Clinical trial NCT02970292
Conditions: Schizophrenia
Sponsor: ACADIA Pharmaceuticals Inc.
Start date: 2016-10-26; Completion date: 2019-06-25
Enrollment: 396 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate the efficacy and safety of adjunctive pimavanserin compared with adjunctive placebo in the treatment of schizophrenia

Detailed description:

Arms: arm 1: Drug- pimavanserin 34 mg, 20 mg, or 10 mg taken as two tablets + background antipsychotic, once daily by mouth arm 2: Placebo + background antipsychotic, taken as two tablets, once daily by mouth
Interventions: intervention 1: Pimavanserin intervention 2: Placebo
Intervention descriptions: intervention 1: Pimavanserin 34 mg, 20 mg, or 10 mg , taken as two tablets once daily by mouth intervention 2: Placebo, taken as two tablets, once daily by mouth

Protocol documents:
Prot_000.pdf: 
Official Title: A Phase 3, randomized, double-blind, placebo-controlled study to 
evaluate the efficacy and safety of adjunctive pimavanserin for the treatment of 
schizophrenia 
NCT Number: NCT02970292 
Date of IRB Approval: 30 Mar 2017 


 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
 
ACADIA Pharmaceuticals Inc. 
 
 
Clinical Study Protocol 
Amendment 2 
 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of Adjunctive Pimavanserin for the 
Treatment of Schizophrenia 
Protocol No. ACP-103-034 
EudraCT Number:  2016-003434-24 
 
Original Protocol Date:  29 August 2016 
Amendment 1 Date:  28 November 2016 
Amendment 2 Date:  30 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 Team Lead: 
 
 
 
 
 
 
 
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PROTOCOL SYNOPSIS 
Sponsor:  ACADIA Pharmaceuticals Inc. 
Name of Study Drug:  Pimavanserin 
Indication:  Adjunctive treatment of schizophrenia 
Protocol Title:  A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of Adjunctive Pimavanserin for the Treatment of 
Schizophrenia 
Protocol Number:  ACP-103-034 
EudraCT Number:  2016-003434-24 
Objectives 
Primary Objective: 
 To evaluate the efficacy of adjunctive pimavanserin compared with 
adjunctive placebo in the treatment of schizophrenia 
Secondary Objectives: 
 To evaluate the safety and tolerability of adjunctive pimavanserin 
compared with adjunctive placebo in the treatment of schizophrenia 
 To characterize the pharmacokinetics (PK) and pharmacodynamics 
(PD) of adjunctive pimavanserin for the treatment of schizophrenia 
Methodology 
This study will be conducted as a Phase 3, 6-week, randomized, double-
blind, placebo-controlled, multicenter, multinational outpatient study in 
subjects with schizophrenia with an inadequate response to current 
antipsychotic treatment.  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 schizophrenia and an inadequate response to 
antipsychotic medications.  On the first day of the randomized treatment 
phase (Baseline), eligible subjects will be randomly assigned to receive 
adjunctive pimavanserin 20 mg per day 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).  Subjects will participate in the 
study for up to 14 weeks, including a Screening Period of up to 
4 weeks, a 6-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. 
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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: 
 Male or female, ≥18 and ≤55 years of age at the time of 
Screening 
 Able to understand and provide signed informed consent 
 Able to sign and date a request for medical records and/or subject 
privacy form if applicable according to local regulations 
 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 
 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 
 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 
 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]) 
 Diagnosis of schizophrenia made ≥1 year prior to randomization 
 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.  
The subject may be taking a second antipsychotic at the time of 
Screening. 
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 If the subject is taking two antipsychotics at Screening, the 
Investigator will: 
 Determine which antipsychotic is the main antipsychotic  
 Discontinue the other antipsychotic at least 5 half-lives 
before randomization 
 Discontinue the other antipsychotic only if it is clinically 
appropriate; the other antipsychotic should not be 
discontinued solely to make the subject eligible for 
enrollment in the study 
 The main 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 
 Lurasidone 
 Olanzapine 
 Risperidone 
 Risperidone long-acting injection 
 Has had a partial but inadequate response to the antipsychotic 
treatment 
 If taking an oral antipsychotic, no dose change within 4 weeks 
prior to Screening or during the Screening Period 
 If taking a long-acting injectable antipsychotic, no dose change 
within 16 weeks prior to Screening or during the Screening 
Period 
 PANSS total score ≥65 and ≤110 at Screening and Baseline and 
there is no change in PANSS total score >30% from Screening to 
Baseline 
 PANSS score ≥4 (moderate or worse) on at least two of the 
following items at both Screening and Baseline: 
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 P1 (delusions)  
 P3 (hallucinatory behavior)  
 P6 (suspiciousness/persecution) 
 A CGI-S score ≥4 (moderately ill or worse) at Screening and 
Baseline 
 Has a history of response to antipsychotic treatment other than 
clozapine 
 Must be medically stable and has been medically stable for at 
least 12 weeks prior to Screening, in the opinion of the 
Investigator 
 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 females must have a negative serum human chorionic 
gonadotropin (hCG) pregnancy test at Screening and a 
negative urine pregnancy test at Baseline 
Exclusion Criteria: 
 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)  
 Has a history of resistance to antipsychotic treatment, as defined 
by either of the following criteria: 
 Failed to show even minimal response to ≥2 adequate 
antipsychotic medications prescribed at adequate doses for 
adequate length of time; failure to tolerate a medication does 
not constitute failure to respond 
 History of treatment with clozapine for refractory psychosis 
or use of clozapine within the past 12 weeks prior to 
Screening 
 
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 Is at a significant risk of suicide, or is a danger to self or others, 
in the opinion of the Investigator 
 Has a significant risk of violent behavior in the opinion of the 
Investigator 
 Has met DSM-5 criteria for substance use disorders within the 
last 6 months prior to randomization (other than caffeine and/or 
nicotine) 
 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 
 Subject was treated with 3 or more antipsychotics, for any 
indication, within 8 weeks prior to Screening 
 Laboratory testing confirms the absence of the identified main 
antipsychotic 
 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) 
 Known family or personal history or symptoms of long QT 
syndrome 
 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 
 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 
 Has moderate to severe congestive heart failure (New York Heart 
Association [NYHA] class III and class IV) 
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 Has a history of myocardial infarction within 6 months prior to 
enrollment 
 Has a history of uncontrolled diabetes mellitus Type 1 or 2 
requiring insulin treatment, or glycosylated hemoglobin (HbA1c) 
>7% at Screening 
 Has a clinically significant thyroid function test result at 
Screening 
 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  
 Known to be positive for hepatitis C virus (HCV) or human 
immunodeficiency virus (HIV) 
 Has a body mass index (BMI) <19 or ≥35 at Screening 
 Has a history of neuroleptic malignant syndrome 
 Is breastfeeding or lactating 
 Has a significant sensitivity or allergic reaction to pimavanserin 
or its excipients 
 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 
 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 
 Is an employee of ACADIA, or has a family member who is an 
employee of ACADIA 
 Has participated in >2 pharmaceutical research studies within the 
previous 2 years 
 Subject is judged by the Investigator or the Medical Monitor to 
be inappropriate for the study 
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8 
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 14 weeks.  Each subject will participate in a Screening 
Period of up to 4 weeks, a 6-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 6 in the Positive and Negative 
Syndrome Scale (PANSS) total score 
Secondary Endpoints 
Key Secondary Endpoint: 
 Change from Baseline to Week 6 in the Clinical Global Impression 
– Severity scale (CGI-S) score 
Other Secondary Endpoints: 
 Change from Baseline to Week 6 in PANSS subscores 
 Clinical Global Impression – Improvement (CGI-I) score at Week 6 
 Proportion of responders at Week 6 according to each of the 
following: 
 PANSS (≥20% and ≥30% reduction in PANSS total 
score) 
 CGI-I (CGI-I score of 1 or 2) 
 Change from Baseline to Week 6 in Personal and Social 
Performance (PSP) score 
 Change from Baseline to Week 6 in 10-item Drug Attitude Inventory 
(DAI-10) score 
 Change from Baseline to Week 6 in Karolinska Sleepiness Scale 
(KSS) score 
 
 
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Exploratory Endpoints: 
 Change from Baseline 6 in PANSS Marder factor scores 
 Change from Baseline to Week 6 in Calgary Depression Scale for 
Schizophrenia (CDSS) score 
 Change from Baseline to Week 6 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 and 
Endpoints 
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 
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 
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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 PANSS total 
score from Baseline to Week 6 is 6.0 points between the adjunctive 
pimavanserin group and the adjunctive placebo group, and the common 
standard deviation is 17.0 points, 171 evaluable subjects per treatment 
group will provide 90% power to detect a difference between the 
adjunctive pimavanserin group and the adjunctive 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 (adjunctive pimavanserin or adjunctive 
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 PANSS total score.  Subjects 
will be analyzed based on their randomized treatment group.  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).  
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, median, 
standard deviation, minimum, and maximum.  For each categorical 
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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 PANSS total score will be analyzed using mixed model repeated 
measures (MMRM).  The dependent variable will be the change from 
Baseline in the PANSS total score.  The independent variables in the 
model will include the following:  treatment group (adjunctive 
pimavanserin or adjunctive placebo), visit (Week 1, Week 2, Week 3, 
Week 4, Week 5, and Week 6), the treatment-by-visit interaction, 
geographic region (North America, Europe, or rest of world), the 
Baseline PANSS total score, and the Baseline-by-visit interaction.  The 
treatment comparison will be based on the difference in least squares 
means at Week 6 and will be tested at an alpha level of 0.05 (2-sided) 
using the full analysis set. 
The change from Baseline in the CGI-S score will be analyzed using an 
MMRM model similar to that described above for the primary endpoint, 
except that the Baseline CGI-S score will be included in the model 
instead of the Baseline PANSS total score.  The treatment comparison 
will be based on the difference in least squares means at Week 6 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, serious adverse events (SAEs), and 
SAEs related to study drug will all be summarized.  Other TEAEs of 
special interest may also be 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 
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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 
30 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 ........................................................................................................................ 39 
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 
Positive and Negative Syndrome Scale ..................................................................... 43 
6.1.2 
Informant Questionnaire for the Positive and Negative Syndrome Scale ................. 43 
6.1.3 
Clinical Global Impression – Severity Scale ............................................................. 43 
6.1.4 
Clinical Global Impression – Improvement Scale ..................................................... 44 
6.1.5 
Personal and Social Performance Scale ..................................................................... 44 
6.1.6 
Calgary Depression Scale for Schizophrenia ............................................................ 44 
6.1.7 
36-Item Short Form Health Survey ........................................................................... 44 
6.1.8 
10-Item Drug Attitude Inventory ............................................................................... 44 
6.1.9 
Karolinska Sleepiness Scale ...................................................................................... 45 
6.2 
Safety Scales .................................................................................................................. 45 
6.2.1 
Abnormal Involuntary Movement Scale ................................................................... 45 
6.2.2 
Barnes Akathisia Rating Scale ................................................................................... 45 
6.2.3 
Simpson-Angus Extrapyramidal Side Effects Scale .................................................. 45 
6.2.4 
Columbia-Suicide Severity Rating Scale .................................................................. 46 
6.3 
Safety Measures ............................................................................................................. 46 
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6.3.1 
Medical and Psychiatric History ................................................................................ 46 
6.3.2 
Medication History .................................................................................................... 46 
6.3.3 
Physical Examination ................................................................................................ 46 
6.3.4 
Vital Sign Measurements ........................................................................................... 46 
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 ....................................................................................... 48 
6.4.2.1 
Confirmation of Main Antipsychotic ..................................................................... 48 
6.4.2.2 
Pharmacokinetic Assessments ............................................................................... 48 
6.4.2.3 
Specimen Preparation, Handling, Storage, and Shipment ..................................... 49 
6.4.2.4 
Pharmacogenomic Assessment .............................................................................. 49 
6.5 
Study Schedule .............................................................................................................. 49 
6.5.1 
Screening Period (Day -28 to Day -7) ....................................................................... 49 
6.5.2 
Treatment Period ....................................................................................................... 51 
6.5.2.1 
Baseline Visit (Visit 2/Day 1) ................................................................................ 51 
6.5.2.2 
Weeks 1, 2, 3, 4, and 5 (Visits 3, 4, 5, 6, and 7) ..................................................... 51 
6.5.2.3 
Week 6 (End-of-Study/Early Termination Visit) ................................................... 52 
6.5.3 
Follow-up Period (Week 10) ..................................................................................... 53 
6.5.4 
Unscheduled Visit(s) .................................................................................................. 53 
6.5.5 
Schedule of Events and Assessments ........................................................................ 53 
7 ASSESSMENTS OF SAFETY ......................................................................................... 57 
7.1 
Specification of Safety Parameters ................................................................................ 57 
7.1.1 
Definition of Adverse Event ...................................................................................... 57 
7.1.2 
Definition of Serious Adverse Event ......................................................................... 58 
7.2 
Classification of an Adverse Event ................................................................................ 59 
7.2.1 
Severity of Event ....................................................................................................... 59 
7.2.2 
Relationship to Study Drug ....................................................................................... 59 
7.2.2.1 
Duration ................................................................................................................. 60 
7.2.2.2 
Frequency ............................................................................................................... 60 
7.2.2.3 
Action Taken with Study Drug .............................................................................. 60 
7.2.2.4 
Therapy .................................................................................................................. 60 
7.2.2.5 
Outcome ................................................................................................................. 60 
7.2.2.6 
Seriousness ............................................................................................................. 60 
7.2.3 
Definition of Unexpectedness ................................................................................... 61 
7.3 
Time Period and Frequency for Event Assessment and Follow-up ............................... 61 
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7.4 
Reporting Procedures .................................................................................................... 61 
7.4.1 
Adverse Event Reporting ........................................................................................... 61 
7.4.2 
Serious Adverse Event Reporting .............................................................................. 61 
7.4.3 
Reporting of Pregnancy ............................................................................................. 62 
7.4.4 
Reporting of Overdose ............................................................................................... 63 
7.5 
Safety Oversight ............................................................................................................ 63 
8 CLINICAL MONITORING .............................................................................................. 63 
9 STATISTICAL CONSIDERATIONS ................................................................................ 63 
9.1 
Statistical and Analytical Plans...................................................................................... 63 
9.2 
Statistical Hypotheses .................................................................................................... 63 
9.3 
Analysis Datasets ........................................................................................................... 64 
9.4 
Description of Statistical Methods ................................................................................ 64 
9.4.1 
General Approach ...................................................................................................... 64 
9.4.2 
Analysis of the Primary Efficacy Endpoint ............................................................... 65 
9.4.3 
Analysis of the Secondary Endpoints ........................................................................ 65 
9.4.3.1 
Key Secondary Endpoint ....................................................................................... 65 
9.4.3.2 
Other Secondary Endpoints and Exploratory Endpoints ....................................... 65 
9.4.4 
Safety Analyses .......................................................................................................... 67 
9.4.4.1 
Adverse Events ...................................................................................................... 67 
9.4.4.2 
Clinical Laboratory Values..................................................................................... 67 
9.4.4.3 
Vital Signs and Body Weight ................................................................................. 67 
9.4.4.4 
Electrocardiogram .................................................................................................. 67 
9.4.4.5 
Physical Examinations ........................................................................................... 68 
9.4.4.6 
Columbia Suicide Severity Rating ......................................................................... 68 
9.4.4.7 
Extrapyramidal Symptom Measures ...................................................................... 68 
9.4.5 
Confirmation of Main Antipsychotic ......................................................................... 68 
9.4.6 
Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analyses ....................... 68 
9.4.7 
Adherence and Retention Analyses ........................................................................... 68 
9.4.8 
Baseline Descriptive Statistics ................................................................................... 68 
9.4.9 
Planned Interim Analyses .......................................................................................... 69 
9.4.9.1 
Safety Review ........................................................................................................ 69 
9.4.9.2 
Efficacy Review ..................................................................................................... 69 
9.4.10 
Additional Subgroup Analyses .................................................................................. 69 
9.4.11 
Multiple Comparison/Multiplicity ............................................................................. 69 
9.4.12 
Tabulation of Individual Response Data.................................................................... 69 
9.5 
Sample Size ................................................................................................................... 69 
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9.6 
Measures to Minimize Bias ........................................................................................... 70 
9.6.1 
Enrollment/Randomization/Masking Procedures ...................................................... 70 
9.6.2 
Breaking the Study Blind/Subject Code .................................................................... 70 
10 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ... 70 
10.1 Case Report Forms and Data Verification ..................................................................... 70 
10.2 Source Documentation .................................................................................................. 71 
11 QUALITY ASSURANCE AN D QUALITY CONTROL .......................................... 71 
11.1 Quality Control and Quality Assurance ......................................................................... 71 
12 ETHICS/PROTECTION OF HUMAN SUBJECTS .................................................... 72 
12.1 Ethical Standard ............................................................................................................. 72 
12.2 Institutional Review Board/Ethics Committee .............................................................. 72 
12.3 Informed Consent Process ............................................................................................. 72 
12.3.1 
Consent and Other Informational Documents Provided to Subjects ......................... 73 
12.3.2 
Consent Procedures and Documentation ................................................................... 73 
12.4 Subject and Data Confidentiality ................................................................................... 73 
13 DATA HANDLING AND RECORD KEEPING .............................................................. 74 
13.1 Data Collection and Management Responsibilities ....................................................... 74 
13.2 Study Records Retention ............................................................................................... 74 
13.3 Protocol Exceptions and Deviations .............................................................................. 74 
13.4 Protocol Amendments.................................................................................................... 75 
13.5 Publication and Data Sharing Policy ............................................................................. 75 
14 CONFLICT OF INTEREST POLICY ............................................................................... 75 
14.1 Finance, Insurance, and Indemnity ................................................................................ 75 
15 DECLARATION OF INVESTIGATOR ........................................................................... 76 
16 LITERATURE REFERENCES ......................................................................................... 77 
17 APPENDICES ................................................................................................................... 81 
Appendix A 
Prohibited and Restricted Therapy .................................................................. 81 
Appendix B 
Prohibited and Restricted Concomitant Medications:  Inhibitors and 
Inducers of Cytochrome P450 Enzyme 3A4 ..................................................................... 84 
Appendix C 
Structured Clinical Interview – Positive and Negative Syndrome 
Scale (PANSS) ................................................................................................................... 86 
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Appendix D 
Informant Questionnaire for the Positive and Negative Syndrome Scale 
(IQ-PANSS) .......................................................................................................................105
Appendix E 
Clinical Global Impression – Severity (CGI-S) Scale ....................................125 
Appendix F 
Clinical Global Impression – Improvement (CGI-I) Scale .............................127 
Appendix G 
Personal and Social Performance Scale (PSP) ................................................129 
Appendix H 
Calgary Depression Scale for Schizophrenia (CDSS) ....................................132
Appendix I 
36-Item Short Form Health Survey (SF-36) ...................................................135 
Appendix J 
10-Item Drug Attitude Inventory (DAI-10) ....................................................141 
Appendix K 
Karolinska Sleepiness Scale (KSS) .................................................................143 
Appendix L 
Abnormal Involuntary Movement Scale (AIMS) ...........................................144 
Appendix M 
Barnes Akathisia Rating Scale (BARS) ..........................................................146 
Appendix N 
Simpson-Angus Extrapyramidal Side Effects Scale (SAS) ............................149 
Appendix O 
Columbia-Suicide Severity Rating Scale (C-SSRS) .......................................152 
 
