controlled (Marder et al., 2013). 
This study will enroll approximately 380 subjects (190 subjects per treatment group) with 
predominant negative symptoms of schizophrenia across approximately 70 study sites 
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globally.  On the first day of the randomized treatment phase (Baseline), eligible subjects will 
be randomly assigned to receive pimavanserin or placebo daily in a 1:1 ratio, according to a 
computer-generated randomization schedule.  The randomization will be stratified according 
to geographic region (North America, Europe, or rest of world).  The initial daily dose of 
study drug is pimavanserin is 20 mg or matching placebo.  The daily dose of pimavanserin 
may be increased or decreased after the first two weeks of treatment through Week 8 but must 
remain stable thereafter as described in Table 5–1.  The daily dose of the main antipsychotic 
must remain stable and may not be changed from Screening through the duration of the study.  
Subjects will participate in the study for up to 34 weeks, including a Screening Period of up 
to 4 weeks, a 26-week Treatment Period, and a 4-week safety follow-up (telephone call) for 
those subjects who discontinue prematurely from the study or who do not enroll in the 
52-week, open-label, extension study (Study ACP-103-035). 
3.2 
Screening Period 
During a Screening Period of up to 4 weeks, subjects will be assessed for study eligibility.  
All prohibited medications should be discontinued during the Screening Period (i.e., prior to 
the Baseline visit).  Only outpatients with stable living conditions and a reliable informant 
may enter the study.  Although subjects up to age ≤55 are allowed to participate, in order to 
provide appropriate age representation, Investigators are encouraged to enroll an equal 
number of subjects who are ≤35 and who are >35 years old. 
Subjects who are deemed eligible for inclusion at the initial screening visit are scheduled to 
have a structured telemedicine (i.e., live unrecorded video) interview by an independent 
clinician to confirm that the subject has schizophrenia with predominant negative symptoms 
while on adequate treatment with an antipsychotic. 
Subjects must be taking only one antipsychotic, which will be continued throughout the 
subject’s participation in this study (see inclusion criterion #12 in Sections 4.1). 
In order to provide appropriate representation of all antipsychotics in the study, Investigators 
are encouraged to enroll subjects with a range of allowable antipsychotics 
(see inclusion criterion #13 in Section 4.1).  The objective is that at any given site no more 
than one-third of total subjects enrolled are on the same antipsychotic. 
Subjects who meet the criteria for study eligibility will continue to receive their antipsychotic 
at a stable dose for the duration of the study and will be randomly assigned to receive either 
pimavanserin 20 mg or matching placebo in a 1:1 ratio. 
At any time during the study, the subject may sign a separate informed consent to obtain a 
pharmacogenomics DNA sample. 
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3.3 
Double-blind Treatment Period 
The Baseline visit (Day 1) may occur as soon as all screening procedures are completed and 
subject eligibility has been confirmed.  Subjects will be randomly assigned in a 1:1 ratio to 
receive either pimavanserin 20 mg or matching placebo, and stratified according to 
geographic region (North America, Europe, or rest of world).  Study drug will continue daily 
at this dose level for the first two weeks of treatment.  Study drug will be administered under 
double-blind conditions throughout the Treatment Period.  The designated main antipsychotic 
medication will be continued at a stable dose. 
At the Weeks 2, 4, and 8 visits, the daily dose of pimavanserin may remain at 20 mg or it may 
be either increased to 34 mg (for symptom improvement) or decreased to 10 mg daily (if the 
20 mg dose is not well tolerated).  After the Week 8 visit, no study drug dose changes may be 
made.  Clinic visits occurring after Baseline will be conducted at Weeks 2, 4, 8, 14, 20, and 
26 (End-of-Study [EOS]/Early Termination [ET] visit). 
3.4 
Follow-up 
Subjects who successfully complete the 26-week Treatment Period may enroll in a 52-week, 
open-label, extension study (Study ACP-103-035) if they qualify.  For subjects who 
discontinue prematurely from the study or who do not enroll in the extension study 
(Study ACP-103-035), a safety follow-up telephone call will occur approximately 4 weeks 
after the last dose of study drug and they should return to standard of care treatment 
following the treatment period. 
Figure 3–1 illustrates the study design. 
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Page 31 of 100 
Figure 3–1 
Schematic of Study Design for ACP-103-038 
 
 
 
Subjects with 
predominant 
negative symptoms of 
schizophrenia while on 
adequate treatment with 
an antipsychotic 
Main antipsychotic + placebo 
Double-Blind Treatment Period 
26 weeks 
1:1 Randomization 
Main antipsychotic + pimavanserin 
Screening Period 
Up to 4 weeks 
Follow-up Period 
4 weeks 
EOS/ET* 
4-week follow-up 
(telephone call) 
*Subjects who complete the 26-week Treatment Period may be eligible to enroll in a 52-week, open-label extension study (Study ACP-103-035).  
Subjects entering ACP-103-035 will not complete a follow-up telephone call as they will be immediately enrolled in ACP-103-035. 
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4 STUDY POPULATION AND WITHDRAWAL CRITERIA 
Subjects must meet all of the inclusion and none of the exclusion criteria (Sections 4.1and 
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 post-randomization 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. 
Subjects who screen fail will be allowed to rescreen with the permission of the Medical 
Monitor, provided the screen failure was due to a temporary condition that subsequently 
resolved.  Subject randomization will occur at the end of the Screening Period for those who 
continue to meet enrollment criteria. 
In order to participate in the optional pharmacogenomics component of the study, subjects 
must sign a separate pharmacogenomics informed consent form (ICF), indicating their 
willingness to have their DNA sample stored for future use.  Refusal to consent for this 
component does not exclude a subject from participation in the clinical study. 
4.1 
Inclusion Criteria 
A subject must meet all of the following inclusion criteria: 
1. Male or female, ≥18 and ≤55 years of age at the time of Screening 
2. Able to understand and provide signed informed consent 
3. Able to sign and date a request for medical records and/or subject privacy form if 
applicable according to local regulations 
4. In the Investigator’s opinion, is able to understand the nature of the trial, follow 
protocol requirements, be willing to comply with study drug administration, and 
discontinue prohibited concomitant medications 
5. 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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6. Able to complete subject-reported outcome measures, can be reliably rated on 
assessment scales, and is willing to participate in audio recording of assessment scales 
and in an unrecorded telemedicine interview 
7. Diagnosis of schizophrenia according to Diagnostic and Statistical Manual of Mental 
Disorders – Fifth Edition (DSM-5) criteria (confirmed using a customized module of 
the Structured Clinical Interview for DSM-5, Clinical Trials Version [SCID-5-CT]) 
8. Diagnosis of schizophrenia made ≥1 year prior to randomization 
9. Score ≥20 on the sum of the 7 PANSS Marder negative factor items at Screening and 
Baseline 
AND 
Score ≥4 on at least 3, or ≥5 on at least 2, of the 7 PANSS Marder negative factor 
items 
10. Score ≤22 on the sum of the 8 PANSS Marder positive factor items 
AND 
PANSS score where no more than two of the following items have a score of 4 and 
none of the following items has a score ≥5 at both Screening and Baseline (see 
Appendix G): 
• P1 (delusions) 
• P3 (hallucinatory behavior) 
• P6 (suspiciousness/persecution) 
11. A CGI-SCH-S for the negative symptoms of schizophrenia score ≥4 (moderately ill or 
worse) at Screening and Baseline 
12. Has been treated with an adequate dose of an antipsychotic within the dose range 
recommended according to the local Prescribing Information for at least 8 weeks prior 
to Screening and remains at the same dose during the Screening Period  
13. The antipsychotic with which the subject is being treated must be one of the 
antipsychotics listed below: 
• Aripiprazole 
• Aripiprazole long-acting injectables 
– Abilify Maintena® 
– Aristada® 
• Asenapine 
• Brexpiprazole 
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• Cariprazine 
• Lurasidone 
• Olanzapine 
• Risperidone 
• Risperidone long-acting injection 
14. If taking an oral antipsychotic, no dose change within 4 weeks prior to Screening or 
during the Screening Period 
15. If taking a long-acting injectable antipsychotic, no dose change within 16 weeks prior 
to Screening or during the Screening Period 
16. If taking an antidepressant medication or an anxiolytic medication, no dose change 
within 4 weeks of Screening or during the Screening Period (see also Appendix A for 
restrictions/prohibitions during the study) 
17. Must be medically stable and has been medically stable for at least 12 weeks prior to 
Screening, in the opinion of the Investigator 
18. If female, must 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 (e.g., oral, intrauterine device [IUD], diaphragm plus 
spermicide, injectable, transdermal, or implantable contraception)  
• All female subjects must have a negative serum human chorionic gonadotropin 
(hCG) pregnancy test at Screening and a negative urine pregnancy test at Baseline 
4.2 
Exclusion Criteria 
A subject must meet none of the following exclusion criteria: 
1. Based on the SCID-5-CT, has a current comorbid psychiatric disorder other than 
schizophrenia (e.g., bipolar disorder, obsessive compulsive disorder, substance abuse) 
or a disorder that would interfere with the ability to complete study assessments (e.g., 
intellectual disability) 
2. Score ≥2 for two or more movements or a score of 3 or 4 for any single movement on 
the Abnormal Involuntary Movement scale (AIMS) 
3. Total score ≥2 on the Barnes Akathisia Rating scale (BARS) 
4. Total score ≥5 on the Simpson-Angus Extrapyramidal Side Effects Scale (SAS) 
5. Calgary Depression Scale for Schizophrenia (CDSS) score ≥9 at both Screening and 
Baseline 
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6. Is at a significant risk of suicide or is a danger to self or others, in the opinion of the 
Investigator 
7. Has a significant risk of violent behavior in the opinion of the Investigator 
8. Has met DSM-5 criteria for substance use disorders within the last 6 months prior to 
randomization (other than caffeine and/or nicotine) 
9. A urine drug screen result at Screening or Baseline that indicates the presence of any 
tested prohibited substance of potential abuse, except marijuana 
• Subjects with a result indicating the presence of marijuana are permitted if they 
agree to abstain from marijuana use during the study and the medical monitor 
approves the subject’s participation 
10. Subject was treated with 2 or more antipsychotics, for any indication, within 8 weeks 
prior to Screening 
11. Laboratory testing confirms the absence of the identified antipsychotic 
12. 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 (see Appendix A and Appendix 
B) 
13. Known family or personal history or symptoms of long QT syndrome 
14. Has a QRS interval <120 ms and QTcF ≥460 ms OR 
has a QRS interval ≥120 ms and QTcF ≥480 ms at Screening or Baseline 
15. Current evidence, or history within the previous 12 weeks prior to Screening, of 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 
16. Has moderate to severe congestive heart failure (New York Heart Association [NYHA] 
class III and class IV) 
17. Has a history of myocardial infarction (MI) within 6 months prior to enrollment. 
18. Has a history of uncontrolled diabetes mellitus (DM), Type 1 or 2 DM requiring 
insulin treatment, or glycosylated hemoglobin (HbA1c) >7% at Screening 
19. Has a clinically significant thyroid function test result at Screening 
20. Has clinically significant laboratory abnormalities that in the judgment of the 
Investigator or Medical Monitor would jeopardize the safe participation of the subject 
in the study 
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21. Known to be positive for hepatitis C virus (HCV) or human immunodeficiency virus 
(HIV) 
22. Has a body mass index (BMI) <19 or ≥35 at Screening 
23. Has a history of neuroleptic malignant syndrome 
24. Is breastfeeding or lactating 
25. Has a significant sensitivity or allergic reaction to pimavanserin or its excipients 
26. Has previously been randomized in any prior clinical study with pimavanserin, and/or 
received any other investigational (either approved or unapproved) drug within 
30 days or 5 half-lives (whichever is longer) prior to Screening 
27. Has any condition that, in the opinion of the Investigator, would interfere with the 
ability to comply with study instructions, or that might confound the interpretation of 
the study results or put the subject at undue risk 
28. Is an employee of ACADIA, or has a family member who is an employee of ACADIA 
29. Has participated in >2 pharmaceutical clinical research studies within the previous 
2 years 
30. Subject is judged by the Investigator or the Medical Monitor to be inappropriate for 
the study 
31. Subject has had a social hospitalization, defined as admission to the hospital as a result 
of inadequate family support or care at the subject’s primary residence, during the 
8 weeks prior to screening 
4.3 
Withdrawal of Subjects 
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. 
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 
• Investigator determines that continuation in the study would be detrimental to a 
subject’s well-being (e.g., a clinically significant risk of suicidality is identified for a 
subject) 
• Subject fails to comply with protocol requirements 
• Subject is lost to follow-up 
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• At the discretion of the Sponsor 
• If, during the course of a subject’s post-randomization participation in the trial, it is 
discovered that the subject did not meet all eligibility criteria (e.g., Baseline ECG 
central read is exclusionary or Baseline laboratory/urine drug screen [UDS] is 
exclusionary), she or he will be discontinued, unless the discontinuation presents an 
unacceptable medical risk. 
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. 
Should a subject request or decide to withdraw, every reasonable effort should be made to 
complete and report observations as thoroughly as possible up to the date of withdrawal, 
including the evaluations specified at the Week 26 (EOS/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 or who do not enroll in the 52-week pimavanserin 
open-label, safety extension study (ACP-103-035).  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 effort should 
be made to follow 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, serious adverse events (SAEs) should 
continue to be reported as described in Section 7.4.2. 
A subject is considered to have completed planned participation in the study if all treatment 
visits including the EOS visit have been completed. 
4.4 
Premature Study Termination 
This study may be prematurely terminated.  In such case, written notification, documenting 
the reason for study suspension or termination, will be provided by the Sponsor.  If the study 
is prematurely terminated or suspended, the Investigator will promptly inform the 
Institutional Review Board (IRB/EC). 
Circumstances that may warrant termination may include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Insufficient compliance to protocol requirements 
• Business reasons 
 
