Clinical trial NCT04531982
Conditions: Schizophrenia
Sponsor: ACADIA Pharmaceuticals Inc.
Start date: 2020-08-05; Completion date: 2024-02-19
Enrollment: 454 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 negative symptoms of schizophrenia

Detailed description:

Arms: arm 1: Pimavanserin 34 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, taken as two blinded 17 mg tablets once daily by mouth intervention 2: Placebo, taken as two blinded tablets once daily by mouth

Protocol documents:
Prot_000.pdf: 
 
 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc. 
Page 1 of 94 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of Pimavanserin as Adjunctive Treatment 
for the Negative Symptoms of Schizophrenia (ADVANCE-2) 
 
Protocol Number: ACP-103-064 
Amendment 3 
 
EudraCT Number: 2019-003343-29 
 
Original Protocol Date: 04 September 2019 
Protocol Amendment 1 Date: 14 January 2020 
Protocol Amendment 2 Date: 07 August 2020 
Protocol Amendment 3 Date: 05 October 2022 
 
Protocol Template Version: 0.2 
Confidentiality Statement 
This protocol is the confidential information of Acadia Pharmaceuticals Inc. and is intended solely for the 
guidance of the clinical investigation. This protocol may not be disclosed to parties not associated with the 
clinical investigation or used for any purpose without the prior written consent of Acadia Pharmaceuticals Inc. 


Study: ACP-103-064 
 
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Date: 05 October 2022 
 
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SPONSOR SIGNATURE PAGE 
Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the 
Efficacy and Safety of Pimavanserin as Adjunctive Treatment for the Negative 
Symptoms of Schizophrenia (ADVANCE-2) 
 
 Clinical 
Development: 
 MD 
(delegate of 
 
of Acadia) 
Acadia Pharmaceuticals Inc. 
 
 
  
Phone: 
 
See appended electronic signature page 
 
 
Signature 
Date 
 
 
 
Acadia Study Lead: 
 MD 
 Clinical Development 
Acadia Pharmaceuticals GmbH 
 
 
 
Phone: 
 
See appended electronic signature page 
 
 
Signature 
Date 
 
 
 
 
 
 
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PPD
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PPD
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Si g nat ure Pa ge f or A C P- 1 0 3- 0 6 4 Pr ot oc ol A me n d me nt 3
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A p pr o ve
0 6- Oct- 2 0 2 2 1 8: 5 6: 4 1 G M T + 0 0 0 0
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P P D


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DECLARATION OF INVESTIGATOR 
I confirm that I have read the above protocol. I understand it, and I will work according to the 
moral, ethical, and scientific principles governing clinical research as set out in the principles 
of Good Clinical Practice, as required by International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) Guideline E6 and as 
described in the United States (US) Code of Federal Regulations (CFR) 21 CFR parts 50, 54, 
56, 312, and according to applicable local requirements. 
Confidentiality Statement 
The confidential information in this document is provided to you as an Investigator or 
Consultant for review by you, your staff, and the applicable institutional review board/ethics 
committee. Your acceptance of this document constitutes agreement that you will not disclose 
the information contained herein to others without written authorization from the Sponsor. 
Investigator 
 
 
Signature 
 
Date 
 
 
 
Name (printed) 
 
 
 
 


Study: ACP-103-064 
 
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PROTOCOL SYNOPSIS 
Protocol Number 
ACP-103-064 
EudraCT Number 
2019-003343-29 
Protocol Title 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of Pimavanserin as Adjunctive 
Treatment for the Negative Symptoms of Schizophrenia 
(ADVANCE-2) 
Name of 
Investigational 
Product 
Pimavanserin (tablets) 
Indication 
Adjunctive treatment of the negative symptoms of schizophrenia 
Phase of 
Development 
3 
Sponsor 
Acadia Pharmaceuticals Inc. 
12830 El Camino Real, Suite 400 
San Diego, CA 92130 USA  
Primary Objective 
• To evaluate the efficacy of pimavanserin 
compared with placebo in the adjunctive 
treatment of the negative symptoms of 
schizophrenia 
Primary Endpoint 
• Change from Baseline to Week 26 in the 
Negative Symptom Assessment–16 
(NSA-16) total score 
Secondary Objective 
• To evaluate the effect of adjunctive 
pimavanserin compared with adjunctive 
placebo on global impression of severity 
of illness, global improvement of 
symptoms of illness, personal and social 
performance, and response to treatment in 
adults experiencing negative symptoms of 
schizophrenia 
Secondary Endpoints 
Key Secondary Endpoint: 
• Change from Baseline to Week 26 in the 
Clinical Global Impression of 
Schizophrenia Scale–Severity 
(CGI-SCH-S) of negative symptoms score 
Other Secondary Endpoints: 
• Clinical Global Impression of 
Schizophrenia Scale–Improvement 
(CGI-SCH-I) of negative symptoms score 
at Week 26 
• Proportion of CGI-SCH-I of negative 
symptoms responders (CGI-SCH-I of 
negative symptoms score of 1 or 2) at 
Week 26 