LIST OF TABLES 
Table 5–1 
Treatment Administration Schedule for Protocol ACP-103-034 ..................... 39 
Table 6–1 
Schedule of Events and Assessments............................................................... 54 
 
LIST OF FIGURES 
Figure 3–1 
Schematic of Study Design .............................................................................. 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 
BARS 
Barnes Akathisia Rating Scale 
BMI 
body mass index 
CDSS 
Calgary Depression Scale for Schizophrenia 
CFR 
Code of Federal Regulations 
CGI-I 
Clinical Global Impression – Improvement scale 
CGI-S 
Clinical Global Impression – Severity scale 
CNS 
central nervous system 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CYP 
cytochrome P450 
CYP3A4 
CYP 3A4 enzyme 
D2 
dopamine 2 
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 
EC 
Ethics Committee 
EDC 
electronic data capture 
EOS 
End-of-Study 
ET 
Early Termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HbA1c 
glycosylated hemoglobin 
Hct 
Hematocrit 
HCV 
hepatitis C virus 
HDL 
high-density lipoprotein 
HIV 
human immunodeficiency virus 
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Abbreviation 
Definition 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IQ-PANSS 
Informant Questionnaire for the Positive and Negative Syndrome Scale 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
KSS 
Karolinska Sleepiness Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model repeated measures 
MMSE 
Mini-Mental State Examination 
ms 
Millisecond 
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 
TSH 
thyroid stimulating hormone 
UDS 
urine drug screen 
US 
United States 
WBC 
white blood cells 
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1 BACKGROUND INFORMATION 
Schizophrenia is a chronic and debilitating brain disease that affects approximately 
2.4 million adults in the United States.  The lifetime prevalence is about 1% worldwide 
(McGrath et al., 2008).  Symptoms of schizophrenia typically emerge in adolescence and 
early adulthood.  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). 
Atypical antipsychotics are currently the standard of treatment for schizophrenia.  However, a 
good proportion of patients do not achieve full control of their symptoms.  Novick et al. 
(2012), for example, found that even with adequate antipsychotic treatment 15% to 39% of 
patients experience persistent symptoms and 14% to 21% of patients who experience 
remission subsequently relapse within a 3-year period.  Individual patient response to a given 
antipsychotic cannot be predicted.  There are also some patients for whom an effective 
treatment has yet to be identified after multiple trials of medication. 
Although the atypical antipsychotics offer improved safety and tolerability compared to 
older, typical antipsychotics, safety is still an issue.  Significant weight gain leading to 
metabolic disturbances, sexual dysfunction, hyperprolactinemia, and cardiotoxicity are 
common side effects associated with some of the atypical drugs (Leucht et al., 2013).  These 
medications can induce cardiovascular and metabolic abnormalities that are associated with 
an increased risk of type 2 diabetes mellitus and cardiovascular disease (De Hert et al., 2012).  
Thus, there is a need for additional treatment options for patients with schizophrenia. 
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 
(Saeedi et al., 2006; Mehta et al., 2004; Peretti et al., 1997) and an increased risk of mortality 
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in elderly patients with dementia (Wang et al., 2005).  On the basis of its novel receptor 
binding profile, adjunctive pimavanserin may be effective in treating schizophrenia and may 
have added benefits in regard to overall tolerability relative to other antipsychotic agents. 
In April 2016, pimavanserin was approved in the United States for the treatment of 
hallucinations and delusions associated with Parkinson’s disease psychosis. 
1.2 
Previous Clinical Experience 
The clinical efficacy and safety of pimavanserin has been evaluated in a total of 21 completed 
studies.  Approximately 1300 subjects have been exposed to pimavanserin, including 
645 subjects with Parkinson’s disease, 177 subjects with schizophrenia and 346 healthy 
volunteers.  Total patient exposure in Parkinson’s disease psychosis exceeds 900 person-
years, with 172 subjects receiving treatment for at least 2 years, and 279 subjects receiving 
treatment for at least 1 year.  The longest single exposure is in a subject with over 10 years of 
continuous treatment with pimavanserin. 
Pimavanserin is considered to be generally safe and well tolerated.  In single and multiple 
dose studies in healthy volunteers, the highest doses administered were 255 mg and 136 mg, 
respectively.  Across all clinical studies of pimavanserin, the most frequently reported 
adverse events (AEs) were in the central nervous system (CNS), gastrointestinal, and 
psychiatric systems.  Most AEs were mild to moderate in intensity.  The most common CNS 
treatment-emergent adverse events (TEAEs) included dizziness (including postural), 
headache, and somnolence (drowsiness).  Common gastrointestinal disturbances included 
dyspepsia, nausea, constipation, and vomiting; severe nausea and vomiting were dose 
limiting in a few cases.  Reported psychiatric conditions included such events as agitation, 
insomnia, and confusional state. 
 
 
 
 
 
 
 
 
 
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 6-week study was to determine whether a combination of pimavanserin (17 mg once 
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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 
Period.  Subgroup analyses showed consistent trends regardless of subjects’ age, sex or 
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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).  In April 
2016 pimavanserin was approved in the United States for the treatment of hallucinations and 
delusions associated with Parkinson’s disease psychosis. 
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. 
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 
Combining pimavanserin, a selective high affinity 5-HT2A antagonist/inverse agonist with a 
currently available antipsychotic agent would be expected to improve clinical outcome by 
reducing adverse effects associated activity at both the dopamine 2 (D2) receptor and at 
nonspecific (“off target”) receptors.  Minimizing these adverse effects will help to improve 
treatment compliance and thus prevent relapse.  Moreover, since adverse consequences of 
excessive D2 receptor blockade include exacerbation of negative symptoms. 
Pimavanserin has demonstrated efficacy and tolerability as an antipsychotic in patients with 
Parkinson’s disease psychosis (Cummings et al., 2014) and there is evidence of efficacy as an 
antipsychotic in the treatment of patients with schizophrenia in combination with risperidone 
(Meltzer et al., 2012).  Observations in animal models of schizophrenia suggest that 
pimavanserin has antipsychotic effects and the ability to provide additive effects when 
coadministered with standard antipsychotics (Gardell et al., 2007; Vanover et al., 2006; 
McFarland et al., 2011; Price et al., 2012).  Clinical studies of other selective 5-HT2A 
antagonists in patients with schizophrenia have also shown promise (Ebdrup et al., 2011; 
Akhondzadeh et al., 2008; Meltzer et al, 2004; Potkin et al., 2001; Duinkerke et al., 1993). 
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. 
(ACADIA) is currently planning to pursue a new development program for pimavanserin as 
adjunctive treatment for schizophrenia. 
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2 STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Study Objectives 
2.1.1 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of adjunctive pimavanserin 
compared with adjunctive placebo in the treatment of schizophrenia 
2.1.2 
Secondary Objectives 
The secondary objectives of the study are: 
 To evaluate the safety and tolerability of adjunctive pimavanserin compared to adjunctive 
placebo in the treatment of schizophrenia 
 To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of adjunctive 
pimavanserin for the treatment of schizophrenia 
2.2 
Study Endpoints 
2.2.1 
Primary Endpoint 
 Change from Baseline to Week 6 in the Positive and Negative Syndrome Scale (PANSS) 
total score 
2.2.2 
Secondary Endpoints 
2.2.2.1 
Key Secondary Endpoint 
 Change from Baseline to Week 6 in the Clinical Global Impression – Severity scale 
(CGI-S) score 
2.2.2.2 
Other Secondary Endpoints 
 Change from Baseline to Week 6 in PANSS subscores 
 Clinical Global Impression – Improvement (CGI-I) score at Week 6 
 Proportion of responders at Week 6 according to each of the following: 
 PANSS (≥20% and ≥30% reduction in PANSS total score) 
 CGI-I (CGI-I score of 1 or 2) 
 Change from Baseline to Week 6 in Personal and Social Performance (PSP) scale score 
 Change from Baseline to Week 6 in 10-item Drug Attitude Inventory (DAI-10) score 
 Change from Baseline to Week 6 in Karolinska Sleepiness Scale (KSS) score 
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2.2.3 
Exploratory Endpoints 
 Change from Baseline to Week 6 in PANSS Marder factor scores 
 Change from Baseline to Week 6 in Calgary Depression Scale for Schizophrenia (CDSS) 
score 
 Change from Baseline to Week 6 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 3, 6-week, randomized, double-blind, placebo-
controlled, multicenter, multinational outpatient study in subjects with schizophrenia with an 
inadequate response to current antipsychotic treatment.  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 
schizophrenia and an inadequate response to antipsychotic medications across approximately 
70 study sites globally.  On the first day of the randomized treatment phase (Baseline), 
eligible subjects will be randomly assigned to receive adjunctive pimavanserin 20 mg per day 
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).  Subjects will participate in the study for up to 14 weeks, including a 
Screening Period of up to 4 weeks, a 6-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). 
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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 had a partial but inadequate response to his or her 
current antipsychotic treatment. 
Subjects must be taking an antipsychotic, which will be continued throughout the subject’s 
participation in this study.  The subject may be taking a second antipsychotic at the time of 
Screening.  If the subject is taking two antipsychotics at Screening, the Investigator will 
determine which antipsychotic is the main antipsychotic (see inclusion criterion #10 in 
Section 4.1). 
The other (second) antipsychotic must be discontinued before the subject may be considered 
eligible to receive study drug (i.e., the medication considered by the Investigator to be the 
subject’s main antipsychotic will be continued, and all other antipsychotic medications must 
be discontinued for a time period of ≥5 half-lives prior to randomization).  Considering that 
subjects had an inadequate response to the treatment regimen, the other (second) 
antipsychotic must be discontinued only if it is considered clinically appropriate in the 
opinion of the Investigator. 
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 #11 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 main antipsychotic. 
Subjects who meet the criteria for study eligibility will continue to receive their main 
antipsychotic at a stable dose for the duration of the study and will be randomly assigned to 
receive either adjunctive pimavanserin 20 mg or matching adjunctive 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 adjunctive pimavanserin 20 mg or adjunctive 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 week 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 1, 2, and 3 visits, the daily dose of adjunctive 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 3 visit, no study drug 
dose changes may be made.  Clinic visits occurring after Baseline will be conducted at Weeks 
1, 2, 3, 4, 5, and 6 (End-of-Study [EOS]/Early Termination [ET] visit). 
3.4 
Follow-up 
Subjects who successfully complete the 6-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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Figure 3–1 
Schematic of Study Design 
 
 
 
Subjects with 
schizophrenia and 
partial but inadequate 
response to treatment 
Main antipsychotic + adjunctive placebo 
Double-Blind Treatment Period 
6 weeks 
1:1 Randomization 
Main antipsychotic + adjunctive pimavanserin 
Screening Period 
Up to 4 weeks 
Determine main antipsychotic 
 
Discontinue other 
antipsychotic, if applicable 
Follow-up Period 
4 weeks 
EOS/ET* 
4-week follow-up 
(telephone call) 
*Subjects who complete the 6-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 following inclusion and none of the exclusion criteria 
(Sections 4.1 and 4.2, respectively) to be eligible for participation in the study.  Protocol 
waivers for eligibility will not be granted by the Sponsor under any circumstances.  If, during 
the course of a subject’s 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 trial, 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: 
 Male or female, ≥18 and ≤55 years of age at time of Screening 
 Able to understand and provide signed informed consent 
 Able to sign and date a request for medical records and/or subject privacy form if 
applicable according to local regulations 
 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 
 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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 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 
 Diagnosis of schizophrenia according to Diagnosis 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]) 
 Diagnosis of schizophrenia made ≥1 year prior to randomization 
 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.  The subject 
may be taking a second antipsychotic at the time of Screening. 
 If the subject is taking two antipsychotics at Screening, the Investigator will: 
 Determine which antipsychotic is the main antipsychotic 
 Discontinue the other antipsychotic at least 5 half-lives before randomization 
 Discontinue the other antipsychotic only if it is clinically appropriate; the other 
antipsychotic should not be discontinued solely to make the subject eligible for 
enrollment in the study 
 The main 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 
 Lurasidone 
 Olanzapine 
 Risperidone 
 Risperidone long-acting injection 
 Has had a partial but inadequate response to the antipsychotic treatment 
 If taking an oral antipsychotic, no dose change within 4 weeks prior to Screening or 
the Screening Period 
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 If taking a long-acting injectable antipsychotic, no dose change within 16 weeks prior 
to Screening or during the Screening Period 
 PANSS total score ≥65 and ≤110 at Screening and Baseline and there is no change in 
PANSS total score >30% from Screening to Baseline 
 PANSS score ≥4 (moderate or worse) on at least two of the following items at both 
Screening and Baseline (see Appendix C): 
 P1 (delusions) 
 P3 (hallucinatory behavior) 
 P6 (suspiciousness/persecution) 
 A CGI-S score ≥4 (moderately ill or worse) at Screening and Baseline 
 Has a history of response to antipsychotic treatment other than clozapine 
 Must be medically stable and has been medically stable for at least 12 weeks prior to 
Screening, in the opinion of the Investigator 
 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: 
 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) 
 Has a history of resistance to antipsychotic treatment, as defined by either of the 
following criteria: 
 Failed to show even minimal response to ≥2 adequate antipsychotic medications 
prescribed at adequate doses for adequate length of time; failure to tolerate a 
medication does not constitute failure to respond 
 History of treatment with clozapine for refractory psychosis or use of clozapine 
within the past 12 weeks prior to Screening 
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 Is at a significant risk of suicide, or is a danger to self or others, in the opinion of the 
Investigator 
 Has a significant risk of violent behavior in the opinion of the Investigator 
 Has met DSM-5 criteria for substance use disorders within the last 6 months prior to 
randomization (other than caffeine and/or nicotine) 
 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 
 Subject was treated with 3 or more antipsychotics, for any indication, within 8 weeks 
prior to Screening 
 Laboratory testing confirms the absence of the identified main antipsychotic 
 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) 
 Known family or personal history or symptoms of long QT syndrome 
 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 
 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 
 Has moderate to severe congestive heart failure (New York Heart Association [NYHA] 
class III and class IV) 
 Has a history of myocardial infarction within 6 months prior to enrollment. 
 Has a history of uncontrolled diabetes mellitus (DM), Type 1 or 2 DM requiring 
insulin treatment, or glycosylated hemoglobin (HbA1c) >7% at Screening 
 Has a clinically significant thyroid function test result at Screening 
 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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 Known to be positive for hepatitis C virus (HCV) or human immunodeficiency virus 
(HIV) 
 Has a body mass index (BMI) <19 or ≥35 at Screening 
 Has a history of neuroleptic malignant syndrome 
 Is breastfeeding or lactating 
 Has a significant sensitivity or allergic reaction to pimavanserin or its excipients 
 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 
 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 
 Is an employee of ACADIA, or has a family member who is an employee of ACADIA 
 Has participated in >2 pharmaceutical clinical research studies within the previous 
2 years 
 Subject is judged by the Investigator or the Medical Monitor to be inappropriate for 
the study 
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 
 At the discretion of the Sponsor 
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 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. 
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 6 (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 
 Determination of futility 
 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 adjunctive pimavanserin or 
oral adjunctive matching placebo once daily for 6 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 week of treatment. 
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Table 5–1 
Treatment Administration Schedule for Protocol ACP-103-034 
Visit Number(s) 
Once Daily Adjunctive Treatment Regimen 
Baseline (Day 1/Visit 2) 
through 
Week 1 (Visit 3) 
20 mg (2 × 10 mg tablets) pimavanserin or matching placebo 
Week 1 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 2 Visit (Visit 4) 
Week 3 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 4 Visit (Visit 6) 
Week 5 Visit (Visit 7) 
Week 6 Visit (Visit 8) 
Subjects will remain at same daily dose of study drug as they were receiving at 
Week 3 visit. 
No dose modifications are allowed after the Week 3 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 6 
(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 main antipsychotic are not permitted after 
Screening. 
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 
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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 adjunctive pimavanserin 20 mg per day or daily adjunctive 
placebo according to a computer-generated randomization schedule.  Subjects will be 
randomized in a 1:1 ratio to 1 of 2 treatment groups (adjunctive pimavanserin 20 mg or 
adjunctive 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 10 [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 should be followed between the initial Screening 
visit and Visit 8 (Week 6 [EOS/ET]) visit as specified in Appendix A and Appendix B.  These 
appendices do not constitute an exhaustive list and any questions regarding prohibited and 
restricted medications should be discussed with the Medical Monitor or 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.  The metabolism 
of pimavanserin is affected by strong CYP3A4 inhibitors, resulting in a 3-fold increase in 
exposure.  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 PANSS is only to be administered by site personnel certified as qualified to administer 
the scale.  All administrations of the PANSS 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 
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 C. 
6.1.2 
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 D. 
6.1.3 
Clinical Global Impression – Severity Scale 
The CGI-S is a clinician-rated, 7-point scale that is designed to rate the severity of the 
subject's illness, in this case schizophrenia, at the time of assessment, making use of the 
clinician’s judgment and past experience with subjects who have the same disorder 
(Guy 1976a).  A sample CGI-S is provided in Appendix E. 
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6.1.4 
Clinical Global Impression – Improvement Scale 
The CGI-I is a clinician-rated, 7-point scale that is designed to assess how much the subject’s 
illness has improved or worsened relative to a baseline state at the beginning of the 
intervention (Guy 1976a).  A sample of the CGI-I is provided in Appendix F. 
6.1.5 
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 G. 
6.1.6 
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 H. 
6.1.7 
36-Item Short Form Health Survey 
The SF-36 is a 36-item survey that measures the overall health status of a subject (McHorney 
et al., 1994).  The SF-36 assesses eight health concepts.  The scores are weighted sums of the 
questions in each section.  Scores range from 0 to 100 where lower scores indicate greater 
disability, higher scores indicate less disability.  In this study, the SF-36 will be administered 
by a trained interviewer. 
A sample of the SF-36 is provided in Appendix I. 
6.1.8 
10-Item Drug Attitude Inventory 
The DAI-10 is a modified version of the original 30-item Drug Attitude Inventory (Hogan 
et al., 1983).  It is a true-false questionnaire that assesses attitude, experience, and beliefs 
about antipsychotics in subjects diagnosed with schizophrenia.  The items on this 
questionnaire have 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 J. 
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6.1.9 
Karolinska Sleepiness Scale 
The KSS is a 9-item, self-reported subjective measure of a subject's level of drowsiness 
(Akerstedt 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 K. 
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 
L), Barnes Akathisia Rating Scale (BARS; see Appendix M), and the Simpson-Angus 
Extrapyramidal Side Effects Scale (SAS; see Appendix N). 
In addition, the Columbia Suicide Severity Rating Scale (C-SSRS; see Appendix O) will be 
used to assess suicidal ideations and behaviors. 
6.2.1 
Abnormal Involuntary Movement Scale 
The AIMS is a 12-item, physician-administered scale that measures involuntary 
movements known as tardive dyskinesia and aids in the early detection of tardive dyskinesia 
(Lane et al., 1985).  It assesses severity of dyskinesias (orofacial movements and extremity 
and truncal movements).  Additional items assess the overall severity, incapacitation, and the 
subject’s level of awareness of the movements, and associated distress. 
A sample of the AIMS (Guy 1976b) is provided in Appendix L . 
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 M. 
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 
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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 N. 
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 O. 
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 physical examination will be conducted at Screening, Baseline, and Week 6 (EOS/ET).  
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 1, 2, 3, 4, 5, 
and 6 (EOS/ET).  At Baseline, vital signs must be measured before study drug is given. 
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6.3.5 
Height and Weight 
Height will be measured at Screening only.  Weight will be measured at Screening, Baseline 
(Day 1), and Week 6 (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 4, and at the Week 6 (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. 
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 6 (EOS/ET visit).  Pregnancy tests will be performed for all women. 
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 
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 Total cholesterol, high-density lipoprotein (HDL)-cholesterol, 
triglycerides, low-density lipoprotein-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 identified 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 
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 Week 6 (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 
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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 
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 PANSS 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 main antipsychotic throughout the double-blind Treatment 
Period.  Adjustments in the dose of the main 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. 
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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 had a partial but inadequate response to his or her 
current antipsychotic treatment. 
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 virology history (for any history of HIV, hepatitis B, or HCV) 
 Physical examination 
 Vital signs (sitting [at least 3 minutes] blood pressure, pulse, respiratory rate, and 
temperature) 
 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 (UDS) 
 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-S, and CDSS 
 C-SSRS (Baseline/Screening version) 
 Review of current medications/treatments 
 Interview of subject by an independent clinician 
 Assessment of AEs 
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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) 
 PANSS (including the caregiver reported IQ-PANSS), CGI-S, PSP, 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 1, 2, 3, 4, and 5 (Visits 3, 4, 5, 6, and 7) 
Subjects will have the following procedures completed at each visit (unless otherwise 
indicated): 
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 Vital signs (sitting [at least 3 minutes] blood pressure, pulse, respiratory rate, and 
temperature) 
 12-lead ECG (Week 4 only, single recording) 
 PK blood draw (Week 1 and Week 3 only) 
 PANSS (including the caregiver reported IQ PANSS), CGI-S, and CGI-I 
 KSS 
 C-SSRS (Since Last Visit version) 
 AIMS, BARS, and SAS (Week 1 and Week 3 only) 
 Assessment of concomitant medications/procedures 
 Assessment of AEs 
 Study drug dispensing and accountability 
6.5.2.3 
Week 6 (End-of-Study/Early Termination Visit) 
Subjects will have the following procedures completed at the EOS/ET visit: 
 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 
 PANSS (including the caregiver reported IQ PANSS), CGI-S, CGI-I, PSP, 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. 
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6.5.3 
Follow-up Period (Week 10) 
A 4-week safety follow-up telephone contact is to be completed for subjects who complete 
the study and decide not to continue into the open-label study or are not eligible for the open-
label study, as well as 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, 
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 1
Week 2
Week 3 Week 4 Week 5
Week 6
Week 10
Allowable visit window (# days)
±3
±3
±3
±3
±3
±3
+7
Informed consentc 
X 
Inclusion/exclusion criteria 
X 
X 
Medical historyd and demographics 
X 
Schizophrenia disease history 
X 
SCID-5-CT customized module 
X 
Interview by an independent cliniciane 
X 
Physical examinationf 
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 
PK blood drawsl 
X 
X 
X 
X 
Pharmacogenomic blood drawsm 
X 
PANSS and IQ-PANSS 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-S 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-I 
X 
X 
X 
X 
X 
X 
PSP 
X 
X 
CDSS 
X 
X 
X 
SF-36 
X 
X 
DAI-10 
X 
X 
KSS 
X 
X 
X 
X 
X 
X 
X 
C-SSRSn
X 
X 
X 
X 
X 
X 
X 
X 
AIMS 
X 
X 
X 
X 
BARS 
X 
X 
X 
X 
SAS 
X 
X 
X 
X 
Assessment of concomitant medications 
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 
Footnotes for Table 6–1 on next page
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Abbreviations:  AIMS = Abnormal Involuntary Movement Scale; BARS = Barnes Akathisia Rating Scale; CDSS = Calgary Depression Scale for Schizophrenia; 
CGI-I = Clinical Global Impression-Improvement; CGI-S = Clinical Global Impression-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; 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.  The window for the Follow-up visit 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 Baseline 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
Physical examinations may include a review of body systems (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 4, and at the Week 6 
(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. 
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 approx. 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. 
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. 
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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 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: 
ACADIA US Fax Toll Free Number:
 