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5 STUDY TREATMENT 
5.1 
Description of Study Drugs 
Pimavanserin tartrate is a white to off-white powder.  Pimavanserin tablets include the active 
compound (pimavanserin) and the following excipients:  
 
.  The drug 
product is formulated with standard pharmaceutical excipients at 10 mg and 17 mg strengths 
(11.8 mg and 20 mg of pimavanserin tartrate, respectively), immediate-release tablets for 
once-daily oral administration. 
Placebo tablets contain all of the same excipients as pimavanserin 10 mg and 17 mg tablets, 
but do not contain any pimavanserin. 
Pimavanserin and placebo used for the tablets are manufactured under current Good 
Manufacturing Practice compliance by
 
5.2 
Administration of Study Drug 
Eligible subjects will be randomly assigned to receive either oral pimavanserin or oral 
matching placebo once daily for 26 weeks in blinded fashion according to the treatment 
schedule as shown in Table 5–1. 
The first dose of study drug (pimavanserin 20 mg or matching placebo) will be taken at the 
Baseline visit, after all baseline assessments have been completed.  Study drug will continue 
daily at this dose level for at least the first two weeks of treatment. 
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Table 5–1 
Treatment Administration Schedule for Protocol ACP-103-038 
Visit Number(s) 
Once Daily Adjunctive Treatment Regimen 
Baseline (Day 1/ Visit 2) 
through  
Week 2 (Visit 3) 
20 mg (2 × 10 mg tablets) pimavanserin or matching placebo 
Week 2 Visit (Visit 3) 
The daily dose of study drug may be continued at: 
• 
20 mg (2 × 10 mg tablets) pimavanserin or matching placebo 
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 matching placebo 
Or, at Investigator discretion, decreased (to improve tolerability) to: 
• 
10 mg (1 × 10 mg tablet) pimavanserin and 1 placebo tablet) or matching 
placebo 
Week 4 Visit (Visit 4) 
Week 8 Visit (Visit 5) 
The study drug may be continued at the same daily dose. 
Or, at Investigator discretion, the daily dose of study drug may be increased: 
• 
From 10 mg to 20 mg, or 
• 
From 20 mg to 34 mg 
or decreased: 
• 
From 34 mg to 20 mg, or 
• 
From 20 mg to 10 mg 
Week 14 Visit (Visit 6) 
Week 20 Visit (Visit 7) 
Week 26 Visit (Visit 8) 
Subjects will remain at same daily dose of study drug as they were receiving at 
Week 8 visit. 
No dose modifications are allowed after the Week 8 visit. 
 
Each daily dose of study drug consists of 2 individual tablets that should be taken together.  
Subjects should take the study drug at approximately the same time each day until Week 26 
(EOS/ET), except for Day 1(Visit 2) when the dose is taken at the study center.  Subjects 
should take the daily dose of study drug at the same time as they normally take their main 
antipsychotic. 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 kits will be dispensed to the subject to take home. 
Subjects will take study drug adjunctively to their main antipsychotic throughout the 
Treatment Period.  Adjustments in the dose of the main antipsychotic are not permitted after 
Screening. 
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5.3 
Overdose 
An overdose is a deliberate or inadvertent administration of a treatment at a dose higher than 
specified in the protocol.  It must be reported, irrespective of outcome even if toxic effects 
were not observed.  An overdose is considered an AE only if there are symptoms associated 
with the event.  All events of overdose are to be captured on the Overdose Form (see 
Section 7.4.4) and should also be recorded as protocol deviations. 
5.4 
Method of Assigning Subjects to Treatment Groups 
Subjects who have signed the ICF, completed screening procedures and are entered into the 
study or screen failed, will be entered using interactive response technology (IRT) and the 
electronic data capture (EDC) system as appropriate. 
On Day 1 of the treatment phase, eligible subjects who meet all inclusion and none of the 
exclusion criteria will receive pimavanserin 20 mg per day or daily placebo according to a 
computer-generated randomization schedule.  Subjects will be randomized in a 1:1 ratio to 
1 of 2 treatment groups (pimavanserin 20 mg or placebo), and stratified according to 
geographic region (North America, Europe, or rest of world).  The assignments will be 
blinded to all study subjects, investigators, raters, site personnel, and Sponsor personnel. 
5.5 
Prior and Concomitant Medications 
Any medication (including, but not limited to, over-the-counter medicines such as aspirin, 
antacids, vitamins, mineral supplements, and herbal preparations) that the subject has 
received within 12 weeks prior to Baseline (Day 1) or receives during the study (through 
Week 30 [telephone visit] or ET) must be recorded on the appropriate eCRF along with the 
reason for use, dates of administration, and dosages. 
5.5.1 
Prior Medications 
Prior medications are defined as any medication taken before the date of the first dose of 
study drug. 
5.5.2 
Concomitant Medications 
Concomitant medications are defined as any medication taken on or after the date of the first 
dose of study drug. 
Subjects will 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.  The Sponsor or designee, 
and the Investigator, will confer to determine whether it is appropriate to continue such a 
subject in the study if a prohibited medication is prescribed. 
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5.5.3 
Prohibited and Restricted Medications 
Restrictions for concomitant medications (see Appendix A and Appendix B) should be 
followed between the initial Screening visit and Visit 8 (Week 26 [EOS/ET]) visit.  These 
appendices do not constitute an exhaustive list and any questions regarding prohibited and 
restricted medications should be discussed with the Medical Monitor or appropriate designee. 
Medications that can prolong QT interval are prohibited or restricted as specified in 
Appendix A. 
Medications that are strong cytochrome CYP3A4 inhibitors are prohibited.
 