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• Change from Baseline to Week 26 in the 
Personal and Social Performance (PSP) 
scale score 
• Proportion of NSA-16 responders (≥20% 
and ≥30% reduction in NSA-16 total 
score) at Week 26 
• Change from Baseline to Week 26 in the 
Positive and Negative Syndrome Scale 
(PANSS) total score 
• Change from Baseline to Week 26 in 
PANSS negative subscores 
• Change from Baseline to Week 26 in 
PANSS Marder factor (negative 
symptoms) score 
Exploratory Objective 
• To evaluate the effect of adjunctive 
pimavanserin compared with adjunctive 
placebo in adults experiencing negative 
symptoms of schizophrenia with respect to 
change in symptom domains, readiness to 
work, cognition, and depression 
Exploratory Endpoints 
• Change from Baseline to Week 26 in 
PANSS subscores (positive and general) 
• Change from Baseline to Week 26 in 
PANSS Marder factor (positive symptoms, 
disorganized thought, uncontrolled 
hostility/excitement, depression/anxiety) 
scores 
• Change from Baseline to Week 26 in Work 
Readiness Questionnaire (WoRQ) total 
score 
• Change from Baseline to Week 26 in Work 
Readiness Questionnaire (WoRQ) 
readiness to work question (item 8) 
• Change from Baseline to Week 26 in Brief 
Assessment of Cognition in Schizophrenia 
(BACS) score 
• Change from Baseline to Week 26 in 
Calgary Depression Scale for 
Schizophrenia (CDSS) score 
Safety Objective 
• To evaluate the safety and tolerability of 
pimavanserin compared with placebo in 
the adjunctive treatment of the negative 
symptoms of schizophrenia 
Safety Endpoints 
Safety will be evaluated by analyses of the 
following: 
• Treatment-emergent adverse events 


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• Vital signs 
• ECGs 
• Physical examination results 
• Clinical laboratory tests (including 
urinalysis) 
• Abnormal Involuntary Movement 
Scale (AIMS) 
• Barnes Akathisia Rating Scale (BARS) 
• Simpson-Angus Extrapyramidal Side 
Effects Scale (SAS) 
• Columbia–Suicide Severity Rating 
Scale (C-SSRS). 
Pharmacokinetic Objective 
• To characterize the pharmacokinetics (PK) 
and pharmacodynamics of pimavanserin in 
the adjunctive treatment of the negative 
symptoms of schizophrenia 
Pharmacokinetic Endpoints 
• Plasma concentration of pimavanserin, 
AC-279 (N-desmethyl-pimavanserin, 
major metabolite), and the main 
antipsychotic 
• Pimavanserin pharmacokinetic parameters 
using a population pharmacokinetic 
approach 
• Pharmacokinetics/pharmacodynamics 
(PK/PD) using appropriate PK/PD analysis 
methods 
Number of Study 
Sites 
Approximately 88 global sites and 12 countries will participate in this 
study. 
Number of Subjects 
Planned 
Approximately 692 subjects will be screened and 426 subjects are 
planned for randomization (213 subjects in each treatment arm), 
assuming a screen failure rate of 38%. 
Test Product, Dose, 
and Administration 
The test products are pimavanserin 17 mg tablets or matching placebo 
tablets. Daily doses to be studied are: 
• Pimavanserin 34 mg (provided as 2 × 17 mg pimavanserin 
tablets); or  
• Placebo (provided as 2 × placebo tablets).  
All doses will be delivered by mouth. 
Seventeen (17) mg of the active moiety is dosed as 20 mg of the salt 
pimavanserin tartrate. 