Other country-specific toll-free fax numbers will be provided 
ACADIA email:  
 
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 6 in the PANSS total score between the adjunctive pimavanserin and adjunctive 
placebo treatment groups. 
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 The alternative hypothesis is that there is a difference in the mean change 
from Baseline to Week 6 PANSS total score between the adjunctive 
pimavanserin and adjunctive 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 6 CGI-S score between the adjunctive pimavanserin and adjunctive placebo 
treatment groups. 
 The alternative hypothesis is that there is a difference in the mean change 
from Baseline to Week 6 CGI-S score between the adjunctive 
pimavanserin and adjunctive placebo treatment groups. 
9.3 
Analysis Datasets 
The safety analysis set includes all randomized subjects who received at least one dose of 
study drug (adjunctive pimavanserin or adjunctive 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 PANSS 
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 
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and quality control of the tables, listings and figures containing the results of the statistical 
analyses will follow appropriate standard operating procedures. 
9.4.2 
Analysis of the Primary Efficacy Endpoint 
The primary endpoint is the change from Baseline to Week 6 in the PANSS 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 PANSS total score will be analyzed using mixed model repeated measures (MMRM).  
The dependent variable will be the change from Baseline in the PANSS total score.  The 
independent variables in the model will include the following:  treatment group (adjunctive 
pimavanserin or adjunctive placebo), visit (Week 1, Week 2, Week 3, Week 4, Week 5, and 
Week 6), the treatment-by-visit interaction, geographic region (North America, Europe, or 
rest of world), the Baseline PANSS total score, and the Baseline-by-visit interaction.  The 
treatment comparison will be based on the difference in least squares means at Week 6 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 6 timepoint, the treatment 
groups will also be compared at each of the other timepoints (Weeks 1, 2, 3, 4, and 5) 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 6 in the CGI-S score.  The 
change from Baseline in the CGI-S score will be analyzed using an MMRM model similar to 
that described above for the primary endpoint, except that the Baseline CGI-S score will be 
included in the model instead of the Baseline PANSS total score.  The treatment comparison 
will be based on the difference in least squares means at Week 6 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 6 in PANSS subscores (positive scale, negative scale, and 
general psychopathology scale) 
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 Proportion of PANSS responders (≥20% and ≥30% reduction in PANSS total score) at 
Week 6 
 Proportion of CGI-I responders (CGI-I score of 1 or 2) at Week 6 
 CGI-I score at Week 6 
 Change from Baseline to Week 6 in PSP score 
 Change from Baseline to Week 6 in DAI-10 score 
 Change from Baseline to Week 6 in KSS score 
Exploratory endpoints are the following: 
 Change from Baseline to Week 6 in PANSS Marder factor scores (negative symptoms, 
positive symptoms, disorganized thought, uncontrolled hostility/excitement, and 
anxiety/depression factors) 
 Change from Baseline to Week 6 in CDSS score 
 Change from Baseline to Week 6 in SF-36 score 
The change from Baseline to each post-Baseline timepoint in the PANSS subscores, the 
PANSS Marder factor scores (see Appendix C) 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 PANSS total score. 
The CGI-I score at each post-Baseline timepoint will be analyzed using an MMRM model.  
The dependent variable will be the CGI-I score.  The independent variables in the model will 
include the following:  treatment group (adjunctive pimavanserin or adjunctive placebo), visit 
(Week 1, Week 2, Week 3, Week 4, Week 5, and Week 6), the treatment-by-visit interaction, 
geographic region (North America, Europe, or rest of world), the Baseline CGI-S score, and 
the Baseline-by-visit interaction. 
The change from Baseline to Week 6 or early termination in the PSP, DAI-10, CDSS, and 
SF-36 scores will be analyzed using an analysis of covariance (ANCOVA) model with effects 
for treatment group (adjunctive pimavanserin or adjunctive placebo) and geographic region 
(North America, Europe, or rest of world), and the Baseline value of the endpoint being 
analyzed as a covariate. 
The proportion of subjects with ≥20% reduction in the PANSS total score, the proportion of 
subjects with ≥30% reduction in the PANSS total score, and the proportion of subjects with a 
CGI-I score of 1 or 2 will be summarized at each timepoint.  The treatment groups will be 
compared using a Cochran-Mantel-Haenzel test stratified by geographic region (North 
America, Europe, or rest of world).  Since PANSS is an interval scale that lacks a natural 
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zero point (possible scores range from 30 to 210), the percent change in PANSS total score 
will be calculated based on corrected scores after subtracting 30 points from the raw scores. 
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 AEs 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 TEAEs, 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 6 
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 6 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 Baseline and each post-baseline visit by treatment group.  
Body weight only will be measured at Baseline and Week 6 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, Week 4, and Week 6 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. 
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9.4.4.5 
Physical Examinations 
The results of the physical examinations at each visit (Screening, Baseline, and Week 6) will 
be tabulated by treatment group. 
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 of absence of the identified 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) 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 the 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 
One interim analysis to assess futility based on the primary endpoint will be conducted by an 
independent statistician when 152 subjects (40% of the planned sample size) complete the 
Week 6 visit or discontinue from the study.  If the adjunctive pimavanserin arm meets the 
futility criteria then the study may be terminated.  The futility criteria will be pre-specified in 
the interim analysis plan before the interim analysis is conducted.  The study will not be 
stopped early for efficacy and therefore the Type 1 error rate will not be inflated.  
Investigators and Sponsor personnel will remain blinded throughout the 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 PANSS total score from Baseline to 
Week 6 is 6.0 points between the adjunctive pimavanserin group and the adjunctive placebo 
group, and the common standard deviation is 17.0 points, 171 evaluable subjects per 
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treatment group will provide at least 90% power to detect a difference between the adjunctive 
pimavanserin group and the adjunctive 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. 
9.6 
Measures to Minimize Bias 
9.6.1 
Enrollment/Randomization/Masking Procedures 
Eligible subjects will be randomized into 1 of 2 treatment groups (adjunctive pimavanserin or 
adjunctive 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 adjunctive pimavanserin and adjunctive 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 the futility analysis and 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 (adjunctive pimavanserin 
or adjunctive 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 
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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 
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 AN D 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. 
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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. 
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 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 
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Investigator (or designee) together with the protocol, to the appropriate IRB/EC for review 
and approval prior to the start of the study at that investigational site.  Consent forms must be 
in a language fully comprehensible to the prospective subject.  The Investigator must provide 
the Sponsor (or designee) with a copy of the IRB/EC letter approving the protocol and the 
ICF(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, 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 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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Schizophr Res. 1990; 3(4):247-251. 
Addington D, Addington J, Maticka-Tyndale E, Joyce J. Reliability and validity of a 
depression rating scale for schizophrenics. Schizophr Res. 1992;6(3):201-208. 
Åkerstedt T, Gillberg M. Subjective and objective sleepiness in the active individual. Int J 
Neurosci. 1990;52(1-2):29-37.  
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. 
2008;12;32(8):1879-1883. 
Awad AG. Subjective response to neuroleptics in schizophrenia. Schizophr Bull. 
1993;19(3):609-618. 
Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989;154:672-676. 
Cummings J, Isaacson S, Mills R, et al. Pimavanserin for patients with Parkinson's disease 
psychosis: a randomised, placebo-controlled phase 3 trial. Lancet. 2014;383(9916):533-540. 
De Hert M, Detraux J, van Winkel R, Yu W, Correll CU. Metabolic and cardiovascular 
adverse effects associated with antipsychotic drugs. Nat Rev Endocrinol. 2012;8(2):114-126  
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. 
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. 
Gardell LR, Vanover KE, Pounds L, et al. ACP-103, a 5-hydroxytryptamine 2A receptor 
inverse agonist, improves the antipsychotic efficacy and side-effect profile of haloperidol and 
risperidone in experimental models. J Pharmacol Exp Ther. 2007;322(2):862-870. 
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. 
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Guy W. Clinical Global Impressions. In: ECDEU Assessment Manual for 
Psychopharmacology —Revised (DHEW publication number ADM 76–338). Rockville, MD, 
U.S. Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug 
Abuse, and Mental Health Administration, NIMH Psychopharmacology Research Branch, 
Division of Extramural Research Programs, 1976a, 218–222. 
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, 1976b: 534–537. 
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. 
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. 
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. 
Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 
antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 
2013;382(9896):951-962. 
McFarland K, Price DL, Bonhaus DW. Pimavanserin, a 5-HT2A inverse agonist, reverses 
psychosis-like behaviors in a rodent model of Parkinson's disease. Behav Pharmacol. 
2011;22(7):681-692. 
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. 
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Meltzer HY, Arvanitis L, Bauer D, Rein W; Meta-Trial Study Group. Placebo-controlled 
evaluation of four novel compounds for the treatment of schizophrenia and schizoaffective 
disorder. Am J Psychiatry. 2004;161(6):975-984.
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):213-24.
Novick D, Haro JM, Hong J, et al. Regional differences in treatment response and three year 
course of schizophrenia across the world. J Psychiatr Res. 2012;46(7):856-864. 
Opler LA, Ramirez PM. Informant Questionnaire for the Positive and Negative Syndrome 
Scale (IQ-PANSS). North Tonawanda, NY: Multi-Health Systems Publications, Inc. 2009.
Peretti CS, Danion JM, Kauffmann-Muller F, Grangé D, Patat A, Rosenzweig P. Effects of 
haloperidol and amisulpride on motor and cognitive skill learning in healthy volunteers. 
Psychopharmacology (Berl). 1997;131(4):329-338.
Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry. 2011;168(12):1266-1277.
Potkin SG, Shipley J, Bera RB, et al. Clinical and PET effects of M100907, a selective 
5-HT-2A receptor antagonist. Schizophr Res. 2001;49(Suppl 1):242.
Price DL, Bonhaus DW, McFarland K. Pimavanserin, a 5-HT2A receptor inverse agonist, 
reverses psychosis-like behaviors in a rodent model of Alzheimer's disease. Behav 
Pharmacol. 2012;23(4):426-433.
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.
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Simpson GM, Angus JW. A rating scale for extrapyramidal side-effects. Acta Psychiatr Scand 
Suppl. 1970;212:11-19.
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 
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 
Stimulants 
 
methylphenidate 
 
Prohibited at study entry and throughout the 
study 
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Medication Class 
Examples* 
Prohibitions/Restrictions 
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 
 
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 
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Medication Class 
Examples* 
Prohibitions/Restrictions 
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). 
Page 85 of 158


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Appendix C 
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 
Page 86 of 158


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Appendix D 
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.
 
 
Page 105 of 158


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Appendix E 
Clinical Global Impression – Severity (CGI-S) Scale 
Source: 
Adapted from Guy W. ECDEU Assessment Manual for Psychopharmacology. US 
Department of Health, Education, and Welfare publication (ADM) 76-338. Rockville, MD: 
National Institute of Mental Health; 1976. 
Page 125 of 158


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Appendix F 
Clinical Global Impression – Improvement (CGI-I) Scale 
Source: 
Reproduced from Guy W, editor. ECDEU Assessment Manual for Psychopharmacology. 
1976. Rockville, MD, U.S. Department of Health, Education, and Welfare 
Page 127 of 158


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Appendix G 
Personal and Social Performance Scale (PSP) 
Source:  Nasrallah et al. 2008 
Page 129 of 158


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Appendix H 
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. 
Page 132 of 158


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Appendix I 
36-Item Short Form Health Survey (SF-36) 
Source:  McHorney et al. 1994 
Page 135 of 158


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Appendix J 
10-Item Drug Attitude Inventory (DAI-10) 
Source:  Hogan et al. 1983 
Page 141 of 158


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Appendix K 
Karolinska Sleepiness Scale (KSS) 
 
 
 
 
 
 
 
 
 
 
Source:  Åkerstedt et al. 1990 
Page 143 of 158


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Appendix L 
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 
Page 144 of 158


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Appendix M 
Barnes Akathisia Rating Scale (BARS) 
Source:  Barnes, 1989 
Page 146 of 158


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Appendix N 
Simpson-Angus Extrapyramidal Side Effects Scale (SAS) 
Source:  Simpson et al. 1970 
Page 149 of 158


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Appendix O 
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, 
 
 
©2008 The Research Foundation for Mental Hygiene, Inc. 
Page 152 of 158

SAP_001.pdf: 
Official Title: A Phase 3, randomized, double-blind, placebo-controlled study to 
evaluate the efficacy and safety of adjunctive pimavanserin for the treatment of 
schizophrenia 
NCT Number: NCT02970292 


 
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STATISTICAL ANALYSIS PLAN 
 
Protocol No.: 
ACP-103-034 
Protocol Title: 
A Phase 3, Randomized, Double-Blind, Placebo-
Controlled Study to Evaluate the Efficacy and Safety 
of Adjunctive Pimavanserin for the Treatment of 
Schizophrenia 
Drug: 
Pimavanserin 
Sponsor:  
ACADIA Pharmaceuticals Inc. 
 