 
Inhibitors of CYP3A4 are to be stopped at least 7 days or 5 half-lives prior to the 
administration of study drug, whichever is longer.  Inducers of CYP3A4 are to be stopped 
30 days or 5 half-lives prior to the administration of study drug, whichever is longer.  
Moderate inhibitors and inducers of CYP3A4 may be allowed but should be used with 
caution.  Consult with the Medical Monitor if you are unsure.  A list of prohibited CYP3A4 
inhibitors and inducers is provided in Appendix B. 
Subjects who take prohibited concomitant medications during the trial will be discontinued, 
unless the discontinuation presents an unacceptable medical risk.  The justification to allow 
the subject to continue in the trial will be made by the Sponsor with medical input from the 
Investigator, and will be documented.  If allowed to remain in the trial, this will be reported 
as a major protocol deviation and not a waiver. 
5.6 
Blinding 
Treatment assignment will be double-blind such that neither the subjects, Sponsor personnel 
who oversee the study, nor the Investigator and study personnel will know which treatment is 
assigned to each subject.  The Investigator may request unblinding of a specific subject if it’s 
considered necessary for the treatment of an SAE or ethically appropriate.  Such a request 
must be made through the Medical Monitor or appropriate designee.  See Section 9.6.2 for 
details regarding medical emergency unblinding procedures. 
5.7 
Study Drug Handling 
5.7.1 
Study Drug Packaging 
Pimavanserin will be provided as 10 mg and 17 mg strength tablets; matching placebo tablets 
will also be provided.  ACADIA or its designee will supply the pimavanserin and placebo 
tablets. 
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During the Treatment Period, study drug will be supplied in kits which will contain one (1) 
blister card.  Each blister card contains 20 tablets, which is a sufficient number of study drug 
tablets for 10 days of treatment (7 days of treatment plus 3 days extra supply). 
5.7.2 
Study Drug Storage 
The study drug must be kept at 15°C to 30°C (59°F to 86°F) [see USP Controlled Room 
Temperature] in a secure area with restricted access and according to local and national 
regulations.  Neither the Investigator, nor the pharmacist, nor any of his or her designees may 
provide study drug to any person not participating in the study. 
5.7.3 
Record of Dispensing 
Accurate recording of all study drug administration for individual subjects will be made in 
the appropriate section of the subject’s eCRF as well as on the site study drug dispensing and 
reconciliation form.  Drug accountability records must be updated as subjects are enrolled 
and throughout the conduct of the study. 
5.8 
Study Drug Accountability Procedures 
The Investigator or designee will keep current and accurate records of the study drug product 
dispensed, used, and returned for each subject to assure the health authority and Sponsor that 
the study drug is being handled appropriately.  Subjects should be instructed to return all 
used/empty kits, blister cards and unused tablets to the study site at regularly scheduled clinic 
visits and at the EOS/ET visit. 
At appropriate intervals during the study, study drug reconciliation will be performed by the 
Sponsor representative 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 
ACADIA.  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 ACADIA and the Sponsor’s designee. 
5.9 
Treatment 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. 
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6 STUDY PROCEDURES AND SCHEDULE 
It is required that trained and experienced clinicians administer the efficacy and safety scales 
for this protocol.  Training, certification, and materials for rating will be provided by 
ACADIA or its designee. 
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 
other efficacy and safety assessment scales prior to administration of assessment scales to 
subjects. 
6.1 
Efficacy Scales 
6.1.1 
Negative Symptom Assessment-16 (NSA-16) 
The 16-item Negative Symptom Assessment is a validated scale that can be completed in 
approximately15 to 20 minutes (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. 
A sample NSA-16 is provided in Appendix C. 
6.1.2 
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 D. 
6.1.3 
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).  For purposes of this study, only the negative symptoms will be evaluated. 
A sample CGI-SCH-S is provided in Appendix E. 
6.1.4 
Clinical Global Impression of Schizophrenia Scale – Improvement 
The CGI-SCH-I is a clinician-rated, 7-point scale that is designed to evaluate change in 
positive, negative, depressive, cognitive symptoms and overall severity in schizophrenia 
(Haro et al. 2003).  For purposes of this study, only the negative symptoms will be evaluated. 
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A sample CGI-SCH-I is provided in Appendix F. 
6.1.5 
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 G. 
6.1.6 
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). 
A sample IQ-PANSS is provided in Appendix H. 
6.1.7 
Brief Assessment of Cognition in Schizophrenia 
The BACS is a performance-based assessment that measures treatment-related changes in 
cognition and assesses six cognitive domains, including verbal memory and learning (verbal 
memory task), working memory (digit sequencing), motor function (token motor task), verbal 
fluency (semantic and letter fluency), speed of processing (symbol coding), and executive 
function (Tower of London) (Keefe et al., 2004).  The BACS takes approximately 30 minutes 
to administer, and incorporates alternative forms for repeated testing. 
6.1.8 
Calgary Depression Scale for Schizophrenia 
The CDSS is a 9-item scale that was developed specifically to assess the level of depression 
in schizophrenia.  It was originally developed to differentiate depressive symptoms from 
negative symptoms (Addington et al., 1990; Addington et al., 1992). 
A sample of the CDSS is provided in Appendix I. 
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6.1.9 
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. 
A sample of the SF-36 is provided in Appendix J. 
6.1.10 
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 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 will be administered by a trained interviewer. 
A sample of the DAI-10 is provided in Appendix K. 
6.1.11 
Karolinska Sleepiness Scale 
The KSS is a 9-item, self-reported subjective measure of a subject's level of drowsiness 
(Åkerstedt and Gillberg 1990; Johns 2009).  Respondents must choose statements that most 
accurately describes their level of sleepiness over the past few minutes or, with the modified 
version used in this study, over an average period of time (Reyner et al., 1998; 
Geiger Brown et al., 2014).  In this study, the KSS will be administered by a trained 
interviewer. 
A sample of the KSS is provided in Appendix L. 
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 M), 
Barnes Akathisia Rating Scale (BARS; see Appendix N), and the Simpson-Angus 
Extrapyramidal Side Effects Scale (SAS; see Appendix O). 
In addition, the Columbia-Suicide Severity Rating Scale (C-SSRS; see Appendix P) will be 
used to assess suicidal ideations and behaviors. 
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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 (Guy 1976) is provided in Appendix M. 
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. 
A sample of the BARS is provided in Appendix N. 
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 O. 
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 will be used to assess suicidal ideations and behaviors; the Baseline/Screening 
version will be administered at Screening, and the Since Last Visit version will be 
administered at subsequent visits.  The C-SSRS results for each subject should be reviewed 
by the Investigator at each visit.  If at any time the C-SSRS results for a given subject reveal 
potential suicidality, then the Investigator should assess the clinical significance of such 
results.  If a clinically significant risk of suicidality is identified for a subject, then the 
Investigator should discontinue the subject and implement appropriate treatment 
(Section 4.3). 
A sample of the C-SSRS is provided in Appendix P. 
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6.3 
Safety Measures 
6.3.1 
Medical and Psychiatric History 
A thorough medical and psychiatric history, including schizophrenia history, will be obtained 
by interviewing each subject at the Screening visit. 
6.3.2 
Medication History 
Current and past treatments, medication history, or therapies that are specific to their 
diagnosis will be recorded.  A careful review of current, recent, and past medications with 
each subject will also be performed. 
6.3.3 
Physical Examination 
A complete physical examination should be performed at Screening, Baseline, and Week 26 
(EOS/ET); symptom-directed examinations will be performed at Weeks 2 and 14.  Pelvic 
and/or urogenital examination may be deferred, unless the Investigator deems this to be 
clinically indicated. 
6.3.4 
Vital Sign Measurements 
Vital signs, including sitting (at least 3 minutes) blood pressure, pulse rate, respiratory rate, 
and temperature, should be performed at Screening, Baseline (Day 1), and Weeks 2, 4, 8, 14, 
20, and 26 (EOS/ET).  At Baseline, vital signs must be measured before study drug is given. 
6.3.5 
Height and Weight 
Height will be measured at Screening only.  Weight will be measured at Screening, Baseline 
(Day 1), and Week 26 (EOS/ET). 
6.3.6 
Electrocardiograms 
A single 12-lead ECG will be performed in triplicate at Screening.  Single 12-lead ECG 
recordings will be performed at Baseline, Week 14, and at the Week 26 (EOS/ET) visit.  
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 Screening, 
Baseline, and at Week 26 (EOS/ET visit).  Pregnancy tests will be performed for all women. 
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Hematology tests include the following: 
• Complete blood count (CBC) including: 
– White blood cell (WBC) count 
– Complete differential (relative and absolute) 
– Hematocrit (Hct), hemoglobin (Hgb), red blood cells (RBC), platelets 
– Reticulocyte count 
Serum chemistry tests include the following: 
• Sodium (Na) , potassium (K), chloride (Cl), phosphorus (P), calcium (Ca), carbon 
dioxide (CO2), blood urea nitrogen (BUN), creatinine (Cr), uric acid 
• Alanine aminotransferase (ALT/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 
– Total cholesterol, high-density lipoprotein (HDL)-cholesterol, 
triglycerides, low-density lipoprotein (LDL)-cholesterol, cholesterol/HDL 
ratio, non-HDL cholesterol 
• Screening only: 
– HbA1c 
– Thyroid stimulating hormone (TSH); full thyroid panel only if TSH value 
is outside of the laboratory reference range 
– Presence or absence of the main antipsychotic in the plasma will also be 
assessed at Screening 
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: 
• Blood, RBCs, WBCs, protein, glucose, ketones, specific gravity, pH 
The UDS 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 
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benzodiazepines will be evaluated by the Investigator in the context of allowed anxiolytics.  
Additional UDS tests (apart from scheduled timepoints) may be repeated at any time 
throughout the study, at the discretion of the Investigator. 
Pregnancy tests (performed for all women) will include the following: 
• Serum pregnancy test at the Screening visit 
• Urine pregnancy test at Baseline (Day 1) and Weeks 2, 4, 8, 14, 20, and 26 (EOS/ET 
visit) 
Screening and Baseline pregnancy test results must both be confirmed to be negative before a 
subject is randomized and administered any study drug. 
6.4.2 
Other Assays or Procedures 
6.4.2.1 
Confirmation of Main Antipsychotic 
At Screening, a blood sample will be collected to confirm the presence or absence of the 
identified main antipsychotic. 
6.4.2.2 
Pharmacokinetic Assessments 
Blood samples for measurements of concentrations in plasma (PK samples) of pimavanserin, 
the metabolite AC-279, and the main antipsychotic will be collected at the timepoints 
identified in Table 6–1.  The blood draw at Baseline should be completed before the first dose 
of study medication (pre-dose). 
When possible, an additional PK sample will be collected from subjects who experience an 
SAE or AE leading to discontinuation, as soon as possible after experiencing that event. 
For all PK samples (scheduled and unscheduled), the dates and times of administration of the 
last 3 doses of both study drug and the main antipsychotic should be recorded.  For samples 
collected from subjects who experience an SAE or an AE leading to discontinuation, the date 
and time of the last dose prior to the SAE or AE should also be recorded. 
Pimavanserin plasma concentration data will remain blinded until the unblinding of the 
clinical database at the end of the study. 
6.4.2.3 
Specimen Preparation, Handling, Storage, and Shipment 
Procedures for specimen preparation, handling, storage, and shipment are described in a 
separate manual. 
6.4.2.4 
Pharmacogenomic Assessment 
A single blood draw will be performed for subjects who have signed a separate 
pharmacogenomics consent form indicating their willingness to have their DNA sample 
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stored for possible future genetic research related to pimavanserin or the indication(s) for 
which it is developed (where local regulations permit).  Stored DNA samples and relevant 
clinical data will be made non-identifiable after the clinical study report has been issued.  
Personal identifiers will be removed and each study subject identifier will be replaced with a 
new number to limit the possibility of linking genetic data to a subject’s identity. 
6.5 
Study Schedule 
It is recommended that the NSA-16 be the first efficacy assessment scale to be administered. 
6.5.1 
Screening Period (Day -28 to Day -7) 
The Screening Period will be from 7 days to 28 days in duration.  Subjects must have been 
treated with an adequate dose of one antipsychotic, within the dose range approved for 
schizophrenia in the applicable country, for at least 8 weeks prior to Screening.  Subjects will 
continue to receive their single antipsychotic throughout the double-blind Treatment Period.  
Adjustments in the dose of the antipsychotic are not permitted after Screening. 
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. 
Subjects who are deemed eligible for inclusion at the initial screening visit are scheduled to 
have a structured telemedicine (i.e., live unrecorded video) interview by an independent 
clinician to confirm that the subject has schizophrenia with predominant negative symptoms 
while on adequate treatment with an antipsychotic. 
Informed consent must be obtained and the Informed Consent Form (ICF) signed before 
screening procedures commence.  Participation in the collection of pharmacogenomic 
samples is optional; however, pharmacogenomic consenting must be obtained before sample 
collection.  The monitoring and recording of AEs will commence after a subject has agreed to 
participate in the study and has signed the ICF. 
The subject’s caregiver must provide written agreement prior to any Screening procedures 
being performed indicating their agreement to participate in the study in the caregiver role. 
Screening evaluations will include the following: 
• Demography 
• Medical (including review of tobacco and nicotine use) and psychiatric history 
• Review of virology history (for any history of HIV, hepatitis B, or HCV) 
• Complete physical examination 
• Vital signs (sitting [at least 3 minutes] blood pressure, pulse, respiratory rate, and 
temperature) 
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• Height and weight 
• 12-lead electrocardiogram (ECG) (triplicate recordings) 
• Clinical laboratory tests (hematology, serum chemistry, prolactin levels, Hb1Ac, TSH; 
detection/confirmation of the subject’s main antipsychotic;  urinalysis; and urine drug 
screen) 
• Serum pregnancy test for all female subjects.  Results must be negative for subjects to 
be eligible for the study. 
• SCID-5-CT customized module 
• PANSS (including the caregiver reported IQ-PANSS), CGI-SCH-S, and CDSS 
• C-SSRS (Baseline/Screening version) 
• AIMS, BARS, and SAS 
• Review of current medications/treatments 
• Interview of subject by an independent clinician  
• Assessment of AEs 
6.5.2 
Treatment Period 
6.5.2.1 
Baseline Visit (Visit 2/Day 1) 
On Day 1, after screening procedures are completed and reviewed (e.g., acceptable clinical 
laboratory tests), the subject will be evaluated for continued eligibility and, if qualified, may 
enter the treatment phase and receive the first dose study drug.  Subjects will complete the 
following procedures at Baseline: 
• Complete physical examination 
• Vital signs (pre-dose, sitting (at least 3 minutes) blood pressure, pulse, respiratory rate, 
and temperature) 
• Weight 
• 12-lead ECG (single recording) 
• Clinical laboratory tests (hematology, serum chemistry, prolactin levels, urinalysis and 
urine drug screen)  
• Urine pregnancy test for all female subjects 
• Pre-dose PK blood draw 
• Pre-dose pharmacogenomic blood draw (optional) 
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• NSA-16, PANSS (including the caregiver reported IQ-PANSS), CGI-SCH-S, PSP, 
BACS, and CDSS 
• SF-36, DAI-10, and KSS 
• C-SSRS (Since Last Visit version) 
• AIMS, BARS, and SAS 
• Assessment of concomitant medications/treatments 
• Assessment of AEs 
• Randomization 
• Dispense and administer first dose of study drug 
– Each subject will be assigned study drug according to the randomization 
schedule.  The first dose will be administered at the clinic; study drug kits 
will then be dispensed to the subject to take home. 
6.5.2.2 
Weeks 2, 4, 8, 14, and 20 (Visits 3, 4, 5, 6, and 7) 
Subjects will have the following procedures completed at each visit (unless otherwise 
indicated): 
• Symptoms-based physical examination (Weeks 2 and 14 only) 
• Vital signs (sitting [at least 3 minutes] blood pressure, pulse, respiratory rate, and 
temperature) 
• Urine pregnancy test 
• 12-lead ECG (single recording) (Week 14 only) 
• PK blood draw (Weeks 2, 8, and 14 only), 
• NSA-16, CGI-SCH-S, and CGI-SCH-I 
• PSP (Week 8 only) 
• CDSS (Week 8 only) 
• KSS 
• C-SSRS (Since Last Visit version) 
• AIMS, BARS, and SAS (Weeks 2, 8, and 14 only) 
• Assessment of concomitant medications/treatments 
• Assessment of AEs 
• Study drug dispensing and accountability 
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6.5.2.3 
Week 26 (End-of-Study/Early Termination Visit) 
Subjects will have the following procedures completed at the EOS/ET visit: 
• Complete physical examination 
• Vital signs (sitting [at least 3 minutes] blood pressure, pulse, respiratory rate, and 
temperature) 
• Weight 
• 12-lead ECG (single recording) 
• Clinical laboratory tests (hematology, serum chemistry, prolactin levels, urinalysis and 
urine drug screen)  
• Urine pregnancy test for all female subjects 
• PK blood draw 
• NSA-16, PANSS (including the caregiver reported IQ-PANSS), CGI-SCH-S, 
CGI-SCH-I, PSP, BACS, and CDSS 
• SF-36, DAI-10, and KSS 
• C-SSRS (Since Last Visit version) 
• AIMS, BARS, and SAS 
• 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. 
6.5.3 
Follow-up Period (Week 30) 
A 4-week safety follow-up telephone contact is to be completed for subjects who complete 
the study and decide not to continue or are not eligible for the open-label study and those 
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 
6.5.4 
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 AEs, 
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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. 
6.5.5 
 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 
Screening Period 
 