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Study Design 
This study will be conducted as a Phase 3, 26-week, randomized, 
double-blind, placebo-controlled, multicenter, multinational outpatient 
study in subjects with schizophrenia who have predominant negative 
symptoms while on adequate treatment with an antipsychotic. 
Schizophrenia is defined by the Diagnostic and Statistical Manual of 
Mental Disorders, Fifth Edition (DSM-5), confirmed by a customized 
module of the Structured Clinical Interview for DSM-5, Clinical Trials 
Version (SCID-5-CT). 
This study will enroll approximately 426 subjects (213 subjects per 
treatment group) with predominant negative symptoms of 
schizophrenia. On the first day of the randomized treatment phase 
(Baseline), eligible subjects will be randomly assigned to receive 
pimavanserin 34 mg 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 the world). The daily dose of the main antipsychotic must 
remain stable and may not be changed from Screening through the 
duration of the study. Subjects will participate in the study for up to 
36 weeks, including a Screening Period of up to 6 weeks, a 26-week 
Treatment Period, and a 30 (+4) day safety follow-up (telephone call 
visit) 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). 
The schedule of assessments is provided in Table S-1. 
Study Duration 
The duration of participation for individual subjects will be up to 
approximately 36 weeks, consisting of the following 3 periods: 
• Screening Period: up to 6 weeks  
• Treatment Period: 26 weeks 
• Safety follow-up Period: 30 (+4) days 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). 
The study start date is defined as the date the first subject is enrolled, 
which is the date the first subject is randomized. 
The primary completion date is the last date that subject data was 
collected for the primary outcome measure. 
The study completion date is defined as the last date that subject data 
was collected, which includes the safety follow-up telephone call visit. 
Main Criteria for 
Inclusion and 
Exclusion 
To be eligible for this study, subjects must meet all of the inclusion 
criteria and none of the exclusion criteria. 
Inclusion Criteria: 
1. Male or female, ≥18 and ≤55 years of age at the time of 
Screening 


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2. Able to understand and provide signed informed consent 
3. Able to sign and date a request for medical records and/or 
subject privacy form if applicable according to local regulations 
4. In the Investigator’s opinion, is able to understand the nature of 
the trial, follow protocol requirements, be willing to comply 
with study drug administration, and discontinue prohibited 
concomitant medications 
5. Has a caregiver or some other identified responsible person 
(e.g., family member, social worker, caseworker, or nurse) 
considered reliable by the Investigator in providing support to 
the subject to help ensure compliance with study treatment, 
study visits, and protocol procedures, and who is also able to 
provide input helpful for completing study rating scales 
6. Able to complete subject-reported outcome measures, can be 
reliably rated on assessment scales, and is willing to participate 
in audio recording of assessment scales and in an unrecorded 
telemedicine interview  
7. Diagnosis of schizophrenia according to Diagnostic and 
Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) 
criteria (confirmed using a customized module of the Structured 
Clinical Interview for DSM-5, Clinical Trials Version 
[SCID-5-CT]) 
8. Diagnosis of schizophrenia made ≥1 year prior to Screening 
9. Score ≥20 on the sum of the 7 PANSS Marder negative factor 
items at Screening and Baseline 
AND 
Score ≥4 on at least 3, or ≥5 on at least 2, of the 7 PANSS 
Marder negative factor items 
10. Score ≤22 on the sum of the 8 PANSS Marder positive factor 
items 
AND 
PANSS score where no more than two of the following items 
have a score of 4 and none of the following items has a score 
≥5 at both Screening and Baseline: 
• P1 (delusions) 
• P3 (hallucinatory behavior) 
• P4 (excitement) 
• P6 (suspiciousness/persecution) 


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• P7 (hostility) 
11. A Clinical Global Impression of Schizophrenia Scale–Severity 
(CGI-SCH-S) for the negative symptoms of schizophrenia score 
≥4 (moderately ill or worse) at Screening and Baseline 
12. Has been treated with an adequate dose of an antipsychotic 
within the dose range recommended according to the local 
prescribing information for at least 8 weeks prior to Screening 
and remaining at the same dose during the Screening Period  
13. The antipsychotic with which the subject is being treated must 
be one of the antipsychotics listed below: 
• Aripiprazole 
• Aripiprazole long-acting injectables 
o Abilify Maintena® 
o Aristada® 
• Asenapine 
• Brexpiprazole 
• Cariprazine 
• Lurasidone 
• Olanzapine 
• Paliperidone extended release (ER) (≤9 mg) 
• Paliperidone palmitate 
o Invega Sustenna® (≤156 mg) 
o Invega Trinza® (≤546 mg) 
o Trevicta® (≤350 mg) 
o Xeplion® (≤100 mg) 
• Risperidone 
• Risperidone long-acting injection 
14. If taking an oral antipsychotic, no dose change within 4 weeks 
prior to Screening or during the Screening Period 
15. If taking a long-acting injectable antipsychotic, no dose change 
within 16 weeks prior to Screening or during the Screening 
Period 
16. If taking an antidepressant medication or an anxiolytic 
medication, no dose change within 4 weeks of Screening or 
during the Screening Period (see also Appendix A for 
restrictions/prohibitions during the study) 
17. Must be medically stable (including no recent hospitalization 
for exacerbation of psychiatric disorder) and has been medically 