 
Version No. and Date 
Version 1.0, 01 June 2018 
 
 
 
 
 
 
 
 
 


Protocol ACP-103-034 
Statistical Analysis Plan 
SIGNATURE/APPROVAL PAGE 
AUTHOR 
Senior Director, Biostatistics, Biometrics 
ACADIA Pharmaceuticals Inc. 
Senior Vice President, Clinical Development and Chief Medical Officer 
ACADIA Phannaceuticals Inc. 
Vice President, Clinical Development 
ACADIA Phannaceuticals Inc. 
ACADIA Phannaceuticals Inc. 
Executive Director, Biostatistics and SAS Programming 
ACADIA Phannaceuticals Inc. 
Date 
Date 
Date 
Date 
Version 1.0 
01June2018 
01 .::TUN .2018' 
Date 
Confidential and Proprietary Information of ACADIA Phamiaceuticals Inc. 
Page 2 of 57 


Protocol ACP-103-034 
Version 1.0 
Statistical Analysis Plan 
01 June 2018 
 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ........................................................................................................... 3 
LIST OF TABLES ..................................................................................................................... 6 
LIST OF FIGURES ................................................................................................................... 6 
ABBREVIATIONS .................................................................................................................... 7 
1 INTRODUCTION ............................................................................................................... 9 
2 OBJECTIVES ...................................................................................................................... 9 
2.1 
Primary Objective ............................................................................................................ 9 
2.2 
Secondary Objective ........................................................................................................ 9 
3 STUDY DESIGN ................................................................................................................. 9 
3.1 
General Study Design ...................................................................................................... 9 
3.2 
Schedule of Assessments ............................................................................................... 12 
3.3 
Randomization ............................................................................................................... 15 
3.4 
Blinding ......................................................................................................................... 15 
3.5 
Determination of Sample Size ....................................................................................... 15 
4 ANALYSIS SETS .............................................................................................................. 15 
5 DATA HANDLING CONVENTIONS .............................................................................. 16 
5.1 
General Data Reporting Conventions ............................................................................ 16 
5.2 
Derived Variables........................................................................................................... 17 
5.2.1 
Positive and Negative Syndrome Scale (PANSS) ..................................................... 17 
5.2.2 
Clinical Global Impressions – Severity (CGI-S) Scale ............................................. 19 
5.2.3 
Clinical Global Impressions – Improvement (CGI-I) Scales .................................... 20 
5.2.4 
Personal and Social Performance Scale (PSP) .......................................................... 20 
5.2.5 
Drug Attitude Inventory (DAI-10) ............................................................................ 20 
5.2.6 
Karolinska Sleepiness Scale (KSS) ........................................................................... 21 
5.2.7 
Calgary Depression Scale for Schizophrenia (CDSS) ............................................... 21 
5.2.8 
36-Item Short Form Health Survey (SF-36) .............................................................. 21 
5.2.9 
Columbia-Suicide Severity Rating Scale (C-SSRS) ................................................. 24 
5.2.10 
Abnormal Involuntary Movement Scale (AIMS) ...................................................... 25 
5.2.11 
Barnes Akathisia Scale (BARS) ................................................................................ 26 
5.2.12 
Simpson Angus Extrapyramidal Side Effect Scale (SAS) ......................................... 26 
5.3 
Analysis Visit Windows ................................................................................................. 26 
5.3.1 
Unscheduled Assessments ......................................................................................... 27 


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5.3.2 
Multiple Measurements within Visit Windows ......................................................... 27 
5.4 
Missing or Incomplete Date for Last Dose of Study Drug ............................................ 27 
5.5 
Missing or Incomplete Dates for Prior or Concomitant Medications ........................... 28 
5.6 
Missing or Incomplete Dates for Adverse Events ......................................................... 28 
5.7 
Missing Severity Assessment for Adverse Events ......................................................... 28 
5.8 
Missing Relationship to Study Drug for Adverse Events .............................................. 28 
5.9 
Character Values of Clinical Laboratory Variables ....................................................... 28 
5.10 Duplicate Subjects ......................................................................................................... 29 
6 SUBJECT DISPOSITION ................................................................................................. 29 
7 PROTOCOL DEVIATIONS .............................................................................................. 30 
8 DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS .......................... 30 
9 MEDICAL HISTORY ....................................................................................................... 31 
10 EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE ................................... 31 
10.1 Exposure to Study drug ................................................................................................. 31 
10.2 Measurement of Treatment Compliance ........................................................................ 32 
11 PRIOR, CONCOMITANT AND POST-TREATMENT MEDICATION .......................... 32 
12 EFFICACY ANALYSES ................................................................................................... 32 
12.1 Efficacy Variables .......................................................................................................... 33 
12.2 Adjustment for Covariates ............................................................................................. 33 
12.3 Handling of Missing Data .............................................................................................. 34 
12.4 Multiple Comparisons / Multiplicity ............................................................................. 34 
12.5 Examination of Subgroups ............................................................................................ 34 
13 METHODS OF EFFICACY ANALYSES ........................................................................ 35 
13.1 Primary Efficacy Analysis ............................................................................................. 35 
13.1.1 
Primary Analysis using MMRM in the Full Analysis Set ......................................... 35 
13.1.2 
Sensitivity Analysis using MMRM in the Per-Protocol Analysis Set ....................... 37 
13.1.3 
Sensitivity Analysis using ANCOVA with Missing Data Imputed Using Pattern-
Mixture Models with Placebo-Based Multiple Imputation ....................................... 37 
13.1.4 
Sensitivity Analysis using Van Elteren Test in the Full Analysis Set ........................ 39 
13.1.5 
Complete Case Analysis using ANCOVA in the Full Analysis Set ........................... 40 
13.2 Key Secondary Efficacy Analysis ................................................................................. 40 
13.3 Other Secondary Efficacy Analyses .............................................................................. 40 
13.3.1 
Responder Analysis ................................................................................................... 40 


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13.3.2 
Other Secondary Efficacy Analysis for Continuous Variables .................................. 42 
13.4 Exploratory Efficacy Analyses ...................................................................................... 43 
14 SAFETY ANALYSES ....................................................................................................... 43 
14.1 Adverse Events .............................................................................................................. 43 
14.2 Clinical Laboratory Variables ........................................................................................ 44 
14.3 Vital Signs ...................................................................................................................... 48 
14.4 Electrocardiogram (ECG) .............................................................................................. 49 
14.5 Physical Examination .................................................................................................... 50 
14.6 Other Safety Variables ................................................................................................... 51 
14.6.1 
Suicidality .................................................................................................................. 51 
14.6.2 
Extrapyramidal Symptom Measures ......................................................................... 51 
15 CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES ........ 52 
16 UNBLINDED INTERIM ANALYSIS .............................................................................. 53 
17 DATA MONITORING/REVIEW COMMITTEE ............................................................. 54 
18 COMPUTER METHODS ................................................................................................. 54 
19 CHANGES TO ANALYSES SPECIFIED IN PROTOCOL ............................................. 55 
20 REFERENCES .................................................................................................................. 56 
21 APPENDICES ................................................................................................................... 57 
21.1 Summary of Version Changes ....................................................................................... 57 
 


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LIST OF TABLES 
Table 1 
Schedule of Events and Assessments............................................................... 13 
Table 2 
SF-36 Re-Coding Rules for Individual Items .................................................. 22 
Table 3 
SF-36 Scale Components ................................................................................. 23 
Table 4 
Analysis Visit Windows ................................................................................... 27 
Table 5 
Criteria for Potentially Clinically Important Laboratory Values – 
Hematology and Chemistry ............................................................................. 47 
Table 6 
Criteria for Potentially Clinically Important Laboratory Values - 
Urinalysis ......................................................................................................... 48 
Table 7 
Criteria for Potentially Clinically Important Vital Signs ................................. 49 
Table 8 
Criteria for Potentially Clinically Important ECG Values ............................... 50 
 
LIST OF FIGURES 
Figure 1 
Schematic of Study Design .............................................................................. 11 
 


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ABBREVIATIONS 
AE 
adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
ANCOVA 
analysis of covariance 
ATC 
Anatomical Therapeutic Chemical 
BARS 
Barnes Akathisia Rating Scale 
BLQ 
below the limit of quantification 
BMI 
body mass index 
CDSS 
Calgary Depression Scale for Schizophrenia 
CGI-I 
Clinical Global Impression – Improvement scale 
CGI-S 
Clinical Global Impression – Severity scale 
CMH 
Cochran-Mantel-Haenszel 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DAI-10 
10-item Drug Attitude Inventory 
DSMB 
Data and Safety Monitoring Board 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition  
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOS 
End-of-Study 
ET 
Early Termination 
IRT 
interactive response technology 
KSS 
Karolinska Sleepiness Scale 
LOCF 
last observation carried forward 
MAR 
missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model for repeated measures 
MNAR 
missing not at random 
msec 
milliseconds 
OC 
observed cases 
PANSS 
Positive and Negative Syndrome Scale 
PCI 
potentially clinically important 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PMM 
pattern mixture model 
PSP 
Personal and Social Performance scale 
QTcB 
QT interval corrected for heart rate using Bazett’s formula 


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QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Simpson-Angus Extrapyramidal Side Effects Scale 
SAS® 
Statistical Analysis System 
SD 
standard deviation 
SE 
standard error 
SF-36 
36-item Short Form Health Survey 
SOC 
system organ class 
TEAE   
treatment-emergent adverse event 


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1 INTRODUCTION 
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the 
statistical analyses of efficacy and safety data as described in the final study protocol 
Amendment 2 dated 30MAR2017. Specifications for tables, figures, and listings are 
contained in a separate document. Statistical analyses for population pharmacokinetic (PK) 
and PK/pharmacodynamics (PD) modeling will be presented in a separate report and 
therefore will not be included in this SAP. 
For the Czech Republic, a country-specific protocol amendment (Amendment 2-CZ finalized 
31 January 2018) specifies additional electrocardiogram (ECG) procedures to be conducted 
only at clinical sites within the Czech Republic.  For subjects enrolled at these sites, ECGs 
will be measured at all visits instead of the schedule given in protocol Amendment 2. 
2 OBJECTIVES 
2.1 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of adjunctive pimavanserin 
compared with adjunctive placebo in the treatment of schizophrenia. 
2.2 
Secondary Objective 
The secondary objectives of the study are:  
 To evaluate the safety and tolerability of adjunctive pimavanserin compared to adjunctive 
placebo in the treatment of schizophrenia 
 To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of adjunctive 
pimavanserin for the treatment of schizophrenia 
3 STUDY DESIGN 
3.1 
General Study Design 
This study will be conducted as a Phase 3, 6-week, randomized, double-blind, placebo-
controlled, multicenter, multinational outpatient study in subjects with schizophrenia with an 
inadequate response to current antipsychotic treatment. 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 
schizophrenia and an inadequate response to antipsychotic medications across approximately 


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70 study sites globally. On the first day of the randomized treatment phase (Baseline), 
eligible subjects will be randomly assigned to receive adjunctive pimavanserin 20 mg (free 
base) per day 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). Subjects will participate in the study for up to 
14 weeks, including a Screening Period of up to 4 weeks, a 6-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). 
Study drug will remain at 20 mg/day dose level for the first week 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 1, 2, and 3 visits, the daily dose of adjunctive 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 3 visit, no study drug 
dose changes may be made. Clinic visits occurring after Baseline will be conducted at Weeks 
1, 2, 3, 4, 5, and 6 (End-of-Study [EOS]/Early Termination [ET] visit). 
Figure 1 illustrates the study design. 


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Figure 1 
Schematic of Study Design 
 
 
 
Subjects with 
schizophrenia and 
partial but inadequate 
response to treatment 
Main antipsychotic + adjunctive placebo 
Double-Blind Treatment Period 
6 weeks 
 
1:1 Randomization 
Main antipsychotic + adjunctive pimavanserin  
Screening Period 
Up to 4 weeks 
Determine main antipsychotic 
 
Discontinue other 
antipsychotic, if applicable 
Follow-up Period 
4 weeks 
EOS/ET*      
4-week follow-up 
(telephone call) 
*Subjects who complete the 6-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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3.2 
Schedule of Assessments 
The schedule of events and assessments for the study is presented in Table 1. 


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Table 1 
Schedule of Events and Assessments 
Period 
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 1 Week 2 Week 3 Week 4 Week 5 
Week 6 
Week 10 
Allowable visit window (# days) 
 
 
3 
3 
3 
3 
3 
3 
+7 
Informed consentc 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
Medical historyd and demographics 
X 
 
 
 
 
 
 
 
 
Schizophrenia disease history 
X 
 
 
 
 
 
 
 
 
SCID-5-CT customized module 
X 
 
 
 
 
 
 
 
 
Interview by an independent cliniciane 
X 
 
 
 
 
 
 
 
 
Physical examinationf 
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 
 
PK blood drawsl 
 
X 
X 
 
X 
 
 
X 
 
Pharmacogenomic blood drawsm 
 
X 
 
 
 
 
 
 
 
PANSS and IQ-PANSS 
X 
X 
X 
X 
X 
X 
X 
X 
 
CGI-S 
X 
X 
X 
X 
X 
X 
X 
X 
 
CGI-I 
 
 
X 
X 
X 
X 
X 
X 
 
PSP 
 
X 
 
 
 
 
 
X 
 
CDSS 
X 
X 
 
 
 
 
 
X 
 
SF-36 
 
X 
 
 
 
 
 
X 
 
DAI-10 
 
X 
 
 
 
 
 
X 
 
KSS 
 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRSn 
X 
X 
X 
X 
X 
X 
X 
X 
 
AIMS 
 
X 
X 
 
X 
 
 
X 
 
BARS 
 
X 
X 
 
X 
 
 
X 
 
SAS 
 
X 
X 
 
X 
 
 
X 
 
Assessment of concomitant medications 
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 
 
Footnotes for Table 1 on next page: 


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Abbreviations:  AIMS = Abnormal Involuntary Movement Scale; BARS = Barnes Akathisia Rating Scale; CDSS = Calgary Depression Scale for Schizophrenia; CGI-I 
= Clinical Global Impression-Improvement; CGI-S = Clinical Global Impression-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; 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. The window for the Follow-up visit 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 Baseline 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 
Physical examinations may include a review of body systems (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 4, and at the Week 6 
(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.  
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 approx. 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 the Baseline and Week 6 
visits for all female subjects. 
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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3.3 
Randomization 
Eligible subjects will be randomized into 1 of 2 treatment groups (adjunctive pimavanserin or 
adjunctive 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. 
3.4 
Blinding 
This is a double-blind study. 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 adjunctive pimavanserin and adjunctive placebo treatments. Neither 
the subjects nor the study personnel at the clinical sites will know which treatment is 
administered to each subject. 
3.5 
Determination of Sample Size 
The primary efficacy endpoint is the change from Baseline to Week 6 in the Positive and 
Negative Syndrome Scale (PANSS) total score. 
Let Δ be the difference in the mean change from Baseline to Week 6 in the PANSS total score 
between the adjunctive pimavanserin and the adjunctive placebo groups: 
The null hypothesis for the primary efficacy endpoint is:  
 
Δ = 0 
The alternative hypothesis for the primary efficacy endpoint is:  
Δ ≠ 0 
Assuming the true difference in the mean change in the PANSS total score from Baseline to 
Week 6 is 6.0 points between the adjunctive pimavanserin group and the adjunctive placebo 
group, and the common standard deviation is 17.0 points, 171 evaluable subjects per 
treatment group will provide at least 90% power to detect a difference between the adjunctive 
pimavanserin group and the adjunctive 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. 
4 ANALYSIS SETS 
Randomized Analysis Set 
The Randomized Analysis Set will consist of all unique subjects who were randomized. 


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Note that if there are duplicate subjects (see Section 5.10 for details), only the identity under 
the first enrollment will be included in the Randomized Analysis Set. 
Subjects will be classified according to the randomized treatment assignment. 
Safety Analysis Set 
The Safety Analysis Set will consist of a subset of subjects in the Randomized Analysis Set 
who received at least one dose of study drug. 
Subjects will be classified according to the actual treatment received.  
Full Analysis Set 
The Full Analysis Set will consist of a subset of subjects in the Safety Analysis Set who have 
both a Baseline value and at least one post-Baseline value for the PANSS total score. 
Subjects will be classified according to the randomized treatment assignment. 
Per-protocol Analysis Set 
The Per-protocol Analysis Set will consist of a subset of subjects in the Full Analysis Set who 
are at least 80% compliant (based on drug accountability) and without any protocol deviation 
which is considered to have substantial impact on primary efficacy outcome. The precise 
reasons for excluding subjects from the Per-protocol Analysis Set will be fully defined and 
documented a priori before the clinical database lock. 
Subjects will be classified according to the randomized treatment assignment. 
Pharmacokinetics Analysis Set 
For pimavanserin and AC-279 plasma concentration summaries, the Pharmacokinetics 
Analysis Set will consist of subjects with at least one measurable pimvanserin plasma 
concentration. 
Subjects will be classified according to the actual treatment received.  
5 DATA HANDLING CONVENTIONS 
All data collected in the study will be listed. 
5.1 
General Data Reporting Conventions 
For continuous variables, the following summary statistics will be provided: number of 
subjects, mean, standard error of the mean (SE), standard deviation (SD), minimum, 
maximum, and median. Unless specified otherwise, means, medians, and confidence 
intervals (CIs) will be presented to one more decimal place than the raw data, and the 


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standard deviations and standard errors will be presented to 2 more decimal places than the 
raw data. 
For categorical variables, summaries will include the number and percentage of subjects in 
each category, using the number of subjects with non-missing values as the denominator for 
the percentages (unless otherwise specified). Categories with zero counts will not have zero 
percentages displayed. Percentages will be presented to 1 decimal place.  
Unless specified otherwise, all statistical tests will be 2-sided hypothesis tests performed at 
the significance level of 5% for main effects and all confidence intervals (CIs) will be 2-sided 
95% CIs. P-values will generally be presented to 4 decimal places; values less than 0.0001 
will be presented as <0.0001. 
When converting number of days to months, it will be calculated as the number of days 
divided by 365.25 and then multiplied by 12. When converting number of days to years, it 
will be calculated as the number of days divided by 365.25. 
5.2 
Derived Variables 
In general, the assessment scale total scores and subscores will be derived within the analysis 
datasets. In the event that total scores and/or subscores are also collected on the electronic 
case report form (eCRF), the derived values will be used for all analyses. Both the raw and 
derived scores will be presented in listings. 
5.2.1 
Positive and Negative Syndrome Scale (PANSS) 
The PANSS is assessed at Screening, Baseline, Weeks 1, 2, 3, 4, 5, and Week 6/ET visits. 
The PANSS is a 30-item scale used to evaluate the presence, absence, and severity of 
schizophrenia symptoms. Items are scored over the past week (7 days) on the following 
7-point scale: 1 = absent; 2 = minimal; 3 = mild; 4 = moderate; 5 = moderate-severe; 
6 = severe; 7 = extreme. The PANSS total score can range from a minimum of 30 to a 
maximum of 210, with higher scores denoting more severe symptoms. 
The following are the 3 PANSS subscales and the PANSS items that define each subscale: 
 Positive Scale: 7 Items (minimum = 7, maximum = 49) 
o P1 
Delusions 
o P2 
Conceptual disorganization 
o P3 
Hallucinatory behavior 
o P4 
Excitement 
o P5 
Grandiosity 
o P6 
Suspiciousness/persecution 
o P7 
Hostility 


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 Negative Scale: 7 Items (minimum = 7, maximum = 49) 
o N1 
Blunted affect 
o N2 
Emotional withdrawal 
o N3 
Poor rapport 
o N4 
Passive/apathetic social withdrawal 
o N5 
Difficulty in abstract thinking 
o N6 
Lack of spontaneity and flow of conversation 
o N7 
Stereotyped thinking 
 
General Psychopathology Scale: 16 Items (minimum = 16, maximum = 
112) 
o G1 
Somatic concern 
o G2 
Anxiety 
o G3 
Guilt feelings 
o G4 
Tension 
o G5 
Mannerisms and posturing 
o G6 
Depression 
o G7 
Motor retardation 
o G8 
Uncooperativeness 
o G9 
Unusual thought content 
o G10 
Disorientation 
o G11 
Poor attention 
o G12 
Lack of judgment and insight 
o G13 
Disturbance of volition 
o G14 
Poor impulse control 
o G15 
Preoccupation 
o G16 
Active social avoidance 
 
The following are the 5 Marder factors and the PANSS items that define each factor: 
 Negative Symptoms: 7 Items (minimum = 7, maximum = 49) 
o N1 
Blunted affect 
o N2 
Emotional withdrawal 
o N3 
Poor rapport 
o N4 
Passive/apathetic social withdrawal 
o N6 
Lack of spontaneity and flow of conversation 
o G7 
Motor retardation 
o G16 
Active social avoidance 
 Positive Symptoms: 8 Items (minimum = 8, maximum = 56) 
o P1 
Delusions 
o P3 
Hallucinatory behavior 
o P5 
Grandiosity 
o P6 
Suspiciousness/persecution 
o N7 
Stereotyped thinking 
o G1 
Somatic concern 
o G9 
Unusual thought content 


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o G12 
Lack of judgment and insight 
 Disorganized Thought: 7 Items (minimum = 7, maximum = 49) 
o P2 
Conceptual disorganization 
o N5 
Difficulty in abstract thinking 
o G5 
Mannerisms and posturing 
o G10 
Disorientation 
o G11 
Poor attention 
o G13 
Disturbance of volition 
o G15 
Preoccupation 
 Uncontrolled Hostility/Excitement: 4 Items (minimum = 4, maximum = 28) 
o P4 
Excitement 
o P7 
Hostility 
o G8 
Uncooperativeness 
o G14 
Poor impulse control 
 Anxiety/Depression: 4 Items (minimum = 4, maximum = 28) 
o G2 
Anxiety 
o G3 
Guilt feelings 
o G4 
Tension 
o G6 
Depression 
For each of the subscales (positive, negative, or general), if more than 1 item score is 
missing, then that particular subscale score and the PANSS total score will be missing. When 
there is only 1 item missing for a subscale, then the missing single item will be imputed using 
the average of the non-missing item scores for that subscale, subject and timepoint, rounded 
to the nearest integer. After the missing item(s) is imputed within the subscale(s), then the 
PANSS total score and Marder factor scores will be computed without further imputation. A 
Marder factor score will be missing if any item score is missing for that factor, after the 
imputations within the subscales were applied. 
5.2.2 
Clinical Global Impressions – Severity (CGI-S) Scale  
The CGI-S is assessed at Screening, Baseline, Weeks 1, 2, 3, 4, 5, and Week 6/ET visits. 
The CGI-S is a clinician-rated, 7-point scale that is designed to rate the severity of the 
subject's illness, in this case schizophrenia, at the time of assessment, making use of the 
clinician’s judgment and past experience with subjects who have the same disorder. The 
7-point scores are: 1 = normal, not ill; 2 = minimally ill; 3 = mildly ill; 4 = moderately ill; 
5 = markedly ill; 6 = severely ill; 7 = among the most severely ill. Higher scores denote more 
severe schizophrenia. The licensed version used in Study 034 is a blend of Guy’s (Guy W; 
Early Clinical Drug Evaluation Unit Assessment Manual for Psychopharmacology; US 
Department of Health, Education, and Welfare; National Institute of Mental Health; 1976) 
and Haro’s (Haro JM; The Clinical Global Impression-schizophrenia scale: a simple 
instrument to measure the diversity of symptoms present in schizophrenia; 2003) versions. 