Treatment Period 
 
Follow-Upa 
Visitb 
1 
2 (Baseline) 
3 
4 
5 
6 
7 
8 (EOS/ET) Telephone call 
Day or Week 
(Days -28 to -7) 
Day 1/Week 0 
Week 2 Week 4 Week 8 Week 14 Week 20 Week 26 
Week 30 
Allowable visit window (# days) 
 
 
±3 
±3 
±3 
±7 
±7 
±7 
+7 
Informed consentc 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
Medical and psychiatric historyd 
X 
 
 
 
 
 
 
 
 
SCID-5-CT customized module 
X 
 
 
 
 
 
 
 
 
Interview by an independent cliniciane 
X 
 
 
 
 
 
 
 
 
Physical examinationf 
X 
X 
X 
 
 
X 
 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height and weightg 
X 
X 
 
 
 
 
 
X 
 
12-lead ECGh 
X 
X 
 
 
 
X 
 
X 
 
Clinical laboratory testsi 
X 
X 
 
 
 
 
 
X 
 
Confirmation of main antipsychoticj 
X 
 
 
 
 
 
 
 
 
Pregnancy testk 
X 
X 
X 
X 
X 
X 
X 
X 
 
PK blood drawsl 
 
X 
X 
 
X 
X 
 
X 
 
Pharmacogenomic blood drawsm 
 
X 
 
 
 
 
 
 
 
NSA-16 
 
X 
X 
X 
X 
X 
X 
X 
 
PANSS and IQ-PANSS 
X 
X 
 
 
 
 
 
X 
 
CGI-SCH-S 
X 
X 
X 
X 
X 
X 
X 
X 
 
CGI-SCH-I 
 
 
X 
X 
X 
X 
X 
X 
 
PSP 
 
X 
 
 
X 
 
 
X 
 
BACS 
 
X 
 
 
 
 
 
X 
 
CDSS 
X 
X 
 
 
X 
 
 
X 
 
SF-36 and DAI-10 
 
X 
 
 
 
 
 
X 
 
KSS 
 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRSn 
X 
X 
X 
X 
X 
X 
X 
X 
 
AIMS, BARS, and SAS 
X 
X 
X 
 
X 
X 
 
X 
 
Assessment of concomitant 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense study drug 
 