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stable for at least 12 weeks prior to Screening, in the opinion of 
the Investigator 
18. If the subject is female, she must not be pregnant or 
breastfeeding. She must also be of non-childbearing potential 
(defined as either surgically sterilized or at least 1 year 
postmenopausal) OR must agree to use TWO clinically 
acceptable methods of contraception, or be abstinent, for at least 
1 month prior to the Visit 2 (Baseline), during the study, and for 
41 days following completion of the study. Abstinence as a 
method of contraception is defined as refraining from 
heterosexual intercourse during the entire period of risk 
associated with the study treatments. This option is usually 
made for a specific moral, religious, legal, or health reason. If 
heterosexual intercourse does occur, two acceptable methods of 
birth control are required. 
Acceptable methods of contraception include the following: 
a. A barrier method (condom, diaphragm, or cervical cap) 
with spermicide 
b. Hormonal contraception, including oral, injectable, 
transdermal, or implantable methods 
c. Intrauterine device (IUD) 
Only one of the two clinically acceptable methods can be a 
hormonal method. 
All female subjects of childbearing potential must have a 
negative serum human chorionic gonadotropin (hCG) 
pregnancy test at Screening and a negative urine pregnancy test 
at Baseline. 
Note: Specific contraceptive methods are not required for male 
subjects with partners of childbearing potential, but may be used 
as a general precaution. 
 Exclusion Criteria: 
1. Based on the SCID-5-CT, has a current comorbid psychiatric 
disorder other than schizophrenia (e.g., bipolar disorder, 
obsessive compulsive disorder, substance abuse) or a disorder 
that would interfere with the ability to complete study 
assessments (e.g., intellectual disability) 
2. Score ≥2 for two or more movements or a score of 3 or 4 for 
any single movement on the Abnormal Involuntary Movement 
scale (AIMS) 
3. Total score ≥2 on the Barnes Akathisia Rating Scale (BARS) 


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4. Total score ≥5 on the Simpson-Angus Extrapyramidal Side 
Effects Scale (SAS) 
5. Calgary Depression Scale for Schizophrenia (CDSS) score ≥9 at 
both Screening and Baseline 
6. Is at a significant risk of suicide (e.g., answers “Yes” to suicidal 
ideation question 4 or 5 [current or over last 6 months] or 
answers “Yes” to suicidal behavior questions on the C-SSRS 
[over last 6 months]), in the opinion of the Investigator 
7. Has a significant risk of violent behavior in the opinion of the 
Investigator 
8. Has met DSM-5 criteria for substance use disorders within the 
last 6 months prior to randomization (other than caffeine and/or 
nicotine) 
9. A confirmed urine toxicity (drug) screen result at Screening or 
Baseline that indicates the presence of any tested prohibited 
substance of potential abuse, including marijuana 
10. Subject was treated with two or more antipsychotics, for any 
indication, within 8 weeks prior to Screening 
11. Laboratory testing confirms the absence of the main 
antipsychotic 
12. Is taking a medication or drug or other substance that is 
prohibited according to this protocol, including medications that 
prolong the QT interval, strong cytochrome P450 (CYP) 3A4 
enzyme (CYP3A4) inhibitors and inducers (see Appendix A and 
Appendix B) 
13. Known family or personal history or symptoms of long QT 
syndrome or risk factors for torsade de pointes and/or sudden 
death, including symptomatic bradycardia, hypokalemia or 
hypomagnesemia, and the presence of congenital prolongation 
of the QT interval 
14. Has an ECG result at Screening or Baseline that meets one of 
the following exclusionary conditions: 
• If QRS interval <120 ms then a QTcF ≥460 ms is 
exclusionary 
• If QRS interval ≥120 ms then a QTcF ≥480 ms is 
exclusionary 