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Missing CGI-S scores will not be imputed. 
5.2.3 
Clinical Global Impressions – Improvement (CGI-I) Scales  
The CGI-I is assessed at Weeks 1, 2, 3, 4, 5, and 6/ET visits. 
The CGI-I is a clinician-rated, 7-point scale that is designed to assess how much the subject’s 
illness has improved or worsened relative to study Baseline. The 7-point scores are: 1 = very 
much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally 
worse; 6 = much worse; 7 = very much worse. Higher scores denote worse or less 
improvement in schizophrenia. 
Missing CGI-I scores will not be imputed. 
5.2.4 
Personal and Social Performance Scale (PSP) 
The PSP is assessed at Baseline and Week 6/ET visits. 
The PSP is a validated 100-point (1 to100) single-item rating scale to assess the psychosocial 
functioning of subjects with schizophrenia. Ratings are based on four main areas: (a) socially 
useful activities, including work and study; (b) personal and social relationships, (c) self-care; 
and (d) disturbing and aggressive behaviors. The time period assessed is “past month” and 
does not take into account suicidal risk and behavior. Higher scores denote better 
psychosocial functioning: scores of 71-100 reflect only mild difficulties; 31-70 reflect 
manifest disabilities of various degrees; 1-30 reflect functioning so poor that intensive 
support or supervision is needed. 
Missing PSP scores will not be imputed. 
5.2.5 
Drug Attitude Inventory (DAI-10) 
The DAI-10 is assessed at Baseline and Week 6/ET visits. 
The DAI-10 contains 6 items (1, 3, 4, 7, 9, and 10) that a subject who is fully adherent to the 
prescribed medication would answer as "True" and 4 items (2, 5, 6, and 8) that a subject who 
is fully adherent to the prescribed medication would answer as "False."  A correct answer is 
scored +1 and an incorrect answer is scored -1. The total score is the sum of pluses and 
minuses, which can range from -10 to 10 in increments of 2. A positive total score indicates a 
positive subjective response (adherent) and a negative total score indicates a negative 
subjective response (non-adherent). Higher scores denote better adherence. 
Missing DAI-10 item scores will not be imputed. The total score will be missing if any item 
score is missing. 


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5.2.6 
Karolinska Sleepiness Scale (KSS) 
The KSS is assessed at Baseline, Weeks 1, 2, 3, 4, 5, and Week 6/ET visits. 
The KSS is a self-reported subjective measure of a subject’s level of drowsiness. 
Respondents must choose statements that most accurately describe their level of sleepiness 
over the past few minutes or, with the modified version used in this study, over an average 
period of time. In Study 034, sleepiness level during the last week (7 days) is reported. 
Scoring is based on a 9-point verbally anchored scale ranging from 1 (extremely alert) to 9 
(very sleepy, great effort to keep awake, fighting sleep). Higher scores denote more 
drowsiness. In Study 034, the KSS will be administered by a trained interviewer. 
Missing KSS scores will not be imputed. 
5.2.7 
Calgary Depression Scale for Schizophrenia (CDSS) 
The CDSS is assessed at Screening, Baseline, and Week 6/ET visits. 
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. Items are scored over the past 2 weeks (14 days) on the following 
4-point scale: 0 = absent; 1 = mild; 2 = moderate; 3 = severe. The total score is the sum of the 
9 item scores which can range from 0 to 27, with higher scores denoting more severe 
depression. 
Missing CDSS item scores will not be imputed. The total score will be missing if any item 
score is missing. 
5.2.8 
36-Item Short Form Health Survey (SF-36) 
The SF-36 is assessed at Baseline and Week 6/ET visits. 
The SF-36 is a 36-item survey that measures the overall health status of a subject. The SF-36 
assesses eight health concepts during the past 4 weeks: physical functioning, bodily pain, role 
limitations due to physical health problems, role limitations due to personal or emotional 
problems, emotional well-being, social functioning, energy/fatigue, and general health 
perceptions. It also includes a single item that provides an indication of perceived change in 
health compared to one year ago. In Study 034, the RAND 36-Item Health Survey 
(Version 1.0) is used. 
Scoring the SF-36 is a 2-step process. First, pre-coded numeric values are re-coded per the 
scoring key given in Table 2. Note that all items are scored so that a high score defines a 
more favorable health state and less disability. In addition, each item is scored on a 0 to 100 
range so that the lowest and highest possible scores are 0 and 100, respectively. Scores 


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represent the percentage of total possible score achieved, with higher scores denoting higher 
level of functioning. In step 2, items in the same scale are averaged together to create the 8 
scale scores. Table 3 lists the items averaged together to create each scale. Items that are left 
blank (missing data) are not taken into account when calculating the scale scores. Hence, 
scale scores represent the average for all items in the scale that the respondent answered. 
Table 2 
SF-36 Re-Coding Rules for Individual Items 
Item Number 
Original Response Category1 
Re-Coded Value 
2, 20, 34, 36 
1 
100 
2 
75 
3 
50 
4 
25 
5 
0 
3, 4, 5, 6, 7, 8, 9, 10, 11, 12 
1 
0 
2 
50 
3 
100 
13, 14, 15, 16, 17, 18, 19 
1 
0 
2 
100 
23, 26, 27, 30 
1 
100 
2 
80 
3 
60 
4 
40 
5 
20 
6 
0 
24, 25, 28, 29, 31 
1 
0 
2 
20 
3 
40 
4 
60 
5 
80 
6 
100 
32, 33, 35 
1 
0 
2 
25 
3 
50 
4 
75 
5 
100 
1 
1 
100 
2 
85 
3 
60 
4 
25 
5 
0 
21 
1 
100 
2 
88 
 


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Table 2 
SF-36 Re-Coding Rules for Individual Items (Continued) 
Item Number 
Original Response Category1 
Re-Coded Value 
 
3 
64 
4 
42 
5 
24 
6 
0 
22 
1 (Item 21 = 1 or .) 
100 
1 (Item 21 = 2 to 6) 
80 
2 (Item 21 = .) 
75 
2 (Item 21 ^= .) 
60 
3 (Item 21 = .) 
50 
3 (Item 21 ^= .) 
40 
4 (Item 21 = .) 
25 
4 (Item 21 ^= .) 
20 
5  
0 
1 
Pre-coded response choices as printed in the questionnaire. 
 
Table 3 
SF-36 Scale Components 
Scale 
Items 
PHYFUN10: Physical functioning  
3, 4, 5, 6, 7, 8, 9, 10, 11, 12 
ROLEP4: Role limitations due to physical health 
13, 14, 15, 16 
ROLEE3: Role limitations due to emotional problems 
17, 18, 19 
ENFAT4: Energy/fatigue 
23, 27, 29, 31 
EMOT5: Emotional well-being 
24, 25, 26, 28, 30 
SOCFUN2: Social functioning 
20, 32 
SFPAIN2: Pain 
21, 22 
SFGENH5: General health 
1, 33, 34, 35, 36 
 
To enable meaningful comparisons across scales, the 8 scale scores are converted to norm-
based z-scores based on 1998 General Population statistics: 
   PF_Z = (PHYFUN10 - 82.96845) / 23.83795 ; 
   RP_Z = (ROLEP4 - 77.93107) / 35.34865 ; 
   RE_Z = (ROLEE3 - 83.10276) / 31.64149 ; 
   EN_Z = (ENFAT4 - 56.99917) / 21.12677 ; 
   EM_Z = (EMOT5 - 75.21913) / 17.60698 ; 
   SF_Z = (SOCFUN2 - 83.56494) / 23.02758 ; 
   BP_Z = (SFPAIN2 - 70.22865) / 23.35310 ; 
   GH_Z = (SFGENH5 - 70.10060) / 21.35900 ; 


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In addition, physical and mental health composite scores will also be computed using the 
individual-scale z-scores:    
Physical health composite scores AGPHYS_Z  
= (PF_Z * 0.42402) + (RP_Z * 0.35119) + (BP_Z * 0.31754) + 
              (GH_Z * 0.24954) + (EM_Z * -.22069) + (RE_Z * -.19206) + 
              (SF_Z * -.00753) + (EN_Z * 0.02877); 
 
Mental health composite scores AGMENT_Z  
= (PF_Z * -.22999) + (RP_Z * -.12329) + (BP_Z * -.09731) + 
              (GH_Z * -.01571) + (EM_Z * 0.48581) + (RE_Z * 0.43407) + 
              (SF_Z * 0.26876) + (EN_Z * 0.23534); 
 
The 2 composite scores will not be calculated if any individual scale score is missing. 
Finally, the z-scores will be transformed to t-scores for data analyses which will be detailed 
in Section 13.4. 
   AGPHYS_T = 50 + (AGPHYS_Z * 10); 
   AGMENT_T = 50 + (AGMENT_Z * 10); 
   PF_T = 50 + (PF_Z * 10) ; 
   RP_T = 50 + (RP_Z * 10) ; 
   RE_T = 50 + (RE_Z * 10) ; 
   EN_T = 50 + (EN_Z * 10) ; 
   EM_T = 50 + (EM_Z * 10) ; 
   SF_T = 50 + (SF_Z * 10) ; 
   BP_T = 50 + (BP_Z * 10) ; 
   GH_T = 50 + (GH_Z * 10) ; 
 
5.2.9 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is assessed at Screening, Baseline, Weeks 1, 2, 3, 4, 5, and Week 6/ET visits. 
The C-SSRS monitors changes in suicidal thinking and behavior over time, in order to 
determine risk. Four constructs are measured: the severity of ideation, the intensity of 
ideation, behavior, and lethality. 
The C-SSRS Baseline/Screening version will be completed at the Screening visit and the 
version assessing information since the last visit will be completed at all following visits 
(including the Baseline visit). The C-SSRS results for each subject should be reviewed by the 
Investigator at each visit. If at any time the C-SSRS results for a given subject reveal 
potential suicidality, then the Investigator should assess the clinical significance of such 
results. If a clinically significant risk of suicidality is identified for a subject, then the 
Investigator should discontinue the subject and implement appropriate treatment. 


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There are 5 questions about suicidal ideation, representing 5 types of suicidal ideation: wish 
to be dead; non-specific active suicidal thoughts; active suicidal ideation with any methods 
(not plan) without intent to act; active suicidal ideation with some intent to act, without 
specific plan; active suicidal ideation with specific plan and intent. If a subject answers “yes” 
to any of these 5 questions, this subject will be counted as having suicidal ideation. 
There are 5 questions about suicidal behavior, representing 5 types of suicidal behavior: 
preparatory acts or behavior; aborted attempt; interrupted attempt; actual attempt; suicide. If 
a subject answers “yes” to any of these 5 questions, this subject will be counted as having 
suicidal behavior. 
Missing C-SSRS item scores will not be imputed. 
5.2.10 Abnormal Involuntary Movement Scale (AIMS) 
The AIMS is assessed at Baseline, Weeks 1, 3, and Week 6/ET visits. 
The AIMS is a rating scale that was designed to measure involuntary movements known as 
tardive dyskinesia. The AIMS has a total of 12 items rating involuntary movements of 
various areas of the subject's body.  
 Items 1 to 7 assess the severity of dyskinesia (orofacial, extremity and truncal 
movements) are rated on a 5-point scale of severity: 0 (none), 1 (minimal; may be 
extreme normal), 2 (mild), 3 (moderate), and 4 (severe).  
 Items 8 and 9 assess the overall severity and incapacitation, and are also rated on a 
5-point scale of severity: 0 (none, normal), 1 (minimal), 2 (mild), 3 (moderate), and 
4 (severe).  
 Item 10 assesses the subject’s level of awareness of the movements with associated 
distress and is rated on a 5-point scale: 0 (no awareness), 1 (aware, no distress), 2 (aware, 
mild distress), 3 (aware, moderate distress), and 4 (aware, severe distress).  
 Items 11 and 12 refer to dental status and the responses are yes (scored as 1) or no (scored 
as 0).  
The AIMS total score is the sum of the 12 item scores which can range from 0 to 42, with 
higher scores denoting more severe dyskinesia symptoms. 
Missing AIMS item scores will not be imputed. The total score will be missing if any item 
score is missing. 
 


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5.2.11 Barnes Akathisia Scale (BARS)  
The BARS is assessed at Baseline, Weeks 1, 3, and Week 6/ET visits. 
The BARS is a 4-item, physician-administered scale that assesses the severity of drug-
induced akathisia. Items 1 to 3 assess the objective presence and frequency of akathisia, the 
subjective awareness of restlessness, and the subjective distress related to restlessness. These 
3 items are rated on a 4-point scale from 0 to 3 and the total score is the sum of these 3 item 
scores, which can range from 0 to 9. Additionally, there is a global clinical assessment of 
akathisia which is rated on a 6-point scale from 0 to 5. For total or global clinical assessment 
scores, higher scores denote more severe akathisia symptoms. 
Missing BARS item scores will not be imputed. The total score will be missing if any non-
global item score is missing. 
5.2.12 Simpson Angus Extrapyramidal Side Effect Scale (SAS) 
The SAS is assessed at Baseline, Weeks 1, 3 and Week 6/ET visits. 
The SAS is a 10-item physician-administered scale commonly used for the assessment of 
parkinsonian movement disorder related to psychiatric drug treatment. One item on the SAS 
measures gait/hypokinesia; 6 items measure rigidity (arm-dropping, shoulder shaking, elbow 
rigidity, wrist rigidity or fixation of position, head rotation, and akathisia); and 3 items 
measure glabella tap, tremor, and salivation, respectively. The grade of severity of each item 
is rated using a 5-point scale from 0 to 4. The SAS total score is the sum of the 10 items, 
which can range from 0 to 40, with higher scores denoting more severe parkinsonian 
symptoms. 
Missing SAS item scores will not be imputed. The total score will be missing if any item 
score is missing. 
5.3 
Analysis Visit Windows  
Baseline will be defined as the last non-missing result, including results from repeated and 
unscheduled measurements, before dosing.  
Efficacy, safety and PK assessments will be summarized by analysis visit as presented in 
Table 4 below. 