X 
Xo 
Xo 
Xo 
Xo 
Xo 
 
 
Study drug accountability 
 
 
X 
X 
X 
X 
X 
X 
 
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Abbreviations:  AIMS = Abnormal Involuntary Movement Scale; BACS = Brief Assessment of Cognition for Schizophrenia scale; BARS = Barnes Akathisia 
Rating Scale; CDSS = Calgary Depression Scale for Schizophrenia; CGI-SCH-I = Clinical Global Impression of Schizophrenia – Improvement; 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; ET = Early Termination; HCV = hepatitis C virus; HIV = human immunodeficiency virus; IQ-PANSS = 
Informant Questionnaire for the Positive and Negative Syndrome Scale; KSS = Karolinska Sleepiness Scale; NSA-16 = Negative Symptom Assessment-16 
scale; PANSS = Positive and Negative Syndrome Scale; PK = pharmacokinetic; PSP = Personal and Social Performance scale; SAS = Simpson-Angus 
Extrapyramidal Side Effects Scale; SCID 5 CT = Structured Clinical Interview for DSM-5, Clinical Trials Version; SF-36 = 36-item Short Form Health 
Survey 
a  
For subjects who discontinue prematurely from the study or who do not enroll in the 52-week, open-label, extension study (ACP-103-035), 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 3, 4, and 5 and of ±7 days for Visits 6, 7, 
and 8.  The window for the 4-week follow-up telephone call is +7 days. 
c 
To participate in the optional pharmacogenomic component of the study, subjects must sign a separate pharmacogenomic informed consent form, indicating 
their willingness to participate.  The pharmacogenomic ICF may be signed at Screening or at any time during the study.  The subject’s caregiver must 
provide written agreement prior to any Screening procedures being performed indicating their agreement to participate in the study in the caregiver role. 
d 
Medical history is to include a history of tobacco and nicotine use.  A review of any history of HIV, hepatitis B, or HCV will also be performed. 
e 
A structured telemedicine interview of the subject by an independent clinician is to be performed during the Screening period.  The interview will be 
conducted by video and will not be recorded.   
f 
A complete physical examination should be performed at Screening, Baseline, and Week 26; symptom-directed examinations will be performed at Weeks 2 
and 14.  Pelvic and/or urogenital examination may be deferred, unless the Investigator deems this to be clinically indicated. 
g 
Height will only be measured at the Screening visit. 
h 
A single 12-lead ECG will be performed in triplicate at Screening.  Single 12-lead ECG recordings will be performed at Baseline, Week 14, and at the Week 
26 (EOS/ET) visit.  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. 
i 
To include hematology, serum chemistry, prolactin levels, urinalysis, and urine drug screen (note: 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. 
j 
Blood samples for measurement of the following will be obtained at Screening only:  glycosylated hemoglobin (HbA1c), thyroid stimulating hormone 
(TSH), and main antipsychotic detection.  Measurement of a full thyroid panel will be conducted only if the TSH value is outside of the laboratory reference 
range. 
k 
A serum pregnancy test will be completed at the Screening visit for all female subjects; urine pregnancy tests will be completed at all other scheduled time-
points for all female subjects. 
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l 
At the Screening visit, a PK sample will be collected for the presence or absence of the subject’s main antipsychotic.  At each subsequent timepoint, a PK 
sample will be collected for pimavanserin, the metabolite AC-279, and the main antipsychotic.  The Baseline PK sample should be collected pre-dose.  When 
possible, an additional PK sample will be collected from subjects who experience an SAE or an AE leading to discontinuation, as soon as possible after the 
occurrence of that event.  For all PK samples (scheduled and unscheduled), the dates and times of administration of the last 3 doses of both study drug and 
the main antipsychotic should be recorded.  For samples collected from subjects who experience an SAE or an AE leading to discontinuation, the date and 
time of the last dose prior to the SAE or AE should also be recorded. 
m 
A blood sample will be collected from subjects who give informed consent for the pharmacogenomic component of the study.  The blood draw should be 
completed pre-dose.  A sample collected at a later timepoint does not constitute a protocol violation and would not require protocol amendment. 
n 
The Baseline/Screening version of the C-SSRS will be administered at Screening, and the Since Last Visit version of the C-SSRS will be administered at all 
subsequent visits. 
o 
Subjects are to return unused study drug and all kit materials at each subsequent visit; a new kit will be dispensed at each identified visit. 
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7 ASSESSMENTS OF SAFETY 
7.1 
Specification of Safety Parameters 
7.1.1 
Definition of Adverse Event 
An AE is defined as “any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related” (CDER 2012). 
An AE can therefore be any unfavorable and unintended sign (e.g., an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a drug, without any 
judgment about causality or seriousness.  An AE can arise from any use of the drug (e.g., 
off-label use, use in combination with another drug) and from any route of administration, 
formulation, or dose, including an overdose. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
drug caused the AE. 
AEs do not include the following: 
• Stable or intermittent chronic conditions (such as myopia requiring eyeglasses) that are 
present prior to baseline 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 either study drug (see Section 7.4.2) or concomitant medication without 
any signs or symptoms unless the subject is hospitalized for observation 
• Hospitalization for elective surgery planned prior to study (situation where an 
untoward medical occurrence has not occurred) 
• Pregnancy will not be considered an AE, but if it occurs, it will be reported on a 
pregnancy form 
For subjects who enroll into ACP-103-035, AEs will be recorded from the time informed 
consent is obtained through the until the first dose of open-label study drug in ACP-103-035. 
For subjects who discontinue from the study or do not enroll into ACP-103-035, AEs will be 
recorded from the time informed consent is obtained until 30 days after the last dose of study 
drug. 
All AEs must be either resolved or stable at end of study.  If ongoing at the end of the study 
the subject should be referred for appropriate treatment. 
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Serious AEs occurring after the AE reporting described above but prior to clinical database 
lock 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. 
7.1.2 
Definition of Serious Adverse Event 
In addition to the severity rating, each AE will be classified by the Investigator as “serious” 
or “not serious.”  The seriousness of an event will be defined according to the applicable 
regulations and generally refers to the outcome of an event.  An SAE is one that meets one or 
more of the following: 
• Is fatal 
• Is immediately life threatening 
• Results in disability or permanent damage 
• Requires hospitalization 
• Prolongs existing hospitalization 
• Is a congenital anomaly or birth defect (in an offspring) 
• Is medically significant 
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 ACADIA 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 
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Definition of Disability or Permanent Damage 
Disability is defined as a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions. 
Definition of Medically Significant 
Important medical events (medically significant events) that may not result in death, be life 
threatening, or require hospitalization may be considered to be an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject or may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition.  Examples of 
such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalization or 
development of drug dependency or drug abuse. 
An SAE may also include any other event that the Investigator or Medical Monitor judges to 
be serious or that suggests a significant hazard, contraindication, side effect, or precaution. 
7.2 
Classification of an Adverse Event 
7.2.1 
Severity of Event 
The severity of each AE will be graded on a 3-point scale and reported in detail as indicated 
on the eCRF: 
• Mild:  awareness of sign or symptom but easily tolerated, causing minimal 
discomfort, and not interfering with normal everyday activities 
• Moderate:  sufficiently discomforting to interfere with normal everyday activities 
• Severe:  incapacitating and/or preventing normal everyday activities 
7.2.2 
Relationship to Study Drug 
The causality of each AE should be assessed and classified by the Investigator as “related” or 
“not related.”  An event is considered related if there is a reasonable possibility that the event 
may have been caused by the product under investigation (i.e., there are facts, evidence, or 
arguments to suggest possible causation). 
Consider the following when assessing causality: 
• Temporal associations between the agent and the event 
• Response to cessation (de- challenge) or re-challenge 
• Compatibility with known class effect 
• Known effects of concomitant medications 
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• Pre-existing risk factors 
• A plausible mechanism 
• Concurrent illnesses 
7.2.2.1 
Duration 
The start and stop dates for AEs will be recorded using the following criteria: 
• Start:  Date of the first episode of the AE or date of significant sustained worsening in 
severity 
• Stop:  Date when AE either ceased permanently or changed in severity 
7.2.2.2 
Frequency 
The frequency of the AE should be indicated according to the following definitions: 
• Single:  Experienced once, without recurrence 
• Recurrent:  More than one discrete episode with the same severity 
7.2.2.3 
Action Taken with Study Drug 
• Dose not changed:  No change in study drug 
• Drug interrupted:  Study drug temporarily stopped 
• Drug withdrawn:  Study drug discontinued permanently 
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 
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7.2.3 
Definition of Unexpectedness 
Unexpectedness is defined as an AE, the nature or severity of which is not consistent with the 
information provided in the Reference Safety Information section of the current 
Pimavanserin Investigator’s Brochure. 
7.3 
Time Period and Frequency for Event Assessment and Follow-up 
In the event that a subject is withdrawn from the study because of an AE, the subject should 
be followed and treated by the Investigator until the AE has resolved, stabilized, or a new 
chronic baseline has been established. 
7.4 
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 will be coded by Data Management using the Medical Dictionary for Regulatory 
Activities (MedDRA). 
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 as described above. 
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 ACADIA 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 adverse events and other reportable information must be reported within 24 hours of 
discovery to ACADIA or its designee. An SAE (initial and/or follow-up) or, pregnancy must 
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be reported within 24 hours by completing the AE, SAE, and/or pregnancy forms, as 
appropriate (details on how to report SAEs are provided in a separate study reference 
manual). 
At a minimum, events identified by ACADIA to require expedited reporting as serious, 
unexpected, and possibly related to study drug must be brought to the attention of the 
responsible IRB/EC.  For European Union member states, ACADIA or its designee will 
provide reports of suspected unexpected serious adverse reactions (SUSARs) directly to the 
ECs, as required by local legislation.  In all other countries, it is the Investigator’s 
responsibility to provide these expedited reports to the responsible IRB/EC.  It is also the 
Investigator’s responsibility to notify the responsible IRB/EC regarding any new and 
significant safety information. 
For this study, sites will complete the paper SAE and/or Pregnancy form (for initial and/or 
follow-up information) and cover sheet, including available supporting documentation 
relevant to the event and fax or email (within 24 hours of discovery) to the following: 
 
 
 