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15. Current evidence, or history within the previous 12 weeks prior 
to Screening, of a serious and/or unstable psychiatric, 
neurologic, cardiovascular, respiratory, gastrointestinal, renal, 
hepatic, hematologic, or other medical disorder, including 
cancer or malignancies that in the judgment of the Investigator 
would jeopardize the safe participation of the subject in the 
study 
16. Has moderate to severe congestive heart failure (New York 
Heart Association [NYHA] class III and class IV) 
17. Has a history of myocardial infarction within 6 months prior to 
enrollment 
18. Has a history of uncontrolled diabetes mellitus (DM), Type 1 or 
2 DM requiring insulin treatment, or glycosylated hemoglobin 
(HbA1c) >7% at Screening 
19. Has a clinically significant thyroid function test result at 
Screening as defined by abnormal thyroid stimulating hormone 
(TSH) that reflexes to abnormal thyroxine (T4). If TSH is 
abnormal and the reflex free T4 is normal, the subject may be 
enrolled. 
20. Has clinically significant laboratory abnormalities that in the 
judgment of the Investigator or Medical Monitor would 
jeopardize the safe participation of the subject in the study 
21. Known to be positive for hepatitis C virus (HCV) or human 
immunodeficiency virus (HIV) 
22. Has a body mass index (BMI) <19 or ≥35 at Screening 
23. Has a history of neuroleptic malignant syndrome 
24. Is breastfeeding or lactating 
25. Has a significant sensitivity or allergic reaction to pimavanserin 
or its excipients 
26. Has previously been randomized in any prior clinical study with 
pimavanserin, and/or received any other investigational (either 
approved or unapproved) drug within 30 days or 5 half-lives 
(whichever is longer) prior to Screening 
27. Has any condition that, in the opinion of the Investigator, would 
interfere with the ability to comply with study instructions, or 
that might confound the interpretation of the study results or put 
the subject at undue risk 
28. Is an employee of Acadia, or has a family member who is an 
employee of Acadia 
29. Has participated in >2 pharmaceutical clinical research studies 
within the previous 2 years 
30. Subject is judged by the Investigator or the Medical Monitor to 
be inappropriate for the study 


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31. Subject has had a social hospitalization, defined as admission to 
the hospital as a result of inadequate family support or care at 
the subject’s primary residence, during the 8 weeks prior to 
Screening 
Pharmacokinetic 
Assessments 
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 to the 
Investigators and the Sponsor 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 
Sample Size 
Calculations 
The planned sample size is approximately 426 (213 subjects per 
treatment group). 
Assuming the true difference in the mean change in the NSA-16 total 
score from Baseline to Week 26 is 3.0 points between the pimavanserin 
group and the placebo group, and the common standard deviation is 
9 points, 191 subjects who complete the study per treatment group will 
provide 90% power to detect a difference between the pimavanserin 
group and the placebo group at a significance level of 0.05, using a 
2-sided t-test. 
Adjusting for a potential discontinuation rate of up to 10%, 
approximately 426 subjects (213 subjects per treatment group) will be 
randomized. 
Statistical Methods 
Analysis Sets 
The Safety Analysis Set includes all randomized subjects who 
received at least one dose of study drug (pimavanserin or placebo). 


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Subjects will be analyzed based on the treatment that they received. 
The Safety Analysis Set will be used for all safety analyses. 
The Full Analysis Set includes all randomized subjects who received 
at least one dose of study drug and who have both a baseline value and 
at least one post-baseline value for the NSA-16 total score. Subjects 
will be analyzed based on their randomized treatment. The Full 
Analysis Set will be used for the analysis of all efficacy endpoints. 
The Per protocol (PP) Analysis Set will consist of those subjects in 
the Full Analysis Set without any protocol deviations that could 
potentially have a substantial impact on the primary efficacy outcome. 
The precise reasons for excluding subjects from the PP Analysis Set 
will be fully defined and documented prior to the clinical database 
lock. Subjects will be analyzed based on their randomized treatment 
assignment. The PP Analysis Set will be used for sensitivity analyses 
of selected efficacy endpoints. 
For pimavanserin and AC-279 plasma concentration summaries, the 
Pharmacokinetics Analysis Set will consist of subjects with at least 
one measurable pimavanserin plasma concentration. 
Subgroup Analysis 
Selected analyses will be performed in subgroups defined in the 
statistical analysis plan (SAP). 
Descriptive Statistics 
Continuous measurement results will be reported using the number of 
subjects with data values, mean, standard error of the mean, standard 
deviation, minimum, maximum, and median. For each categorical 
outcome, the number and percentage of subjects in each category will 
be reported. 
Missing Data 
Handling of missing values will be described in detail in the SAP. 
Sensitivity analyses will be performed to assess the impact of missing 
data, including analyses based on a missing not at random assumption. 
EFFICACY ANALYSES 
All efficacy endpoints will be summarized by treatment group using 
descriptive statistics. 
Primary Analysis 
The NSA-16 total score will be analyzed using mixed-effect model 
repeated measures (MMRM). The model will include effects for 
treatment group (pimavanserin or placebo), visit (Week 2, Week 4, 
Week 8, Week 14, Week 20, and Week 26), the treatment-by-visit 
interaction, geographic region (North America, Europe, or rest of 
world), the Baseline NSA-16 total score, and the Baseline-by-visit 