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Table 4 
Analysis Visit Windows 
Analysis Visit Name 
Target Study Day1 
Study Day Interval 
Baseline  
1 
≤1 
Week 1 
8 
2 to 11 
Week 2 
15 
12 to 18 
Week 3 
22 
19 to 25 
Week 4 
29 
26 to 32 
Week 5 
36 
33 to 39   
Week 6 
43 
40 to 50 
Follow-up 
71 
≥51 
1 
Study day = assessment date - first dose date + 1 if the assessment date ≥ first dose date, otherwise study 
day = assessment date – first dose date. Study day 1 is the day of first administration of study drug 
(adjunctive pimavanserin or adjunctive placebo). 
5.3.1 
Unscheduled Assessments 
Both scheduled and unscheduled assessments, including early termination visits, will be 
considered for planned timepoint analyses. All assessments will be presented in data listings. 
5.3.2 
Multiple Measurements within Visit Windows 
If more than one assessment falls within a given window then the assessment closest to the 
target study day will be selected for the by-visit analyses. In these analyses, if two 
assessments are equidistant from the target day then the chronologically last assessment will 
be used. Exceptions may be made for incomplete assessments, in which case, more complete 
assessments may be given priority.  Details are provided in a separate programming 
conventions document. 
For safety analysis where the most extreme values should be selected (e.g. overall post-
baseline minimum, overall post-baseline maximum, and potentially clinically important 
values), all non-missing post-Baseline values should be considered, regardless of whether the 
value is selected for the by-visit summaries. All results will be presented in data listings. 
When ECG is collected in triplicate, the average of the triplicate will be considered as one 
assessment for the analyses.  
5.4 
Missing or Incomplete Date for Last Dose of Study Drug 
In the Safety Analysis Set, if the last dose date of study drug is missing for a subject who 
completed or early terminated from the study, then the date of the end-of-study/early 
termination visit will be used in the calculation of treatment duration. For the incomplete last 
dose date of the study drug, the imputation algorithms will be detailed in the analysis dataset 


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specification document. The missing or incomplete dates will be displayed in the data listings 
as reported on the eCRF rather than the imputed dates. 
For the data summarization before final database lock, if a subject is still ongoing, then this 
subject’s last dose date will be imputed using the database extract date.  
5.5 
Missing or Incomplete Dates for Prior or Concomitant Medications 
Missing or incomplete medication start or end dates will be imputed for the purpose of 
determining whether the medications are taken concomitantly (see Section 11 for definition). 
When the chronological order of medication use relative to the study drug treatment period is 
unclear due to missing or incomplete date(s), the medication will be considered as 
concomitant. The imputation algorithms will be detailed in the analysis dataset specification 
document. The missing or incomplete dates will be displayed in the data listings as reported 
on the eCRF rather than the imputed dates. 
5.6 
Missing or Incomplete Dates for Adverse Events  
Missing or incomplete adverse event (AE) start dates will be imputed for the purpose of 
determining whether the AEs are treatment-emergent (see Section 14.1 for definition). When 
the chronological order of an AE onset relative to the study drug treatment period is unclear 
due to missing or incomplete date(s), the AE will be considered as treatment-emergent. The 
imputation algorithms will be detailed in the analysis dataset specification document. The 
missing or incomplete dates will be displayed in the data listings as reported on the eCRF 
rather than the imputed dates. 
5.7 
Missing Severity Assessment for Adverse Events 
If the severity is missing for an AE starting on or after the date of the first dose of study drug, 
then a severity of “Severe” will be assigned. The imputed values for severity assessment will 
be used for incidence summaries, and the actual values will be presented in data listings. 
5.8 
Missing Relationship to Study Drug for Adverse Events 
If the relationship to study drug is missing for an AE starting on or after the date of the first 
dose of study drug, a causality of “Related” will be assigned. The imputed values for 
relationship to study drug will be used for incidence summaries, and the actual values will be 
presented in data listings. 
5.9 
Character Values of Clinical Laboratory Variables  
If the reported value of a clinical laboratory variable cannot be used in a statistical analysis 
due to, for example, a character string reported for a numeric variable, an appropriately 


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determined coded value will be used in the statistical analysis. The coding algorithms will be 
detailed in the analysis dataset specification document. The actual values as reported in the 
database will be presented in data listings. 
5.10 Duplicate Subjects  
Duplicate-subject screening will be performed throughout the schizophrenia program to 
identify whether there are individuals who are randomized more than once into the double-
blind schizophrenia studies ACP-103-034, -038 or -039. Confirmed duplicates will only be 
included for statistical analyses under the subject number and study to which they were first 
randomized. Data collected under other subject number(s) or study (studies) will be listed but 
will not be analyzed or summarized. Case narratives will be provided for duplicate subjects. 
6 SUBJECT DISPOSITION 
For subjects who participate in the screening phase but are not randomized (screen failures), 
their demographics information (including age, sex, and primary race), screen failure reasons 
(the specific inclusion/exclusion criterion (or criteria) not met or other reason) and protocol 
version will be listed. If a subject is re-screened, then the re-screening subject ID and the 
final enrollment status (whether eventually enrolled) will also be displayed in this listing. In 
addition, the frequency that the screen failure reasons are reported will also be summarized. 
Note that one subject may be deemed ineligible for multiple inclusion/exclusion criteria and 
may be allowed to rescreen with the permission of the Medical Monitor, provided the screen 
failure was due to a temporary condition that subsequently resolved.   
The number of sites that screened at least 1 subject, number of sites that randomized at least 
1 subject, number of subjects screened, and number of unique subjects screened will be 
summarized by region and overall. In addition, the number of subjects enrolled at each site 
will also be tabulated by Analysis Set and by treatment group and overall. 
For randomized subjects, number and percentage of subjects in Safety Analysis Set, Full 
Analysis Set, and Per-protocol Analysis Set will be summarized by treatment group and 
overall. A listing will be provided displaying all subjects excluded from the Safety, Full or 
Per-protocol Analysis Sets, and will include reason(s) for exclusion. The number and 
percentage of subjects who are excluded from the Per-protocol Analysis Set will be presented 
in a summary table by reason, and by treatment group and overall.  
Within each analysis set, the number and percentage of subjects who completed the study or 
discontinued (all discontinued and by discontinuation reason) will also be summarized by 
treatment group and overall. 


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7 PROTOCOL DEVIATIONS 
Protocol deviations will be reviewed periodically over the course of the study. The review 
process, definition of the deviation categories, and the classification of a deviation as major 
or minor are detailed in the Protocol Deviation Project Instruction document. 
A summary of the number and percentage of subjects with major protocol deviations for each 
deviation category will be presented by treatment group and overall. A listing of protocol 
deviations by site and subject will also be provided. 
8 DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
Demographics and baseline characteristics will be summarized by treatment group and 
overall for Randomized Analysis Set, Safety Analysis Set, Full Analysis Set, and Per-Protocol 
Analysis Set using descriptive statistics. For the Full Analysis Set, summaries by region will 
also be presented. Variables include age, sex, primary race (subjects of multi-racial 
background can only identify/select one primary race on eCRF, or choose “other” and 
specify), ethnicity, height, weight, body mass index (BMI), region, current smoking status, 
highest education level, marital status, employment status, Baseline PANSS total score, and 
Baseline CGI-S.  
The reported age reflect a subject’s age at the informed consent date. Age, Baseline PANSS 
total score and Baseline CGI-S will be presented as both continuous and categorical 
variables. Age categories will be presented as 18 to 35 and >35 years old. Baseline PANSS 
will be presented as <90 (lower symptom severity) or >90 (higher symptom severity). 
Baseline CGI-S categories will be presented as scores 1 to 7 as well as 4 (lower disease 
severity) or >5 (higher disease severity). 
Schizophrenia disease history will be summarized by treatment group for Randomized 
Analysis Set, Safety Analysis Set, Full Analysis Set and Per-protocol Analysis Set using 
descriptive statistics. Variables include:  
 Age (years) at diagnosis of schizophrenia disease 
 Age (years) when received first antipsychotic medication for schizophrenia 
 Duration (years) of schizophrenia disease  
 Time (years) since first antipsychotic treatment  
 Treated with clozapine in the past (yes or no) 
 Number of hospitalizations for treatment of schizophrenia (0, 1 to 5, 6 to 10, or >10) 
 Time (years) since last hospitalization 


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 Current main background antipsychotic medication 
 Duration (months) of current main background antipsychotic medication 
 Ever had suicidal ideation or behavior (yes or no) 
 Had suicidal ideation or behavior within past 6 months (yes or no) 
Informed consent date will be used as the reference date for calculating the durations listed 
above. 
Additional information will be listed, including the name of first antipsychotic medication 
and the dose and frequency of the current main background antipsychotic medication. For 
subjects who had received clozapine, date of last clozapine dose and the dose level will also 
be listed. For subjects who had been hospitalized before, date of last hospitalization and 
treatment received in the hospital will also be listed.  
9 MEDICAL HISTORY 
Medical and surgical history data will be coded using Medical Dictionary for Regulatory 
activities (MedDRA) version 19.0 or newer. The subject incidence will be summarized for 
each system organ class (SOC) and preferred term by treatment group and overall for Safety 
Analysis Set, Full Analysis Set, and Per-protocol Analysis Set. A subject will be counted only 
once per SOC or per preferred term for the summary. 
A listing of the SOC, preferred term, body system, verbatim term for the medical history 
condition/event, start and stop dates (when available), and an indicator for whether or not the 
condition is ongoing will be provided. 
10 EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE 
Summaries of exposure and compliance to study drug will be provided for the Safety 
Analysis Set and Full Analysis Set. 
10.1 Exposure to Study drug  
For each subject, the duration of exposure to study drug (last dose date – first dose date + 1), 
cumulative dose (first multiply the number of doses taken by the dose level for each kit 
utilized, then sum the results from all kits), and average daily dose (cumulative dose in mg 
divided by duration of exposure in days) will be calculated and summarized by treatment 
group. Duration of exposure will be summarized as both continuous and categorical 
variables. For categorical presentation, the number and percentage of subjects in each of the 
following categories will be presented: <1week (1 to 6 days), 1 to <2 weeks (7 to 13 days), 2 
to <3 weeks (14 to 20 days), 3 to <5 weeks (21 to 34 days), and >5 weeks (35 days or 


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longer). Kaplan-Meier curves of duration on study drug will also be presented for each 
treatment group. In addition, whether subject had any dose change (yes vs. no), highest dose 
level (20 mg or 34 mg), lowest dose level (10 mg or 20 mg), and last dose level (10 mg, 20 
mg, or 34 mg) will also be summarized by category and treatment group. 
The pimavanserin dose levels are expressed as free base.  
10.2 Measurement of Treatment Compliance 
Study drug dosing compliance (in percentage) for a subject is defined as the total number of 
tablets actually taken divided by the number of tablets expected to be taken and then 
multiplied by 100. The total number of tablets actually taken is calculated by the total number 
of tablets dispensed minus the total number of tablets returned. The number of tablets 
expected to be taken is calculated as the duration of exposure multiplied by 2 (the planned 
number of tablets taken per day). 
Compliance will be summarized as both continuous and categorical variables by treatment 
groups. For categorical presentation, the number and percentage of subjects in each of the 
following categories will be presented: <80%, 80 to 120%, and >120%. 
11 PRIOR, CONCOMITANT AND POST-TREATMENT MEDICATION 
For a subject, prior medication is defined as any medication with the start and stop dates prior 
to the date of the first dose of study drug. Concomitant medication is defined as any 
medication that is taken while this subject is also treated with the study drug. Any medication 
with a start date after the date of the last dose of study drug will be considered as post-
treatment medication. Prior, concomitant, or post-treatment medications will be summarized 
separately. Medications will be coded using WHO Drug Dictionary (WHODRUG-DDE-B2) 
2016 March or newer version. The number and percentage of subjects taking each drug class 
(ATC Level 3) and medication preferred term will be tabulated by treatment group and 
overall for Safety Analysis Set. Multiple medication usage by a subject in the same category 
will be counted only once. 
12 EFFICACY ANALYSES 
All efficacy analyses will be performed using the planned treatment assignments based on the 
randomization schedule. 
 
 


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12.1 Efficacy Variables 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from Baseline to Week 6 in the PANSS total 
score. 
Key Secondary Efficacy Endpoint 
The key secondary efficacy endpoint is the change from Baseline to Week 6 in the CGI-S 
score.  
Other Secondary Efficacy Endpoints 
Other secondary efficacy endpoints are the following: 
 CGI-I score at Week 6 
 Proportion of PANSS responders (≥20% and ≥30% reduction in PANSS total score) at 
Week 6 
 Proportion of CGI-I responders (CGI-I score of 1 or 2) at Week 6 
 Change from Baseline to Week 6 in PSP score 
 Change from Baseline to Week 6 in DAI-10 score 
 Change from Baseline to Week 6 in KSS score 
 Change from Baseline to Week 6 in PANSS subscale scores (positive scale, negative 
scale, and general psychopathology scale) 
Exploratory endpoints are the following: 
 Change from Baseline to Week 6 in PANSS Marder factor scores (negative symptoms, 
positive symptoms, disorganized thought, uncontrolled hostility/excitement, and 
anxiety/depression factors) 
See Section 5.2.1 for the PANSS items included in each Marder factor. 
 Change from Baseline to Week 6 in CDSS score 
 Change from Baseline to Week 6 in SF-36 score 
 Change from Baseline to Week 6 in PANSS individual item scores 
12.2 Adjustment for Covariates 
For continuous variables (except CGI-I) analyzed using the mixed model for repeated 
measures (MMRM) or analysis of covariance (ANCOVA), the Baseline value of the endpoint 


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being analyzed and geographic region (North America, Europe, or rest of world) will be 
included as covariates as described in Section 13. For CGI-I, the Baseline CGI-S score and 
geographic region will be included as covariates in the MMRM analysis. 
12.3 Handling of Missing Data 
The primary analysis of the primary efficacy variable will be performed assuming missing at 
random (MAR) using an MMRM method. Total scores that are missing, after any imputation 
of individual missing items as described in Section 5.2.1, will not be imputed. Sensitivity 
analyses of the primary efficacy variable will be performed as described in Section 13. 
12.4 Multiple Comparisons / Multiplicity 
A hierarchical testing procedure will be used to control the type 1 error rate across the 
primary and key secondary endpoints. That is, if there is no evidence to show the superiority 
of the adjunctive pimavanserin treatment over the adjunctive placebo with respect to the 
primary efficacy endpoint at the 2-sided significance level of 0.05, no formal testing for the 
key secondary efficacy endpoint will be performed. If the primary endpoint test is not 
significant at the 0.05 level then the key secondary endpoint is also not significant at the 0.05 
level.  
12.5 Examination of Subgroups 
Treatment comparisons will be made with respect to the primary and key secondary efficacy 
variables using the MMRM analysis described in Section 13.1.1 separately for each subgroup 
by: 
 region (North America, Europe, or rest of world) 
 age group (18 to 35 or >35 years old) 
 sex (male or female) 
 primary race (white, black or African American, or other) 
 main background antipsychotic medication (aripiprazole, asenapine, brexpiprazole, 
cariprazine, lurasidone, olanzapine, or risperidone) 
 duration of schizophrenia (<5 or >5 years) 
 Baseline smoking status (smoker or non-smoker) 
 Baseline BMI (<25, 25 to 30, or >30) 
 Baseline symptom severity measured by PANSS total score (<90 or >90) 
 Baseline disease severity measured by CGI-S score (4 or >5) 


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The LS mean differences with corresponding 95% CIs from the subgroups will also be 
graphically presented in forest plots for the primary efficacy variable and for the key 
secondary efficacy variable. 
13 METHODS OF EFFICACY ANALYSES 
13.1 Primary Efficacy Analysis  
The primary endpoint is the change from Baseline to Week 6 in the PANSS total score. The 
primary analysis will be based on the Full Analysis Set. The Randomized Analysis Set and 
Per-Protocol Analysis Set will be used for sensitivity analyses. 
Let Δ be the difference in the mean change from Baseline to Week 6 in the PANSS total score 
between the adjunctive pimavanserin and adjunctive placebo groups: 
The null hypothesis for the primary efficacy endpoint is:  
 
Δ = 0 
The alternative hypothesis for the primary efficacy endpoint is:  
Δ ≠ 0 
13.1.1 Primary Analysis using MMRM in the Full Analysis Set 
The PANSS total score will be analyzed using mixed model repeated measures (MMRM) in 
the Full Analysis Set. The dependent variable will be the change from Baseline in the PANSS 
total score. The independent variables in the model will include the following:  treatment 
group (adjunctive pimavanserin or adjunctive placebo), visit (Week 1, Week 2, Week 3, 
Week 4, Week 5, and Week 6), treatment-by-visit interaction, Baseline-by-visit interaction, 
geographic region (North America, Europe, or rest of world), and the Baseline PANSS total 
score (continuous covariate). An unstructured covariance matrix will be used and the 
Kenward-Roger approximation will be used to adjust the denominator degrees of freedom. 
Observed cases will be analyzed in the model and the least squares (LS) means will be 
estimated using observed margins. 
 
 
 
        
 
        
 
 
        
 
        
 
 
In the event that the model fails to converge using the unstructured  covariance matrix, the 
following covariance structures will be modeled in the order given: heterogeneous Toeplitz, 
heterogeneous compound symmetry, heterogeneous autoregressive(1), Toeplitz, compound 


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symmetry, autoregressive(1), variance components. The first covariance structure that allows 
for convergence will be selected for the final model. 
At each visit, the effect size (Cohen’s d) for the change from Baseline between the treatment 
groups will be calculated using the following formula: 
𝐸𝑓𝑓𝑒𝑐𝑡 𝑠𝑖𝑧𝑒= 𝐿𝑆 𝑚𝑒𝑎𝑛 𝑑𝑖𝑓𝑓𝑒𝑟𝑒𝑛𝑐𝑒
√𝑣𝑎𝑟𝑖𝑎𝑛𝑐𝑒
 
The variance at a given visit will be obtained from the covariance matrix estimated for the 
MMRM model. The sign (+ or -) of the effect size will be chosen so that a positive value 
favors pimavanserin. 
Summary statistics for the PANSS total score (observed and change from baseline) will be 
presented for all visits from Baseline through Week 6. For change from Baseline values at 
each post-Baseline visit, LS means and standard errors (SE), the between-group difference in 
LS means with the corresponding 95% confidence interval, p-value and effect size will also 
be presented. In addition, LS mean ± SE over time for the change from Baseline values by 
treatment group will also be presented in line plots. 
The hypothesis testing will be performed based on the difference in LS means at Week 6 and 
will be tested at an alpha level of 0.05 (2-sided). The treatment-group comparisons at each of 
the other timepoints (Weeks 1, 2, 3, 4, and 5) using the same MMRM model will be 
considered exploratory.  
The LS mean differences with corresponding 95% CIs from the primary and sensitivity 
analyses (see following sections for details regarding the sensitivity analyses) will also be 
graphically presented in a forest plot. 
Since the treatment dose level can be adjusted during the first 3 weeks in the study, 
descriptive summary statistics for the PANSS total score (observed and change from 
baseline) will also be presented by pimavanserin last dose level for all visits from Baseline 
through Week 6. In addition, the LS mean changes in PANSS total score from Baseline with 
corresponding 95% CIs by visit and last dose level will also be estimated using a MMRM 
including the following independent variables: last dose level (adjunctive placebo, adjunctive 
pimavanserin 10mg, adjunctive pimavanserin 20mg, or adjunctive pimavanserin 34mg), visit 
(Week 1, Week 2, Week 3, Week 4, Week 5, and Week 6), treatment-by-visit interaction, 
Baseline-by-visit interaction, geographic region (North America, Europe, or rest of world), 
and the Baseline PANSS total score (continuous covariate). Like the primary MMRM, an 
unstructured covariance matrix will be used and the Kenward-Roger approximation will be 
used to adjust the denominator degrees of freedom. Observed cases will be analyzed in the 
model and the least squares (LS) means will be estimated using observed margins. 


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13.1.2 Sensitivity Analysis using MMRM in the Per-Protocol Analysis Set 
The same MMRM model as described in Section 13.1.1 will be performed in the Per-
Protocol Analysis Set to assess the consistency of the conclusions from different analysis 
sets. Results will be presented in a summary table similar to the outputs described in 
Section 13.1.1. 
13.1.3 Sensitivity Analysis using ANCOVA with Missing Data Imputed Using Pattern-
Mixture Models with Placebo-Based Multiple Imputation  
Because it is not possible to be certain that the data are missing at random (MAR), sensitivity 
analyses will be conducted so that the robustness of the primary endpoint with regard to 
missing data can be assessed, as recommended by the National Research Council report on 
missing data (National Research Council, 2010) and the European Medicines Agency 
Guidance on missing data (European Medicines Agency, 2010). Therefore, models that 
assume data is missing not at random (MNAR) will be used to test the robustness of the 
conclusions from MMRM results. 
In this sensitivity analysis the assumption is that the adjunctive pimavanserin subjects who 
discontinue early will display the same trajectory of disease as the adjunctive placebo 
subjects who remain on study. Formally, this means that subjects who drop out will be 
assumed to have correlation with future visits similar to subjects in the adjunctive placebo 
arm. Thus, missing observations in the adjunctive placebo group are imputed assuming 
MAR, while missing values adjunctive in the adjunctive Pimavanserin group are imputed 
assuming MNAR. This approach may be described as a pattern mixture model (PMM) as 
defined by Molenberghs and Kenward (2007), with the patterns in this case defined by 
treatment group and time of withdrawal. 
The PMM approach will be implemented using multiple imputation (MI) using the following 
3 steps: 
1. The posterior mean and covariance estimates from the SAS® MI procedure using the 
available non-missing placebo data and a random number seed of 103034 will be 
utilized to impute missing data in the PANSS total score. The imputed values will be 
constrained to be within the range of 30 to 210 and the imputed values will not be 
rounded.  
 