Subjects will be followed until EOS/ET for any SAEs and/or other reportable information or 
until such events have resolved or the Investigator, in conjunction with ACADIA, 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. 
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 ACADIA or its designee (see fax numbers and email address in 
Section 7.4.2).  Any female subject who becomes pregnant during the study will be followed 
through the first well-baby visit. 
Any AEs that are the consequence of pregnancy and which meet the criteria for serious 
should also be reported via the SAE forms. 
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7.4.4 
Reporting of Overdose 
An overdose of study drug (i.e., any amount more than the prescribed number of tablets in a 
given day) must be reported on the Overdose Form within 24 hours of discovery to ACADIA 
or its designee (see fax numbers and email address in Section 7.4.2). 
7.5 
Safety Oversight 
A Safety Management Team (SMT), internal to ACADIA, 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 (blinded) non-serious AEs, 
clinical laboratory data, and other relevant safety data. 
An independent Data and Safety Monitoring Board (DSMB) will review interim safety data 
including data on AEs and SAEs.  Additional information regarding the DSMB is provided in 
Section 9.4.9.1. 
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 trial data are accurate, complete, and verifiable, and 
that the conduct of the trial is in compliance with the currently approved protocol and 
amendment(s) as applicable, with GCP, and with applicable regulatory requirements.  Details 
of the study site monitoring process are described in a separate clinical monitoring plan 
document. 
9 STATISTICAL CONSIDERATIONS 
9.1 
Statistical and Analytical Plans 
Statistical methods will be documented in detail in a statistical analysis plan (SAP) to be 
approved by ACADIA prior to database lock. 
9.2 
Statistical Hypotheses 
The hypotheses for the primary endpoint are the following: 
• The null hypothesis is that there is no difference in the mean change from Baseline to 
Week 26 in the NSA-16 total score between the pimavanserin and placebo treatment 
groups. 
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– The alternative hypothesis is that there is a difference in the mean change 
from Baseline to Week 26 NSA-16 total score between the pimavanserin 
and placebo treatment groups. 
The hypotheses for the key secondary endpoint are the following: 
• The null hypothesis is that there is no difference in the mean change from Baseline to 
Week 26 PSP score between the pimavanserin and placebo treatment groups. 
– The alternative hypothesis is that there is a difference in the mean change 
from Baseline to Week 26 PSP score between the pimavanserin and 
placebo treatment groups. 
9.3 
Analysis Datasets 
The safety analysis set includes all randomized subjects who received at least one dose of 
study drug (pimavanserin or placebo).  Subjects will be analyzed based on the treatment 
which they actually received.  The safety analysis set will be used for all safety analyses. 
The full analysis set includes all randomized subjects who received at least one dose of study 
drug and who have both a baseline value and at least one post-baseline value for the NSA-16 
total score.  Subjects will be analyzed based on their randomized treatment.  The full analysis 
set will be used for the analysis of all efficacy endpoints. 
The per-protocol (PP) analysis set will be defined prior to unblinding the study for the final 
analysis.  Subjects will be analyzed based on their randomized treatment.  The PP analysis set 
will be used for sensitivity analyses of selected efficacy endpoints. 
The PK analysis set includes all subjects in the safety analysis set who have sufficient PK 
data. 
9.4 
Description of Statistical Methods 
9.4.1 
General Approach 
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). 
Unless otherwise specified, all reported p-values will be two-sided.  All analyses will be 
performed using SAS® V9.2 (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. 
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9.4.2 
Analysis of the Primary Efficacy Endpoint 
The primary endpoint is the change from Baseline to Week 26 in the NSA-16 total score.  
The primary analysis will be based on the full analysis set.  The per-protocol analysis set will 
be used for sensitivity analyses. 
The NSA-16 total score will be analyzed using mixed model repeated measures (MMRM).  
The dependent variable will be the change from Baseline in the NSA-16 total score.  The 
independent variables in the model will include the following:  treatment group 
(pimavanserin or placebo), visit (Week 2, Week 4, Week 8, Week 14, Week 20, and Week 26), 
the treatment-by-visit interaction, geographic region (North America, Europe, or rest of 
world), the Baseline NSA-16 total score, and the Baseline-by-visit interaction.  The treatment 
comparison will be based on the difference in least squares means at Week 26 and will be 
tested at an alpha level of 0.05 (two-sided) using the full analysis set. 
In addition to the primary treatment comparisons for the Week 26 timepoint, the treatment 
groups will also be compared at each of the other timepoints (Weeks 2, 4, 8, 14, and 20) 
using the same MMRM model described above.  These other comparisons will be considered 
exploratory. 
Handling of missing values will be described in detail in the SAP.  Sensitivity analyses will 
be performed to assess the impact of missing data, including analyses based on a missing not 
at random assumption. 
9.4.3 
Analysis of the Secondary Endpoints 
9.4.3.1 
Key Secondary Endpoint 
The key secondary endpoint is the change from Baseline to Week 26 in the PSP score.  The 
change from Baseline in the PSP score will be analyzed using an MMRM model similar to 
that described above for the primary endpoint, except that the visits will include Week 8 and 
Week 26, and that the Baseline PSP score will be included in the model instead of the 
Baseline NSA-16 total score.  The treatment comparison will be based on the difference in 
least squares means at Week 26 and will be tested at an alpha level of 0.05 (two-sided) using 
the full analysis set. 
9.4.3.2 
Other Secondary Endpoints and Exploratory Endpoints 
Other secondary endpoints are the following: 
• Change from Baseline to Week 26 in CGI-SCH-S score 
• CGI-SCH-I score at Week 26 
• Change from Baseline to Week 26 in the PANSS total score 
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• Change from Baseline to Week 26 in PANSS subscores (positive scale, negative scale, 
and general psychopathology scale) 
• Change from Baseline to Week 26 in BACS score 
• Change from Baseline to Week 26 in DAI-10 score 
• Change from Baseline to Week 26 in KSS score 
Exploratory endpoints are the following: 
• Change from Baseline to Week 26 in PANSS Marder factor scores (negative 
symptoms, positive symptoms, disorganized thought, uncontrolled 
hostility/excitement, and anxiety/depression factors) 
• Change from Baseline to Week 26 in CDSS score 
• Change from Baseline to Week 26 in SF-36 score 
The change from Baseline to each post-Baseline timepoint in the CGI-SCH-S score and the 
KSS score will be analyzed using an MMRM model similar to that described above for the 
primary endpoint, except that the Baseline value of the endpoint being analyzed will be 
included in the model instead of the Baseline NSA-16 total score. 
The CGI-SCH-I score at each post-Baseline timepoint will be analyzed using an MMRM 
model.  The dependent variable will be the CGI-SCH-I score.  The independent variables in 
the model will include the following:  treatment group (pimavanserin or placebo), visit 
(Week 2, Week 4, Week 8, Week 14, Week 20, and Week 26), the treatment-by-visit 
interaction, geographic region (North America, Europe, or rest of world), the Baseline 
CGI-SCH-S score, and the Baseline-by-visit interaction. 
The change from Baseline to each post-Baseline timepoint in the CDSS score will be 
analyzed using an MMRM model similar to that described above for the primary endpoint, 
except that the visits will include Weeks 8 and Week 26, and that the Baseline CDSS score 
will be included in the model instead of the Baseline NSA-16 total score. 
The change from Baseline to Week 26 or early termination in the PANSS total score, the 
PANSS Marder factor scores (see Appendix G), the PANSS subscores, the BACS score, the 
DAI-10 score, and the SF-36 score will be analyzed using an analysis of covariance 
(ANCOVA) model with effects for treatment group (pimavanserin or placebo), geographic 
region (North America, Europe, or Rest of World), and the Baseline value of the endpoint 
being analyzed. 
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9.4.4 
Safety Analyses 
Safety results will be summarized by treatment group using descriptive statistics.  No formal 
statistical testing will be performed for any of the safety endpoints. 
9.4.4.1 
Adverse Events 
All AEs will be coded using the MedDRA coding dictionary.  All adverse events will be 
listed and TEAEs will be summarized by system organ class and preferred term.  A TEAE is 
defined as an AE that started after the first dose of study drug.  Summaries by maximum 
severity and by relationship will also be provided.  Serious adverse events, fatal TEAEs, and 
TEAEs leading to discontinuation will also be summarized.  Other TEAEs of special interest 
may also be summarized. 
9.4.4.2 
Clinical Laboratory Values 
The serum clinical chemistry, hematology, and urinalysis results at Baseline and at Week 26 
will be summarized by treatment group.  Change from baseline values will also be 
summarized. 
The number and percentage of subjects with potentially clinically important post-baseline 
laboratory values will be summarized by treatment group at Week 26 for selected parameters.  
The criteria for potentially clinically important values will be specified in the SAP. 
9.4.4.3 
Vital Signs and Body Weight 
Vital signs will be measured at Screening, Baseline, and each post-baseline visit by treatment 
group.  Body weight only will be measured at Screening, Baseline, and Week 26 and will be 
summarized by treatment group.  Change from baseline values will also be summarized.  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. 
9.4.4.4 
Electrocardiogram 
ECG parameters at Baseline, Weeks 14 and 26 will be summarized by treatment group.  
Change from baseline values will also be summarized.  Categorical analyses will be 
conducted on the incidence of subjects with prolonged QTc intervals and changes in QTc 
intervals in accordance with International Conference on Harmonisation (ICH) guidelines 
and based on the FDA E14 Guidance Document. 
9.4.4.5 
Physical Examinations 
The results of the physical examinations at Screening, Baseline, Weeks 2, 14, and 26 will be 
tabulated by treatment group.  A complete physical examination should be performed at 
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Screening, Baseline, and Week 26; symptom-directed examinations will be performed at 
Weeks 2 and 14. 
9.4.4.6 
Columbia Suicide Severity Rating 
For the C-SSRS, the number and percentage of subjects with suicidal ideation or suicidal 
behavior during the study will be tabulated. 
9.4.4.7 
Extrapyramidal Symptom Measures 
The AIMS score, the BARS score, and the SAS score, along with change from Baseline, will 
be summarized by treatment group and visit using descriptive statistics. 
9.4.5 
Confirmation of Main Antipsychotic 
Presence or absence of the main antipsychotic will be listed and summarized using standard 
summary statistics. 
9.4.6 
Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analyses 
Plasma concentration data for pimavanserin and its metabolite (AC-279), as well as for 
antipsychotics, will be listed and summarized using standard summary statistics. 
If data allow, population PK and PK/PD analyses will be performed to further characterize 
the PK profile and exposure response relationship of pimavanserin and its metabolite using 
measures of safety, and efficacy parameters.  The results of population PK and PK/PD 
modeling will be presented in a separate report.  Pimavanserin plasma concentration data will 
remain blinded until unblinding of the clinical database at the end of the study. 
9.4.7 
Adherence and Retention Analyses 
Study enrollment by center will be summarized.  The number and percentage of subjects 
randomized and treated in the study will be presented, together with the number and 
percentage of subjects in each analysis set, and 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. 
Study medication exposure and compliance will also be summarized by treatment group and 
overall for the safety analysis set. 
9.4.8 
Baseline Descriptive Statistics 
Demographics and Baseline characteristics, including sex, age, race, ethnicity, weight, and 
schizophrenia duration, will be summarized. 
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9.4.9 
Planned Interim Analyses 
No interim analysis for efficacy is planned for this study. 
9.4.9.1 
Safety Review 
An independent DSMB will review interim safety data, including data on AEs and SAEs.  