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interaction. The treatment comparison will be based on the difference 
in least squares means at Week 26 and will be tested at an alpha level 
of 0.05 (2-sided) using the Full Analysis Set. 
Secondary Analysis 
The key secondary endpoint is the change from Baseline to Week 26 in 
the CGI-SCH-S of negative symptoms score. The change from 
Baseline in the CGI-SCH-S of negative symptoms score will be 
analyzed using an MMRM model. The model will include effects for 
treatment group, visit, the treatment-by-visit interaction, geographic 
region, the Baseline CGI-SCH-S of negative symptoms total score, and 
the Baseline-by-visit interaction. The treatment comparison will be 
based on the difference in least squares means at Week 26 and will be 
tested at an alpha level of 0.05 (2-sided) using the Full Analysis Set. 
A hierarchical testing procedure will be used to control the Type 1 
error rate across the primary and key secondary endpoint. 
SAFETY ANALYSES 
Safety results will be summarized by treatment group using descriptive 
statistics. No formal statistical testing will be performed for any of the 
safety endpoints. Adverse events will be classified into standard 
terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA). Treatment-emergent adverse events (TEAEs), TEAEs 
leading to discontinuation, TEAEs related to study drug, TEAEs by 
maximum severity, fatal TEAEs, SAEs, and SAEs related to study 
drug will all be summarized. Other TEAEs of special interest may also 
be summarized. 
Descriptive statistics for ECG, vital signs and weight, and clinical 
laboratory parameters, including changes from Baseline, will be 
tabulated by timepoint. Additionally, categorical analyses will be 
conducted on the incidence of subjects with prolonged QTc intervals 
and changes in QTc intervals in accordance with International Council 
for Harmonisation (ICH) guidelines. 
An independent data and safety monitoring board (DSMB) will review 
interim safety data including data on AEs and SAEs. 
PHARMACOKINETIC ANALYSES 
Plasma concentration data for pimavanserin, its major 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. 


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PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES 
A population 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 
05 October 2022 


Study: ACP-103-064 
 
 Final Version: 1.0 
Clinical Study Protocol Amendment 3 
 
Date: 05 October 2022 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc. 
 
 
 
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Figure S–1 
Schematic of Study Design for ACP-103-064 
 
 
Main antipsychotic + pimavanserin 34 mg 
Subjects with 
predominant negative 
symptoms of 
schizophrenia while on 
adequate treatment with 
an antipsychotic 
Main antipsychotic + placebo 
Double-Blind Treatment Period 
26 weeks 
1:1 Randomization 
Screening Period 
Up to 6 weeks 
Follow-up Period 
30 (+4) days 
EOT/ET* 
30 (+4) day follow-
up (telephone call 
visit) 
*Subjects who complete the 26-week Treatment Period may be eligible to enroll in a 52-week, open-label extension study (Study ACP-103-035). 
Subjects entering ACP-103-035 will not complete a follow-up telephone call visit as they will be immediately enrolled in ACP-103-035. 


Study: ACP-103-064 
 
Final Version: 1.0 
Clinical Study Protocol Amendment 2 
 
Date: 05 October 2022 
 
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Table S-1 
Schedule of Events and Assessments for ACP-103-064 
Period 
Screening Period 
Treatment Period 
 
Follow-Upa 
Visitb 
1 
2 (Baseline) 
3 
4 
5 
6 
7 
8 (EOT/ET) Safety Follow-
up 
Day or Week 
(Up to 42 days) 
Day 1/Week 0 Week 2 Week 4 Week 8 Week 14 Week 20 
Week 26 
Week 30 
Allowable visit window (# days) 
 
 
±3 
±3 
±3 
±7 
±7 
±7 
+4 
Informed consentc 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
Medical and psychiatric historyd 
X 
 
 
 
 
 
 
 
 
Schizophrenia disease history 
X 
 
 
 
 
 
 
 
 
SCID-5-CT customized module 
X 
 
 
 
 
 
 
 
 
Interview by an independent cliniciane 
X 
 
 
 
 
 
 
 
 
Physical examinationf 
X 
X 
X 
 
 
X 
 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height and weightg 
X 
X 
 
 
 
 
 
X 
 
12-lead ECGh 
X 
X 
 
 
 
X 
 
X 
 
Clinical laboratory testsi 
X 
X 
 
 
 
 
 
X 
 
Confirmation of main antipsychoticj 
X 
 
 
 
 
 
 
 
 
Pregnancy testk 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urine toxicity (drug) screen 
X 
X 
 
 
 
 
 
X 
 
PK blood drawsl 
 
X 
X 
 
X 
X 
 
X 
 
NSA-16 
 
X 
X 
X 
X 
X 
X 
X 
 
PANSS and IQ-PANSS 
X 
X 
 
 
 