 
 
 
        
                         
 
        
 
          
 
  
        
 


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2. The change from baseline in the PANSS total score will then be calculated and 
analyzed by visit for each of the fully imputed datasets using an ANCOVA model with 
treatment group and region as factors and the Baseline value as a covariate.  
3. The treatment LS mean differences will be averaged and the associated standard errors 
will be summarized based on within-imputation and between-imputation variance 
using the SAS® MIANALYZE procedure, to yield a combined estimate for treatment 
effect with its associated 95% CI and p-value for each visit. 
At each visit, the effect size (Cohen’s d) for the change from Baseline between the treatment 
groups will be calculated using the following formula: 
𝐸𝑓𝑓𝑒𝑐𝑡 𝑠𝑖𝑧𝑒= √1
𝑛1
+ 1
𝑛2
(
𝐿𝑆 𝑚𝑒𝑎𝑛 𝑑𝑖𝑓𝑓𝑒𝑟𝑒𝑛𝑐𝑒
𝑠𝑡𝑎𝑛𝑑𝑎𝑟𝑑 𝑒𝑟𝑟𝑜𝑟 𝑜𝑓 𝐿𝑆 𝑚𝑒𝑎𝑛 𝑑𝑖𝑓𝑓𝑒𝑟𝑒𝑛𝑐𝑒) 
Where 𝑛1 and 𝑛2 are the sample size in the adjunctive pimavanserin and the adjunctive 
placebo treatment groups at a given visit after missing data have been imputed. 
The LS mean difference and its standard error will be obtained from the SAS® MIANALYZE 
procedure. The sign (+ or -) of the effect size will be chosen so that a positive value favors 
pimavanserin. 
This sensitivity analysis will be performed in the Full Analysis Set and Randomized Analysis 
Set. 
Results will be presented in a summary table similar to the outputs described in 
Section 13.1.1. 


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13.1.4 Sensitivity Analysis using Van Elteren Test in the Full Analysis Set 
In order to assess the sensitivity to the normality and missing at random assumptions, a 
nonparametric stratified Wilcoxon rank sum test with modified ridit scores (van Elteren test) 
will be performed on the primary endpoint at Week 6, stratified by the geographic region 
(North America, Europe, or rest of world), using the Full Analysis Set. 
This analysis will consist of two steps. In step 1, subjects will be ranked first according to the 
timepoint of the last observed PANSS total change score and then by the magnitude of the 
last observed PANSS total change score. In other words, subjects who have the change from 
Baseline in PANSS total score at Week 6 will be ranked higher (better) than subjects with 
missing Week 6 data. Among the subjects with missing Week 6 data, the rank will be based 
on the timepoint that the subject’s last change from Baseline in PANSS total score is 
recorded: the later, the better. For subjects with the same last PANSS assessment timepoint, 
the rank will be based on the magnitude of the change score at the last assessment timepoint: 
the larger the reduction from Baseline, the better. In step 2, the rank scores computed in step 
1 will be analyzed using the van Elteren test, stratified by region. 
In addition to the p-value from the van Elteren test, the stratified Mann-Whitney estimator for 
the probability of a better outcome for the adjunctive pimavanserin treatment group 
compared to the adjunctive placebo treatment group and its 95% CI will also be presented. 
The summary table will also present the probability and its corresponding 95% CI for each 
region separately. 
The stratified Mann-Whitney estimator will be calculated as follows: 
For each region, the Mann-Whitney estimator for the probability of a better outcome (based 
on the rank scores from step 1 above) for the adjunctive pimavanserin treatment group 
compared to the adjunctive placebo treatment group will be calculated from Somers’ D 
(which can be obtained from the SAS® FREQ procedure): 
𝑀𝑊= (1 + 𝐷)/2 
The stratified Mann-Whitney estimator for all regions will then be calculated as the weighted 
average across the regions: 
𝑆𝑡𝑟𝑎𝑡𝑀𝑊= ∑
𝑤ℎ𝑀𝑊ℎ
3
ℎ=1
∑
𝑤ℎ
3
ℎ=1
 
Where  𝑤ℎ=
𝑛ℎ1𝑛ℎ2
𝑛ℎ1+𝑛ℎ2+1 ; 
and 𝑛ℎ1 and 𝑛ℎ2 are the sample size in the adjunctive pimavanserin and the adjunctive 
placebo treatment groups within region h.     


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13.1.5 Complete Case Analysis using ANCOVA in the Full Analysis Set 
The observed cases excluding missing values will be analyzed using an ANCOVA model 
with treatment group and region as factors and the Baseline value as a covariate. 
At each visit, the effect size (Cohen’s d) for the change from Baseline between the treatment 
groups will be calculated using the following formula: 
𝐸𝑓𝑓𝑒𝑐𝑡 𝑠𝑖𝑧𝑒= 𝐿𝑆 𝑚𝑒𝑎𝑛 𝑑𝑖𝑓𝑓𝑒𝑟𝑒𝑛𝑐𝑒
√𝑀𝑆𝐸
 
Where MSE is the mean squared error from the ANCOVA model. The sign (+ or -) of the 
effect size will be chosen so that a positive value favors pimavanserin. 
13.2 Key Secondary Efficacy Analysis 
The key secondary endpoint is the change from Baseline to Week 6 in the CGI-S score. The 
change from Baseline in the CGI-S score will be analyzed using an MMRM model similar to 
that described in Section 13.1.1 for the primary endpoint, except that the Baseline CGI-S 
score will be included in the model instead of the Baseline PANSS total score. The treatment 
comparison will be based on the difference in LS means at Week 6 and will be tested at an 
alpha level of 0.05 (2-sided) using the Full Analysis Set. 
Let Δ be the difference in the mean change from Baseline to Week 6 in the CGI-S score 
between the adjunctive pimavanserin and adjunctive placebo groups: 
The null hypothesis for the key secondary efficacy endpoint is:  
 
Δ = 0 
The alternative hypothesis for the key secondary efficacy endpoint is:  
Δ ≠ 0 
The MMRM analysis as described above will also be repeated in the Per-Protocol Analysis 
Set. 
Results will be presented in a summary table and line plots similar to the outputs described in 
Section 13.1.1. 
13.3 Other Secondary Efficacy Analyses 
13.3.1 Responder Analysis 
Three types of responders will be counted within each treatment group at each post-Baseline 
visit: 
 ≥ 20% reduction in the corrected PANSS total score (subtracting 30 points from the raw 
scores; see details below) from Baseline 


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 ≥ 30% reduction in the corrected PANSS total score (subtracting 30 points from the raw 
scores; see details below) from Baseline 
 CGI-I score of 1 (very much improved) or 2 (much improved) 
Note that since PANSS is an interval scale that lacks a natural zero point, the percent change 
in PANSS total score will be calculated based on corrected scores after subtracting 30 points 
from the raw scores (Leucht et al., 2007; Leucht et al., 2009; Obermeier et al., 2010; 
Obermeier et al., 2011). For example, if a subject’s Baseline PANSS total score is 80 and 
Week 6 PANSS total score is 30 (absent of all symptoms), the percent change from Baseline 
to Week 6 in PANSS total score will be calculated as [(30 – 30) – (80 – 30)] ÷ (80 – 30) × 
100% = -100%. 
For each responder analysis at each timepoint, the proportion of responders will be 
summarized by treatment group. The treatment groups will be compared using a Cochran-
Mantel-Haenszel (CMH) test stratified by geographic region (North America, Europe, or rest 
of world). The adjusted difference in percent responders between the treatment groups 
(adjunctive pimavanserin group minus adjunctive placebo group) using the weighting scheme 
of CMH and Newcombe’s 95% CI will also be presented.  
At any given visit, the subjects with missing values will be imputed as non-responders for 
that visit. Using this imputation method, the proportion of responders (≥ 20% reduction in the 
corrected PANSS total score, ≥ 30% reduction in the corrected PANSS total score, or with 
CGI-I score of 1 or 2) at Week 6 by treatment group will also be presented in a bar chart. 
In addition, an observed-case responder analysis (subjects with missing values at a given visit 
are excluded from the analysis for that visit) will also be performed. 
For change in PANSS total score from Baseline, the cumulative distribution function at Week 
6 for the observed cases will be plotted by treatment group. 
The proportion of subjects who were worsened or no change, based on CGI-I evaluation, will 
be summarized by treatment group for each visit. Worsening or no change is defined as 
having a CGI-I score of 4 (no change), 5 (minimally worse), 6 (much worse), or 7 (very 
much worse) at a given visit. The treatment groups will be compared using a similar CMH 
test as described above for the responder analyses. Results will be presented using 2 different 
missing-handling methods: (1) subjects with missing CGI-I at a given visit are considered as 
worsened or no change for that visit, and (2) observed-case analysis (subjects with missing 
values at a given visit are excluded from the analysis for that visit). 


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13.3.2 Other Secondary Efficacy Analysis for Continuous Variables 
The change from Baseline to each post-Baseline timepoint in the PANSS subscores (positive 
scale, negative scale, and general psychopathology scale) 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 PANSS total score. 
The CGI-I score at each post-Baseline timepoint will be analyzed using an MMRM model. 
The dependent variable will be the CGI-I score. The independent variables in the model will 
include the following: treatment group (adjunctive pimavanserin or adjunctive placebo), visit 
(Week 1, Week 2, Week 3, Week 4, Week 5, and Week 6), treatment-by-visit interaction, 
Baseline-by-visit interaction, geographic region (North America, Europe, or rest of world) 
and the Baseline CGI-S score (continuous covariate). 
To assess whether there is a linear correlation between the change in PANSS total score from 
Baseline and CGI-I rating, the change in PANSS total score from Baseline will also be 
summarized by CGI-I rating and treatment group for all post-baseline visits.  The mean + SE 
change in PANSS total score from Baseline by CGI-I rating will also be plotted for Week 6 
observed cases. 
The change from Baseline to Week 6 in the PSP and DAI-10 scores will be analyzed using an 
analysis of covariance (ANCOVA) model with treatment group (adjunctive pimavanserin or 
adjunctive placebo) and geographic region (North America, Europe, or rest of world) as 
factors, and the Baseline value of the endpoint being analyzed as a covariate. Missing values 
will be imputed with the previous value (including Baseline) for that subject, i.e. last 
observation carried forward (LOCF). In addition, an observed-case analysis, ignoring missing 
values, will also be performed. 
At Week 6, the effect size (Cohen’s d) for the change from Baseline between the treatment 
groups will be calculated using the following formula: 
𝐸𝑓𝑓𝑒𝑐𝑡 𝑠𝑖𝑧𝑒= 𝐿𝑆 𝑚𝑒𝑎𝑛 𝑑𝑖𝑓𝑓𝑒𝑟𝑒𝑛𝑐𝑒
√𝑀𝑆𝐸
 
Where MSE is the mean squared error from the ANCOVA model. The sign (+ or -) of the 
effect size will be chosen so that a positive value favors pimavanserin. 
Results will be presented in summary tables similar to the outputs described in 
Section 13.1.1. 


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13.4 Exploratory Efficacy Analyses  
The change from Baseline to each post-Baseline timepoint in the PANSS Marder factor 
scores (negative symptoms, positive symptoms, disorganized thought, uncontrolled 
hostility/excitement, and anxiety/depression factors) and the PANSS individual item scores 
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 PANSS total score. 
The change from Baseline to Week 6 in the CDSS and the normalized SF-36 scale scores and 
composite scores (physical functioning, bodily pain, role limitations due to physical health 
problems, role limitations due to personal or emotional problems, emotional well-being, 
social functioning, energy/fatigue, and general health perceptions scale scores; physical 
health composite score, mental health composite score) will be analyzed using an analysis of 
covariance (ANCOVA) model with treatment group (adjunctive pimavanserin or adjunctive 
placebo) and geographic region (North America, Europe, or rest of world) as factors, and the 
Baseline value of the endpoint being analyzed as a covariate. Missing values will be imputed 
using LOCF. In addition, an observed-case analysis, ignoring missing values, will also be 
performed. 
Results will be presented in summary tables similar to the outputs described in 
Section 13.1.1. 
Correlations among efficacy endpoints (observed cases) will be assessed using Spearman’s 
rank correlation coefficient (Spearman’s rho) and presented in a correlation matrix. The 95% 
CIs for the Spearman’s rank correlation coefficients will also be presented. 
14 SAFETY ANALYSES 
The safety analysis will be performed based on the Safety Analysis Set using actual 
treatment. Safety variables include adverse events (AEs), clinical laboratory variables, vital 
signs, body weight, BMI, physical examinations, electrocardiogram (ECG), C-SSRS, AIMS, 
BARS and SAS variables. 
14.1 Adverse Events  
All Adverse events (AEs) will be coded using MedDRA version 19.0 or newer. 
An AE (classified by preferred term) will be considered a treatment-emergent AE (TEAE) if 
it started after first study dose administration and no later than last study dose date + 30. AEs 
reported on Day 1 based on Baseline (pre-dose) findings (e.g. clinically significantly 


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abnormal vital signs, laboratory test results, or electrocardiogram parameters) will not be 
considered as TEAEs.  
The event counts and the number and percentage of subjects reporting TEAEs in each 
treatment group will be tabulated by SOC and preferred term; and, by SOC, preferred term, 
and maximum severity. If more than 1 AE occurs with the same preferred term for the same 
subject, the subject will be counted only once for that preferred term using the most severe 
occurrence for the summarization by severity. In addition, the event counts and the number 
and percentage of subjects with TEAEs classified by the Investigators as related to the study 
drug, with most frequently reported TEAEs (preferred terms reported by ≥ 5% of subjects in 
either treatment group), with treatment-emergent serious AEs (TESAEs), with fatal AEs (i.e. 
events that cause death), and with TEAEs leading to discontinuation of study drug will be 
summarized by SOC and preferred term within each treatment group. The display in these 
tables will be sorted alphabetically by SOC and then by descending subject frequency for the 
preferred terms (combined counts from both treatment groups) within each SOC. 
The event counts and the number and percentage of subjects with any TEAEs will also be 
tabulated by preferred term without SOCs within each treatment group. This table will be 
sorted by descending subject frequency using combined counts from both treatment groups. 
An AE listing by subject will display all events, including those which are not treatment-
emergent, and will include the verbatim term in addition to the MedDRA SOC and preferred 
term. This listing will also include all relevant eCRF data associated with the event: e.g. date 
of onset, date resolved, date of first dose, date of last dose, last prescribed study dose level at 
AE onset, severity, frequency, outcome, relationship to study drug, action taken with study 
drug, and required therapy. When a date is presented, the study day associated with the date 
will also be displayed. Separate listings will be presented for subjects with SAEs, subjects 
with AEs leading to discontinuation and subjects who died (if any). In these listings, an 
indicator for treatment-emergent events will also be included. 
14.2 Clinical Laboratory Variables 
Clinical laboratory tests are performed at Screening, Baseline and Week 6/ET visits. 
• Hematology tests include the following: 
o Complete blood count (CBC) including: 
− 
White blood cell (WBC) count 
− 
Complete differential (relative and absolute) 
− 
Hematocrit (Hct), hemoglobin (Hgb), red blood cells (RBC), platelets 
− 
Reticulocyte  


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 Serum chemistry tests include the following: 
o Sodium (Na) , potassium (K), chloride (Cl), phosphorus (P), calcium (Ca), carbon 
dioxide (CO2), blood urea nitrogen (BUN), creatinine (Cr), uric acid 
o Alanine aminotransferase (ALT/SGPT), aspartate aminotransferase (AST/SGOT), 
gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), total bilirubin 
(TBIL), lactate dehydrogenase (LDH), glucose 
o Albumin (ALB), total protein 
o Creatine kinase (CK)/creatine phosphokinase (CPK) 
o Prolactin 
o Lipid panel  
– Total cholesterol, high-density lipoprotein (HDL)-cholesterol, triglycerides, 
low-density lipoprotein(LDL)-cholesterol, cholesterol/HDL ratio, non-HDL 
cholesterol 
o Screening only: 
– HbA1c 
– Thyroid stimulating hormone (TSH); full thyroid panel only if TSH value is 
outside of the laboratory reference range (full thyroid panel will be listed but 
not summarized)  
– Presence or absence of the identified main antipsychotic in the plasma will 
also be assessed at Screening (will be listed but not summarized) 
 Urinalysis tests include the following: 
o Occult blood, leukocyte esterase, protein, glucose, ketones, specific gravity, pH 
All laboratory test results (including urine drug screen) are from a central laboratory and will 
be listed. The listings will include date and study day of collection. All units will be displayed 
in Système International [SI] units. Out of range values will be flagged in the data listings 
(e.g. ‘L’ or ‘H’). 
Clinical laboratory values for hematology, chemistry and urinalysis (red blood cells, white 
blood cells, specific gravity and pH) will be summarized by treatment group using 
descriptive statistics at Baseline and Week 6 visits. The change from Baseline values will also 
be summarized by treatment group at the Week 6 visit. The overall minimum and maximum 
post-Baseline observed and change from Baseline values will also be summarized. For 
hemoglobin, hematocrit and uric acid, the above summaries will be presented for each gender 
as well as for both genders combined. For urinalysis with categorical results (blood, protein, 
glucose, and ketones), the number and percentage of subjects will be tabulated by category at 
Baseline and Week 6, and the denominator is the number of subjects with non-missing values 
for the given parameter, visit and treatment group. 
Laboratory values (except the ones that were only assessed at screening) will also be 
summarized in shift tables by treatment group, to determine the number and percentage of 


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subjects with values classified as below (low), within (normal), and above (high) normal 
ranges at Week 6, overall post-Baseline minimum and overall post-Baseline maximum, 
relative to the same classification at the Baseline visit. For the by-visit shift summary, the 
denominator is the number of subjects with non-missing values at Baseline and the given 
visit for the given parameter and treatment group. For the shift to the overall post-Baseline 
minimum or maximum, the denominator is the number of subjects with non-missing Baseline 
and at least 1 post-Baseline value for the given parameter and treatment group. For 
hemoglobin, hematocrit and uric acid, the shift summaries will be presented for each gender 
as well as for both genders combined. 
Number and percentage of subjects with potentially clinically important laboratory values 
(PCI) at Week 6 and overall post-Baseline will be summarized by treatment group for 
selected parameters. PCI criteria are listed in Table 5 and Table 6. For the overall post-
Baseline summaries of PCI values, all post-Baseline values will be considered, including 
unscheduled and out of window values. Subjects with multiple PCI values for a given 
parameter will be counted only once for that parameter. For the by-visit summary, the 
numerator for the percentage is the number of subjects with a post-Baseline PCI value for the 
given parameter, visit and treatment group, and the denominator is the number of subjects 
with non-missing values for the given parameter, visit and treatment group. For the overall 
post-Baseline summary, the numerator for the percentage is the number of subjects with at 
least 1 post-Baseline PCI laboratory value for the given parameter and treatment group, and 
the denominator is the number of subjects with at least 1 post-Baseline laboratory value for 
the given parameter and treatment group. For hemoglobin, hematocrit and uric acid, the count 
and percentage of subjects with PCI values will be presented for each gender as well as for 
both genders combined. Subjects with any PCI values will be presented in an additional 
listing. 