The DSMB will be independent of the Sponsor and the Investigators and will be empowered 
to recommend stopping the study due to safety concerns.  The DSMB may review blinded, 
unblinded or partially unblinded data, but the Sponsor and the Investigators will remain 
blinded to the data provided to the DSMB until the official unblinding of the database.  The 
membership, activities, responsibilities, and frequency of meetings will be described 
separately in the DSMB charter. 
9.4.9.2 
Efficacy Review 
The study will not be stopped early for superior efficacy. 
9.4.10 
Additional Subgroup Analyses 
Selected analyses will be performed in subgroups defined by geographic region (North 
America, Europe, or rest of world).  Additional subgroup analyses may be specified in the 
SAP. 
9.4.11 
Multiple Comparison/Multiplicity 
A hierarchical testing procedure will be used to control the Type 1 error rate across the 
primary and secondary endpoints.  Details will be provided in the SAP. 
9.4.12 
Tabulation of Individual Response Data 
Listings of the individual response data will be provided by measure and timepoint. 
9.5 
Sample Size 
The planned sample size is 380 (190 subjects per treatment group). 
Assuming the true difference in the mean change in the NSA-16 total score from Baseline to 
Week 26 is 4.5 points between the pimavanserin group and the placebo group, and the 
common standard deviation is 12.8 points, 171 evaluable subjects per treatment group will 
provide 90% power to detect a difference between the pimavanserin group and the placebo 
group at a significance level of 0.05, using a 2-sided t-test. 
Adjusting for a potential non-evaluable rate of up to 10%, approximately 380 subjects 
(190 subjects per treatment group) will be randomized. 
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9.6 
Measures to Minimize Bias 
9.6.1 
Enrollment/Randomization/Masking Procedures 
Eligible subjects will be randomized into 1 of 2 treatment groups (pimavanserin or placebo) 
in a 1:1 ratio using an interactive response technology (IRT) system.  The randomization will 
be stratified by geographic region (North America, Europe, or rest of world).  The 
assignments will be based on a pre-generated permuted-block randomization schedule.  
Blinding will be assured by restricting access of Investigators and Sponsor personnel and/or 
designee to the treatment codes, and providing identical tablets and packaging for the 
pimavanserin and placebo treatments. 
9.6.2 
Breaking the Study Blind/Subject Code 
For the final analysis, the treatment codes for all subjects will be released to the Sponsor after 
all subjects have completed the study and the clinical database is locked. 
For DSMB safety reviews, the treatment codes will be released to an independent 
statistician/programmer to produce unblinded statistical outputs.  The Sponsor and the 
Investigators will remain blinded. 
Unblinding of individual treatment assignment during the study is discouraged.  The 
Investigator at a site may break the blind for a given subject in the event of a medical 
emergency, where knowledge of the subject’s treatment assignment (pimavanserin or 
placebo) must be known in order to facilitate appropriate emergency medical treatment.  
The Investigator should attempt to contact the study Medical Monitor before unblinding 
a subject’s treatment identity in order to obtain concurrence that unblinding a subject’s 
treatment assignment is necessary.  Details of the process to be followed are provided in a 
separate IRT manual. 
10 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
10.1 Case Report Forms and Data Verification 
Subject data required by this protocol are to be recorded in an electronic data capture (EDC) 
system on eCRFs.  The Investigator and his/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 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 
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Investigator and site personnel will be responsible for answering all queries.  The eCRFs will 
be submitted to ACADIA or its designee for quality assurance 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. 
10.2 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. 
11 QUALITY ASSURANCE AND QUALITY CONTROL 
11.1 Quality Control and Quality Assurance 
ACADIA and/or designee representatives 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 ACADIA and/or designee monitor is responsible for inspecting the eCRFs at regular 
intervals throughout the study to verify adherence to the protocol; completeness, accuracy, 
and consistency of the data; and adherence to local regulations on the conduct of clinical 
research.  The monitor should have access to subject medical records and other study-related 
records needed to verify the entries on the eCRFs. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in 
the course of these monitoring visits are resolved. 
In accordance with ICH Guidance on GCP and ACADIA’s audit plans, a certain percentage 
of sites participating in this study will be audited.  These audits may include a review of site 
facilities (e.g., pharmacy, drug storage areas, and laboratories) and review of study-related 
records may occur in order to evaluate the trial conduct and compliance with the protocol, 
ICH Guidance on GCP, and applicable regulatory requirements. 
ACADIA and/or designee representatives, regulatory authority inspectors and IRB/EC 
representatives who obtain direct access to source documents should also respect subject 
confidentiality, taking all reasonable precautions in accordance with applicable regulatory 
requirements to maintain the confidentiality of subjects’ identities. 
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12 ETHICS/PROTECTION OF HUMAN SUBJECTS 
12.1 Ethical Standard 
The study will be conducted in compliance with the protocol, the Declaration of Helsinki, 
ICH principles of GCP, and other applicable regulatory requirements. 
The study will be performed in accordance with Health Insurance Portability and 
Accountability Act (HIPAA) regulations, FDA GCP Regulations (US CFR 21 parts 50, 54, 
56, and 312), and ICH GCP Guidelines (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 (CSR) will be signed by an Investigator and/or Coordinating Investigator 
who will be designated prior to the writing of the CSR. 
12.2 Institutional Review Board/Ethics Committee 
The Investigator or designee will provide the IRB/EC with all requisite material, including a 
copy of the protocol, informed consent, and any subject information or advertising materials.  
The study will not be initiated until the IRB/EC provides written approval of the protocol and 
the informed consent and until approved documents have been obtained by the Investigator 
and copies received by the Sponsor.  All amendments will be sent to the IRB/EC for 
information (minor amendment) or for submission (major amendment) before 
implementation.  The Investigator will supply the IRB/EC and the Sponsor with appropriate 
reports on the progress of this study, including any necessary safety updates, in accordance 
with the applicable government regulations and in agreement with policy established by the 
Sponsor. 
12.3 Informed Consent Process 
Properly executed, written informed consent must be obtained from each subject prior to 
initiating screening evaluations required by this protocol.  A separate (optional) written 
informed consent must also be obtained for each subject who agrees to have his or her DNA 
sample stored for potential use.  The subject’s caregiver must provide written agreement prior 
to any Screening visit procedures. 
The Informed Consent must, at a minimum, include the elements of consent described in the 
ICH guidance on GCP and the US CFR 21 part 50.25.  A copy of the ICF planned for use 
will be reviewed by the Sponsor (or designee) for acceptability and must be submitted by the 
Investigator (or designee) together with the protocol, to the appropriate IRB/EC for review 
and approval prior to the start of the study at that investigational site.  Consent forms must be 
in a language fully comprehensible to the prospective subject.  The Investigator must provide 
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the Sponsor (or designee) with a copy of the IRB/EC letter approving the protocol and the 
ICF(s) before the study drug supplies will be shipped and the study can be initiated. 
The consent form must be revised if new information becomes available during the study that 
may be relevant to the subject.  Any revision(s) must be submitted to the appropriate IRB/EC 
for review and approval in advance of use. 
12.3.1 
Consent and Other Informational Documents Provided to Subjects 
The subject must be given a copy of the signed informed consent(s). 
12.3.2 
Consent Procedures and Documentation 
It is the Investigator or designee’s responsibility to obtain written informed consent from the 
subject after adequate explanation of the aims, methods, anticipated benefits, and potential 
hazards of the study.  The subject must be given ample time to decide about study 
participation and opportunity to inquire about details of the study.  The IRB/EC-approved 
consent form must be personally signed and dated by the subject and by the person who 
conducted the informed-consent discussion.  The Investigator or appropriate site personnel 
must document the details of obtaining informed consent in the subject’s study documents.  
The subject must be given a copy of the signed informed consent and the original maintained 
in the designated location at the site. 
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 prior to any Screening visit procedures being performed indicating their 
agreement to participate in the study in the caregiver role. 
Consent for pharmacogenomic testing is optional.  Subjects must sign a separate 
pharmacogenomics consent form prior to blood draws.  The pharmacogenomic ICF may be 
signed at Baseline or at any time during the study. 
12.4 Subject and Data Confidentiality 
The Investigator must ensure that each subject’s anonymity is maintained as described below.  
On the eCRFs or other documents submitted to ACADIA and/or designee, subjects must be 
identified by a Subject Identification Number only.  Documents that are not for submission to 
ACADIA and/or designee (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. 
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13 DATA HANDLING AND RECORD KEEPING 
13.1 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 agencies. 
The Investigator and institution must permit authorized representatives of ACADIA and/or 
designee (including monitors and auditors), and the regulatory agency(s) (including 
inspectors), and the IRB/EC direct access to source documents (such as original medical 
records).  Direct access includes permission to examine, analyze, verify, and reproduce any 
records and reports that are needed for the evaluation of the study.  The Investigator must 
ensure the reliability and availability of source documents from which the information on the 
eCRF was derived. 
13.2 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 ACADIA can notify 
an Investigator or vendor when any records may be discarded.  Investigators should contact 
ACADIA before destroying any files. 
13.3 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-randomization participation in the trial it is 
discovered that the subject did not meet all eligibility criteria, s/he will be discontinued, 
unless the discontinuation presents an unacceptable medical risk.  The justification to allow 
the subject to continue in the trial will be made by the Sponsor, with medical input from the 
Investigator, and will be documented.  If allowed to remain in the trial, this will be reported 
as a major protocol deviation and not a waiver.  All follow-up safety assessments must be 
completed and documented as outlined in the protocol.  The Investigator must report any 
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protocol deviation to the Sponsor and, if required, to the IRB/EC in accordance with local 
regulations, within reasonable time. 
A blood sample will be collected from subjects who give informed consent for the 
pharmacogenomic component of the study.  A sample collected at a later timepoint does not 
constitute a protocol violation and would not require protocol amendment. 
13.4 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 the Regulatory Authority, 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. 
13.5 Publication and Data Sharing Policy 
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 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 GCP and as described in 21 CFR parts 50, 54, 56, and 312 and according to 
applicable local requirements. 
Confidentiality Statement 
The confidential information in this document is provided to you as a Principal Investigator 
or Consultant for review by you, your staff and the applicable Institutional Review 
Board/Ethics Committee.  Your acceptance of this document constitutes agreement that you 
will not disclose the information contained herein to others without written authorization 
from the Sponsor. 
 