X 
 
X 
 
CGI-SCH-S of negative symptoms 
X 
X 
X 
X 
X 
X 
X 
X 
 
CGI-SCH-I of negative symptoms 
 
 
X 
X 
X 
X 
X 
X 
 
PSP 
 
X 
X 
 
X 
X 
 
X 
 
BACS 
 
X 
 
 
 
 
 
X 
 
CDSS 
X 
X 
 
 
 
X 
 
X 
 
WoRQ 
 
X 
 
 
X 
X 
 
X 
 
C-SSRSm 
X 
X 
X 
X 
X 
X 
X 
X 
 
AIMS, BARS, and SAS 
X 
X 
X 
 
 
X 
 
X 
 
Assessment of prior and concomitant 
medicationsn 
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 
 


Study: ACP-103-064 
 
Final Version: 1.0 
Clinical Study Protocol Amendment 2 
 
Date: 05 October 2022 
 
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Abbreviations: AIMS=Abnormal Involuntary Movement Scale; BACS=Brief Assessment of Cognition for Schizophrenia; BARS=Barnes Akathisia Rating Scale; 
CDSS=Calgary Depression Scale for Schizophrenia; CGI-SCH-I=Clinical Global Impression of Schizophrenia–Improvement; CGI-SCH-S=Clinical Global 
Impression of Schizophrenia–Severity; C-SSRS=Columbia–Suicide Severity Rating Scale; ECG=electrocardiogram; EOT=end of treatment; ET=early 
termination; HCV=hepatitis C virus; HIV=human immunodeficiency virus; IQ-PANSS=Informant Questionnaire for the Positive and Negative Syndrome 
Scale; NSA-16=Negative Symptom Assessment–16 scale; PANSS=Positive and Negative Syndrome Scale; PK=pharmacokinetic(s); PSP=Personal and 
Social Performance; SAS=Simpson-Angus Extrapyramidal Side Effects Scale; SCID-5-CT=Structured Clinical Interview for DSM-5, Clinical Trials 
Version; WoRQ=Work Readiness Questionnaire 
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 visit will occur 30 (+4) days after the last dose of study drug. 
b 
Study visits are designated by weeks and have a window, calculated from the Baseline visit, of ±3 days for Visits 3, 4, and 5 and of ±7 days for Visits 6, 7, 
and 8. The Screening Period is up to 42 days long (Day -42 to Day -1) and all Screening procedures should be completed as early in the Screening Period as 
possible. The window for the 30-day follow-up telephone call visit is +4 days. Circumstances may arise (e.g., pandemic, natural disaster, or political 
upheaval) when on-site assessments of efficacy and/or safety are not possible. In those cases, assessments may be performed at the subject’s place of 
residence by raters either in person, or via video technology or telephone where possible. The Investigator must contact the Medical Monitor for approval 
with the plan. Sites must keep a log to identify details of all visits that are administered remotely. For some remote efficacy assessments (i.e., NSA-16, 
PANSS, CGI), the vendor will provide additional training to ensure calibration to reduce discrepancy between on-site and remote assessments. 
c 
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 will be performed during the Screening Period. The interview will be 
conducted by video and will not be recorded. 
f 
A complete physical examination should be performed at Screening, Baseline, and Week 26; symptom-directed examinations will be performed at Weeks 2 
and 14. Pelvic and/or urogenital examination may be deferred, unless the Investigator deems this to be clinically indicated. 
g 
Height will only be measured at the Screening visit. 
h 
A 12-lead ECG will be performed in triplicate at Screening. Single 12-lead ECG recordings will be performed at Baseline, Week 14, and at the Week 26 
(EOT/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. 
Circumstances may arise (e.g., pandemic, natural disaster, or political upheaval) when on-site ECG assessment is not possible. In those cases, ECG 
assessments may be performed at the subject’s place of residence by study staff. The Investigator must contact the Medical Monitor for approval with the 
plan. Sites must keep a log to identify details of all visits that are administered remotely. 
i 
To include hematology, serum chemistry, prolactin levels, and urinalysis (note: additional laboratory studies [in addition to scheduled timepoints shown in 
the table] for a given subject may be repeated at any time throughout the Treatment Period, at the discretion of the Investigator). It is preferable but not 
required that subjects be in a fasted state (e.g., fasting for approximately 10 hours) before the blood sample for clinical chemistry is obtained. Circumstances 
may arise (e.g., pandemic, natural disaster, or political upheaval) when on-site clinical laboratory tests are not possible. In those cases, clinical laboratory 
tests may be performed at the subject’s place of residence by study staff or at a local laboratory. The Investigator must contact the Medical Monitor for 
approval with the plan. Sites must keep a log to identify details of all visits that are administered remotely. 
 