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Table 5 
Criteria for Potentially Clinically Important Laboratory Values – 
Hematology and Chemistry 
 
Analyte 
Conventional 
Unit 
Low PCI 
Criteria 
High PCI 
Criteria 
SI Unit 
Low PCI 
Criteria 
High PCI 
Criteria 
Hematology (whole blood) 
Hemoglobin (male) 
g/dL 
<11 
>18 
g/L 
<110 
>180 
Hemoglobin 
(female) 
g/dL 
<10 
>17 
g/L 
<100 
>170 
Hematocrit (male) 
% 
<30 
>55 
L/L 
<0.3 
>0.55 
Hematocrit (female) 
% 
<30 
>50 
L/L 
<0.3 
>0.5 
Leukocyte (White 
Blood Cell Count) 
x 103/uL 
≤2.8 
≥15 
x 109/L 
≤2.8 
≥15 
Neutrophils 
x 103/uL 
≤1.5 
No upper limit 
x 109/L 
≤1.5 
No upper limit 
Platelet Count 
x 103/uL 
≤75 
≥700 
109/L 
≤75 
≥700 
Chemistry (serum or plasma) 
ALT (SGPT) 
U/L 
No lower 
limit  
≥3 X ULN 
U/L 
No lower 
limit  
≥3 X ULN 
AST (SGOT) 
U/L 
No lower 
limit  
≥3 X ULN 
U/L 
No lower 
limit  
≥3 X ULN 
Total Bilirubin 
mg/dL 
No lower 
limit 
≥1.5 ULN 
umol/L 
No lower 
limit 
≥1.5 ULN 
BUN 
mg/dL 
No lower 
limit 
≥30.0 
mmol/L 
No lower 
limit 
≥10.71 
Creatine Kinase 
(CK) 
U/L 
No lower 
limit 
≥3 ULN 
U/L 
No lower 
limit 
≥3 ULN 
Sodium 
mEq/L 
≤125 
≥155 
mmol/L 
≤125 
≥155 
Potassium 
mEq/L 
≤3.0 
≥5.5 
mmol/L 
≤3.0 
≥5.5 
Calcium, total 
mg/dL 
<8.0 
>11.0 
mmol/L 
<2.0 
>2.75 
Lactate 
Dehydrogenase 
(LDH) 
U/L 
No lower 
limit 
≥3 X ULN 
U/L 
No lower 
limit 
≥3 X ULN 
Alkaline 
Phosphatase 
U/L 
No lower 
limit 
≥3 X ULN 
U/L 
No lower 
limit 
≥3 X ULN 
Uric acid (male) 
mg/dL 
No lower 
limit 
≥10.5 
umol/L 
No lower 
limit 
≥624.75 
Uric acid (female) 
mg/dL 
No lower 
limit 
≥8.5 
umol/L 
No lower 
limit 
≥505.75 
Albumin 
g/dL 
≤2.6 
≥6.0 
g/L 
≤26 
≥60 
Total Protein 
g/dL 
≤5.0 
≥10.0 
g/L 
≤50 
≥100 
Chloride 
mEq/L 
≤85 
≥120 
mmol/L 
≤85 
≥120 
Glucose (random) 
mg/dL 
≤45.1 
≥200.0 
mmol/L 
≤2.48 
≥11 
Serum Creatinine 
mg/dL 
Not 
Applicable 
>1.5 ULN 
umol/L 
Not 
Applicable 
>1.5 ULN 
Triglycerides 
mg/dL 
Not 
Applicable 
>300 
mmol/L 
Not 
Applicable 
>3.39 
Gamma-Glutamyl 
Transferase (GGT) 
U/L 
Not 
Applicable 
≥3 ULN 
U/L 
Not 
Applicable 
≥3 ULN 
 


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Table 6 
Criteria for Potentially Clinically Important Laboratory Values - Urinalysis 
Urinalysis (qualitative dipstick) 
Low PCI Criteria 
High PCI Criteria 
Blood (occult blood) 
Not Applicable 
≥+2 
Protein 
Not Applicable 
≥+2 
Glucose 
Not Applicable 
≥+2 
 
The pregnancy results (positive or negative) for female subjects will be presented in a listing. 
14.3 Vital Signs 
Vital signs are assessed at Screening, Baseline, Weeks 1, 2, 3, 4, 5 and Week 6/ET visits. 
Vital signs including weight, height (only at screening), and the derived BMI will be 
summarized by treatment group using descriptive statistics at Baseline and all post-Baseline 
visits. The change from Baseline values will also be summarized by treatment group at the 
post-Baseline visits. 
Vital sign values will be considered PCI if they meet both the observed value criteria and the 
change from baseline criteria listed in Table 7. The number and percentage of subjects with 
post-Baseline vital signs that are PCI will be summarized by treatment group at each post-
Baseline visit and for overall post-Baseline. For the overall post-Baseline summaries, all 
post-Baseline values will be considered, including unscheduled and out of window values. 
Subjects with multiple PCI values for a given parameter will be counted only once for that 
parameter. For the by-visit summary, the numerator for the percentage is the number of 
subjects with a post-Baseline PCI vital sign for the given parameter, visit and treatment 
group, and the denominator is the number of subjects with non-missing values for the given 
parameter, visit and treatment group. For the overall post-Baseline summary, the numerator 
for the percentage is the number of subjects with at least 1 post-Baseline PCI vital sign for 
the given parameter and treatment group, and the denominator is the number of subjects with 
at least 1 post-Baseline vital sign for the given parameter and treatment group. A listing of all 
subjects with any PCI values will be provided. 


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Table 7 
Criteria for Potentially Clinically Important Vital Signs 
 
Vital Sign Parameter 
 
Unit 
Criteriaa 
Observed 
Value 
And/Or 
Change Relative to Baseline 
Systolic blood pressure 
(supine or sitting) 
mmHg 
180 
And 
Increase of ≥20 
90 
And 
Decrease of ≥20 
Diastolic blood pressure 
(supine or sitting) 
mmHg 
105 
And 
Increase of ≥15 
50 
And 
Decrease of ≥15 
Pulse (supine or sitting) 
bpm 
120 
And 
Increase of ≥15 
50 
And 
Decrease of ≥15 
Weight 
kg 
Not Applicable 
Increase of ≥7% 
Decrease of ≥7% 
a 
A post-baseline value is considered as a PCI value if it meets both criteria for observed value and change 
from baseline. 
14.4 Electrocardiogram (ECG) 
Electrocardiogram is performed at Screening, Baseline, Week 4 and Week 6/ET visits. 
All tracings will be evaluated by a central reading laboratory. At the Baseline visit, the 
machine-read results will also be recorded. All data, including the machine-read Baseline 
results, will be listed. ECG data summaries will be performed using the centrally evaluated 
data. 
Observed values of ECG variables (heart rate, PR interval, RR interval, QRS interval, QT 
interval, and QTc intervals) and the changes from baseline at each assessment timepoint will 
be summarized by treatment group. QTc intervals include QTcB (Bazett’s formula) and QTcF 
(Fridericia’s formula). 
QTcF will also be categorized into the following categories (msec) and the number and 
percentage of subjects in each category will be summarized by treatment group at each visit 
and for the overall post-baseline maximum: 
 Observed: ≤450, 451 to 480, 481 to 500, and >500 
 Change from Baseline: ≤10, 11 to 30, 31 to 60, and >60 


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For cardiologist’s interpretations, the number and percentage of subjects with ECG results 
that are determined as normal or abnormal will be summarized at scheduled visits. The 
overall post-baseline worst interpretation will also be summarized (i.e. if a subject has one or 
more post-baseline ECG results that is/are considered as abnormal, this subject will be 
counted in the abnormal category). Cardiologist’s interpretations will also be summarized in 
a shift table to determine the number and percentage of subjects with ECG results classified 
as normal or abnormal at scheduled post-Baseline visits relative to the same classification at 
the Baseline visit. The shifts from Baseline to overall post-Baseline worst interpretation will 
also be presented. For the by-visit shift summary, the denominator is the number of subjects 
with non-missing cardiologist’s interpretation at Baseline and the given visit for the given 
treatment group. For the summaries of shift from Baseline to the overall post-Baseline worst 
interpretation, the denominator is the number of subjects with non-missing Baseline and at 
least 1 post-Baseline cardiologist’s interpretation for the given treatment group.  
Electrocardiogram variable values will be considered PCI if they meet or exceed the upper 
limit values listed in Table 8. The number and percentage of subjects with post-baseline PCI 
values will be summarized by treatment group at each post-Baseline visit and for overall 
post-Baseline. For the by-visit summary, the numerator for the percentage is the number of 
subjects with a post-Baseline PCI ECG for the given parameter, visit and treatment group, 
and the denominator is the number of subjects with non-missing values for the given 
parameter, visit and treatment group. For the overall post-Baseline summary, the numerator 
for the percentage is the number of subjects with at least 1 post-Baseline PCI ECG for the 
given parameter and treatment group, and the denominator is the number of subjects with at 
least 1 post-Baseline ECG value for the given parameter and treatment group. A listing of all 
subjects with any PCI values will be provided. 
Table 8 
Criteria for Potentially Clinically Important ECG Values 
ECG Parameter 
Unit 
High PCI Criteria 
QRS Interval 
msec 
120 
PR Interval 
msec 
220 
QTcB or QTcF 
msec 
>500 
QTcB or QTcF: change from baseline 
>60 msec 
 
14.5 Physical Examination 
Physical examination is performed at Screening, Baseline, and Week 6/ET visits. 
Physical examination results (normal, abnormal, and not done) at Baseline and Week 6 will 
be summarized in a frequency table by treatment group, body system and visit. 


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14.6 Other Safety Variables 
14.6.1 Suicidality 
The C-SSRS is assessed at Screening, Baseline, Weeks 1, 2, 3, 4, 5, and Week 6/ET visits. 
The event counts and the number and percentage of subjects reporting any post-Baseline 
suicidal ideation (wish to be dead; non-specific active suicidal thoughts; active suicidal 
ideation with any methods (not plan) without intent to act; active suicidal ideation with some 
intent to act, without specific plan; active suicidal ideation with specific plan and intent), 
suicidal behavior (preparatory acts or behavior; aborted attempt; interrupted attempt; actual 
attempt; suicide), or suicidality (any suicidal ideation or behavior) will be tabulated for each 
treatment group. 
14.6.2 Extrapyramidal Symptom Measures 
14.6.2.1 
Abnormal Involuntary Movement Scale (AIMS) 
The AIMS is assessed at Baseline, Weeks 1, 3 and Week 6/ET visits. 
The AIMS total score will be summarized by treatment group using descriptive statistics at 
Baseline, Weeks 1, 3 and 6 visits. The change from Baseline scores will also be summarized 
by treatment group at Weeks 1, 3 and 6 visits. 
In addition, the number and percentage of subjects with dyskinesia will be summarized by 
treatment group at each visit and for overall post-Baseline. Dyskinesia is defined as having a 
score of 3 or more on any of the first 7 AIMS items or a score of 2 or more on any two of the 
first 7 AIMS items. If there are multiple assessments performed within the same visit 
window, all assessments will be evaluated using the above criteria. The tabulations will be 
presented for subjects who have at least 1 AIMS assessment as well as for a subset of these 
subjects who do not have dyskinesia at Baseline. 
The individual item scores will be listed but not summarized. 
14.6.2.2 
Barnes Akathisia Scale (BARS)  
The BARS is assessed at Baseline, Weeks 1, 3 and Week 6/ET visits. 
The BARS total score and the Global Clinical Assessment of Akathisia score will be 
summarized by treatment group using descriptive statistics at Baseline, Weeks 1, 3 and 6 
visits. The change from Baseline scores will also be summarized by treatment group at 
Weeks 1, 3 and 6 visits. 
In addition, the number and percentage of subjects with akathisia will be summarized by 
treatment group at each visit and for overall post-Baseline. Akathisia is defined as having a 


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Global Clinical Assessment of Akathisia score ≥2. If there are multiple assessments 
performed within the same visit window, all assessments will be evaluated using the above 
criteria. The tabulations will be presented for subjects who have at least 1 BARS assessment 
as well as for a subset of these subjects who do not have akathisia at Baseline. 
The individual item scores will be listed but not summarized. 
14.6.2.3 
Simpson Angus Scale (SAS) 
The SAS is assessed at Baseline, Weeks 1, 3 and Week 6/ET visits. 
The SAS total score will be summarized by treatment group using descriptive statistics at 
Baseline, Weeks 1, 3 and 6 visits. The change from Baseline scores will also be summarized 
by treatment group at Weeks 1, 3 and 6 visits. 
The number and percentage of subjects with Parkinsonism will be summarized by treatment 
group at each visit and for overall post-Baseline. Parkinsonism is defined as having a SAS 
total score >3. If there are multiple assessments performed within the same visit window, all 
assessments will be evaluated using the above criteria. The tabulations will be presented for 
subjects who have at least 1 SAS assessment as well as for a subset of these subjects who do 
not have Parkinsonism at Baseline. 
The individual item scores will be listed but not summarized. 
15 CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
PK samples for pimavanserin, its metabolite (AC-279), and the main background 
antipsychotic medications are collected pre-dose at Baseline, Weeks 1, 3 and Week 6/ET 
visits. 
For pimavanserin-treated subjects, plasma concentration for pimavanserin and AC-279 will 
be listed. For pimavanserin-treated subjects in the Pharmacokinetics Analysis Set, plasma 
concentration for pimavanserin and AC-279 will be summarized using descriptive statistics 
by visit and the last dose level received before the PK sample is drawn. Note that if there is a 
dose adjustment at Week 1 or Week 3, the dose level of the PK sample will reflect the 
previous dose level before the adjustment since the PK sample is collected before the dose 
adjustment. Concentrations that are below the limit of quantification (BLQ) will be displayed 
as “BLQ” in the data listings and imputed as 0 for computing summary statistics. 
Plasma concentration data for the background main antipsychotics will be listed. 
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 


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modeling will be presented in a separate report. Pimavanserin and AC-279 plasma 
concentration data will remain blinded until the unblinding of the clinical database at the end 
of the study. 
16 UNBLINDED INTERIM ANALYSIS 
One interim analysis to assess futility based on the primary endpoint will be conducted by an 
independent statistician when 152 subjects (40% of the planned sample size) complete the 
Week 6 visit or discontinue from the study before the data extract date. The independent 
statistical group not affiliated with the Sponsor or the DSMB will compute the predictive 
power as detailed below and will communicate to the DSMB. The DSMB chair will 
communicate to the Sponsor designated contact person in writing whether the study met the 
futility criterion or not (a binary outcome “met futility criterion” or “did not meet futility 
criterion”). In order to protect the blinding and the integrity of this study, only the binary 
outcome will be reported to the Sponsor without any specific results. The actual 
computational output will be securely stored by the independent statistical group and retained 
until the study is unblinded after the final database lock.  
For futility evaluation, the predictive power will be computed based on the interim data using 
this formula (Jennison and Turnbull 2000): 
𝑃𝑟𝑒𝑑𝑖𝑐𝑡𝑖𝑣𝑒 𝑃𝑜𝑤𝑒𝑟= 𝛷(
−𝑍𝑘√𝐼𝐹−𝑧1−𝛼/2√𝐼𝑘
√𝐼𝐹−𝐼𝑘
) 
Where 
𝛷 is the cumulative distribution function of the standard normal distribution; 
Zk is the t statistic computed from the interim observed data at time k for the treatment group 
comparison (adjunctive pimavanserin minus adjunctive placebo) of the change from Baseline 
in PANSS total scores at Week 6 using the MMRM model specified in Section 13.1.1; 
𝑧1−𝛼/2 is the standard normal value for the test with a 1-sided type 1 error rate of 𝛼2
⁄  = 
𝑧0.975; 
Ik is the interim information level = 
1
𝜎2 ( 1
𝑛1𝑘
+ 1
𝑛2𝑘
) ; 
IF is the final information level = 
1
𝜎2( 1
𝑛1+ 1
𝑛2) ; 
𝜎2 is the pooled variance from the interim observed data obtained from the covariance matrix 
estimated for MMRM; 


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𝑛1𝑘 and 𝑛2𝑘 are the interim sample size in the adjunctive pimavanserin and the adjunctive 
placebo treatment groups at time k ; 
𝑛1 and 𝑛2 are the final sample size in the adjunctive pimavanserin and the adjunctive placebo 
treatment groups. 
The predictive power assesses the probability that the study will be able to demonstrate a 
significant difference in favor of pimavanserin (for the primary endpoint) at the final 
analysis, given the interim data. At the interim analysis, the study may be terminated if the 
predictive power is less than 0.2. This study will not be stopped early for superior efficacy 
and therefore the type 1 error rate will not be inflated. Investigators and Sponsor personnel 
will remain blinded throughout the study. 
17 DATA MONITORING/REVIEW COMMITTEE 
An independent Data and Safety Monitoring Board (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 roles and responsibilities of DSMB members and planned frequency of 
meetings are detailed in the DSMB Charter.  
An independent statistician (and/or programmer) not affiliated with the Sponsor will produce 
unblinded statistical outputs and provide these outputs to DSMB members using a secure 
method. The Sponsor and the Investigators will remain blinded until the official unblinding 
of the database at the end of the study. The outputs presented to DSMB members will include 
but are not limited to summaries of enrollment and disposition, demographics and baseline 
characteristics, medical and schizophrenia histories, concomitant medications, study drug 
exposure, all treatment-emergent adverse events (including deaths, SAE and AEs leading to 
discontinuation), vital signs, laboratory test results, and ECG parameters. Subject profiles, 
boxplots of Baseline and most extreme post-Baseline values for clinical laboratory data, and 
listings of AEs and potentially clinically important laboratory and QTcF results will also be 
provided to DSMB members for their review. 
18 COMPUTER METHODS  
Statistical analyses will be performed using Version 9.4 (or newer) of SAS (SAS® Institute, 
Inc., Cary, North Carolina) on a suitably qualified and validated environment. 
Validation and quality control of the tables, listings and figures containing the results of the 
statistical analyses will follow appropriate standard operating procedures. 


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19 CHANGES TO ANALYSES SPECIFIED IN PROTOCOL 
The protocol stated that a hierarchical testing procedure will be used to control the Type 1 
error rate across the primary and secondary endpoints. As indicated in this SAP, the 
hypothesis testing for the primary and key secondary efficacy endpoints will be tested in a 
hierarchical (sequential) order. For other secondary endpoints, nominal p-values for the 
treatment-group comparisons will be reported. 


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20 REFERENCES 
Jennison C and Turnbull BW (2000). Group Sequential Methods with Applications to 
Clinical Trials. Chapman & Hall/CRC: New York, NY; 210-213. 
Leucht S, et al. Defining ‘response’ in antipsychotic drug trials: recommendations for the use 
of scale-derived cutoffs. Neuropsychopharmacology. 2007; 32: 1903-1910. 
Leucht S, et al. Definitions of response and remission in schizophrenia: recommendations for 
their use and their presentation. Acta Psychiatr Scand. 2009; 119 (Suppl. 438): 7-14. 
Obermeier M, et al. Should the PANSS be rescaled? Schizophrenia Bulletin. 2010; 36(3): 
455-460. 
Obermeier M, et al. Is the PANSS used correctly? A systematic review. BMC Psychiatry. 
2011; 11:113. 
 
 
 


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21 APPENDICES 
21.1 Summary of Version Changes   
Version No: 
Document History 
Description of Update 
Author(s) 
Version Date 
1.0 
Original version 
 
01 June 2018