Principal Investigator: 
 
 
 
 
Signature 
 
Date 
 
 
 
Name (printed) 
 
 
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16 LITERATURE REFERENCES 
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Addington D, Addington J, Maticka-Tyndale E, Joyce J. Reliability and validity of a 
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Åkerstedt T, Gillberg M. Subjective and objective sleepiness in the active individual. Int J 
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Akhondzadeh S, Malek-Hosseini M, Ghoreishi A, Raznahan M, Rezazadeh SA. Effect of 
ritanserin, a 5HT2A/2C antagonist, on negative symptoms of schizophrenia: a double-blind 
randomized placebo-controlled study. Prog Neuropsychopharmacol Biol Psychiatry. 
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Alphs LD, Summerfelt A, Lann H, Muller RJ. The negative symptom assessment: a new 
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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. 
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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. 
Blanchard JJ, King AM, Horan WP, Gur R. Toward the next generation of negative symptom 
assessments: the collaboration to advance negative symptom assessment in schizophrenia. 
Schizophr Bull. 2011;37(2):291-299. 
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. 
Duinkerke SJ, Botter PA, Jansen AA, et al. Ritanserin, a selective 5-HT2/1C antagonist, and 
negative symptoms in schizophrenia. A placebo-controlled double-blind trial. Br J 
Psychiatry. 1993;163:451-455. 
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. 
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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. 
Geiger Brown J, Wieroney M, Blair L, et al. Measuring subjective sleepiness at work in 
hospital nurses: validation of a modified delivery format of the Karolinska Sleepiness Scale. 
Sleep Breath. 2014;18(4):731-739. 
Guy W. Abnormal Involuntary Movement Scale. In: ECDEU Assessment Manual for 
Psychopharmacology: Revised (DHEW publication number ADM 76-338). Rockville, MD, 
US 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: 534–537. 
Haro JM, Kamath SA, Ochoa S, Novick D, Rele K, Fargas A, 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. 
Johns MW. What is excessive daytime sleepiness? In: Fulke P, Vaughn S (eds). Sleep 
deprivation: causes, effects and treatment. New York, NY: Nova Science. 2009;59-94. 
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. 
Keefe RS, Goldberg TE, Harvey PD, Gold JM, Poe MP, Coughenour L. The Brief 
Assessment of Cognition in Schizophrenia: reliability, sensitivity, and comparison with a 
standard neurocognitive battery. Schizophr Res. 2004; 68(2-3):289-97. 
Kirkpatrick B, Fenton WS, Carpenter WT Jr, Marder SR. The NIMH-MATRICS Consensus 
Statement on Negative Symptoms. Schizophr Bull. 2006;32(2):214-219. 
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. 
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Marder S, Alphs L, Anghelescu IG, Arango C, Barnes TR, Caers I, et al. Issues and 
perspectives in designing clinical trials for negative symptoms in schizophrenia. Schizophr 
Res. 2013;150(2-3):328-333. 
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. 
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. 
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Reyner LA, Horne JA. Falling asleep whilst driving: are drivers aware of prior sleepiness? Int 
J Legal Med. 1998;111(3):120-123. 
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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17 APPENDICES 
Appendix A Prohibited and Restricted Therapy 
Subjects who take prohibited concomitant medications during the trial will be discontinued, 
unless the discontinuation presents an unacceptable medical risk.  The justification to allow 
the subject to continue in the trial will be made by the Sponsor with medical input from the 
Investigator, and will be documented.  If allowed to remain in the trial, this will be reported 
as a major protocol deviation and not a waiver. 
The table below lists prohibitions and restrictions by medication class, including 
representative medications within class.  Medications within each class include, but are not 
limited to, examples listed in this table.  Any questions regarding prohibited and restricted 
medications should be discussed with the Medical Monitor or appropriate designee. 
Medication Class 
Examples* 
Prohibitions/Restrictions 
Antipsychotics 
other than 
pimavanserin 
 
• 
All antipsychotics with the exception of those 
listed in the protocol are prohibited  
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 
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 
prescribed prior to 
Screening/Baseline 
• 
benzodiazepines 
• 
The dose of benzodiazepine must be 
unchanged for at least 4 weeks prior to 
Baseline and should be expected to remain 
unchanged until the subject’s final visit 
• 
May not be used within 12 hours prior to an 
assessment visit 
Anxiolytics 
prescribed during 
the study 
• 
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. 
– 
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 
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Medication Class 
Examples* 
Prohibitions/Restrictions 
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 
• mirtazepine 
• 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 
Antimicrobials 
antifungals, and 
antimalarials 
PROHIBITED 
• azithromycin 
• clarithromycin 
• erythromycin 
• levofloxacin 
• moxifloxacin 
• pentamidine 
• 
Clarithromycin, erythromycin, levofloxacin, 
moxifloxacin, and pentamidine are prohibited 
at study entry and throughout the study 
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Medication Class 
Examples* 
Prohibitions/Restrictions 
 
RESTRICTED 
• artenimol/piperaquine 
• azithromycin 
• bedaquiline 
• ciprofloxacin 
• gemifloxacin 
• norfloxacin 
• ofloxacin 
• quinine 
• roxithromycin 
• 
Ciprofloxacin and azithromycin are restricted: 
• 
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 
RESTRICTED 
• amitriptyline 
• clomipramine 
• desipramine 
• imipramine 
• nortriptyline 
• 
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. 
RESTRICTED 
• citalopram 
• escitalopram 
• 
Citalopram and escitalopram can prolong the 
QT interval and are restricted to a maximum 
dose of 20 mg a day.  The dose must not be 
increased during the course of the study 
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 and moderate CYP 3A4 enzyme (CYP3A4) inhibitors and inducers.  
Any questions should be discussed with the Medical Monitor or appropriate designee. 
Subjects who take prohibited concomitant medications during the trial will be discontinued, 
unless the discontinuation presents an unacceptable medical risk.  The justification to allow 
the subject to continue in the trial will be made by the Sponsor with medical input from the 
Investigator, and will be documented.  If allowed to remain in the trial, this will be reported 
as a major protocol deviation and not a waiver. 
Inhibitors of CYP3A4 are to be stopped at least 7 days or 5 half-lives prior to study drug 
administration, whichever is longer.  Inducers of CYP3A4 are to be stopped 30 days or 
5 half-lives prior to study drug administration, whichever is longer.  Moderate inhibitors and 
inducers of CYP3A4 may be allowed but should be used with caution.  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 
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®)  
Nelfinavir (Viracept®)  
Posaconazole (Noxafil®) 
Quinupristin (Synercid®) 
Ritonavir (Norvir®, part of 
Viekira Pak™)  
Saquinavir (Invirase®)  
Telaprevir (Incivek®) 
Telithromycin (Ketek®)  
Voriconazole (Vfend®) 
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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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 Negative Symptom Assessment-16 (NSA-16) – Long Form 
Source:  Alphs LD. Negative Symptom Assessment-16 (NSA) Instruction Manual. 2006 
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Appendix D Personal and Social Performance Scale (PSP) 
Source:  Nasrallah et al., 2008 
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Appendix E Clinical Global Impression of Schizophrenia Scale – Severity 
(CGI-SCH-S) 
Source:  Adapted from Haro et al. 2003 
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Appendix F Clinical Global Impression of Schizophrenia Scale – Improvement 
(CGI-SCH-I) 
Source:  Adapted from Haro et al. 2003 
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Appendix G 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.  
 
Also:  http://www.mhs.com/product.aspx?gr=cli&id=overview&prod=panss#description 
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Appendix H 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.  
 
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Appendix I 
10-Item Drug Attitude Inventory (DAI-10) 
Source:  Hogan et al. 1983 
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Appendix K Calgary Depression Scale for Schizophrenia (CDSS) 
Source:  Dr. Donald Addington, Department of Psychiatry, Foothills Hospital,
 
 
 Calgary Depression Scale for Schizophrenia, D. Addington 
& J. Addington © Dr. Donald Addington and Dr. Jean Addington. 
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Appendix L 36-Item Short Form Health Survey (SF-36) 
Source:  McHorney et al., 1994 
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Appendix M 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 N Barnes Akathisia Rating Scale (BARS) 
Source:  Barnes, 1989 
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Appendix O Simpson-Angus Extrapyramidal Side Effects Scale (SAS) 
Source:  Simpson et al. 1970 
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P
0 
Appendix P Columbia-Suicide Severity Rating Scale (C-SSRS) 
 
Source:  Columbia-Suicide Severity Rating Scale (C-SSRS) Baseline/Screening and Since 
Last Visit Versions 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,
. (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, 
 inquiries and training requirements 
© 2008 The Research Foundation for Mental Hygiene, 
Inc. 
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