Study: ACP-103-064 
 
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Date: 05 October 2022 
 
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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 of childbearing potential; urine pregnancy tests will be completed at 
all other scheduled time-points for all female subjects of childbearing potential. 
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. Circumstances may arise (e.g., pandemic, natural disaster, or political 
upheaval) when on-site assessment of PK is not possible. In those cases, PK assessments may be performed at the subject’s place of residence by study staff. 
The Investigator must contact the Medical Monitor for approval with the plan. Sites must keep a log to identify details of all visits that are administered 
remotely. 
m 
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. 
n 
Prior medication history will only be collected at the Screening visit. 
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. In addition to the 
study drug dispensed at the site, investigational product may be delivered directly to the subject’s place of residence; related procedures will be described in 
the study-specific pharmacy manual. 
 
 


Study: ACP-103-064 
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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ............................................................................................... 2 
DECLARATION OF INVESTIGATOR ................................................................................... 4 
PROTOCOL SYNOPSIS ........................................................................................................... 5 
TABLE OF CONTENTS ......................................................................................................... 22 
LIST OF TABLES ................................................................................................................... 28 
LIST OF FIGURES ................................................................................................................. 28 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................. 29 
1 
INTRODUCTION ...................................................................................................... 31 
1.1 
Background Information ............................................................................................ 31 
1.2 
Investigational Product ............................................................................................... 31 
1.3 
Previous Clinical Experience ..................................................................................... 32 
1.4 
Study Rationale .......................................................................................................... 36 
1.5 
Benefit/Risk Assessment ............................................................................................ 36 
1.5.1 
Known Potential Risks ............................................................................................... 36 
1.5.2 
Known Potential Benefits ........................................................................................... 37 
2 
STUDY OBJECTIVES AND ENDPOINTS .............................................................. 37 
2.1 
Primary Objective ...................................................................................................... 37 
2.1.1 
Primary Endpoint ....................................................................................................... 38 
2.2 
Secondary Objective .................................................................................................. 38 
2.2.1 
Secondary Endpoints .................................................................................................. 38 
2.2.1.1 Key Secondary Endpoint ............................................................................................ 38 
2.2.1.2 Other Secondary Endpoints ........................................................................................ 38 
2.3 
Exploratory Objective ................................................................................................ 38 
2.3.1 
Exploratory Endpoints ................................................................................................ 38 
2.4 
Safety Objectives ........................................................................................................ 39 
2.4.1 
Safety Endpoints......................................................................................................... 39 
2.5 
Pharmacokinetic Objectives ....................................................................................... 39 
2.5.1 
Pharmacokinetic Endpoints ........................................................................................ 39 
3 
STUDY DESCRIPTION ............................................................................................ 40 
3.1 
Overview of Study Design ......................................................................................... 40 


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3.1.1 
Screening Period (up to 42 Days)............................................................................... 41 
3.1.2 
Double-Blind Treatment Period (26 Weeks) .............................................................. 41 
3.1.3 
Safety Follow-up Period (30 Days) ............................................................................ 42 
4 
SUBJECT ELIGIBILITY AND WITHDRAWAL CRITERIA .................................. 42 
4.1 
Inclusion Criteria ........................................................................................................ 42 
4.2 
Exclusion Criteria ....................................................................................................... 45 
4.3 
Subject Withdrawal of Consent .................................................................................. 47 
4.4 
Subject Discontinuation ............................................................................................. 48 
4.4.1 
Guidance for Investigators on Suicidality, Symptom Worsening, and Relapse ......... 49 
4.4.2 
Handling of Subject Discontinuation During the Treatment Period .......................... 49 
4.5 
Subject Lost to Follow-up .......................................................................................... 50 
4.6 
Study Discontinuation ................................................................................................ 50 
4.7 
Prior and Concomitant Therapy ................................................................................. 50 
4.7.1 
Prior Medication ......................................................................................................... 50 
4.7.2 
Concomitant Medication ............................................................................................ 50 
4.7.2.1 Permitted, Restricted, and Prohibited Medications .................................................... 51 
4.7.2.1.1 
Rationale for Including Paliperidone Extended Release (≤9 mg/day) 
Formulations as Allowed Antipsychotics ................................................................... 51 
5 
INVESTIGATIONAL PRODUCT ............................................................................. 53 
5.1 
Investigational Product Description ........................................................................... 53 
5.1.1 
Formulation, Appearance, Packaging, and Labeling .................................................. 54 
5.1.2 
Product Storage and Stability ..................................................................................... 54 
5.1.3 
Dosing and Administration ......................................................................................... 54 
5.1.4 
Method of Assigning Subjects to Treatment Groups.................................................. 55 
5.1.5 
Blinding ...................................................................................................................... 55 
5.1.6 
Study Drug Compliance ............................................................................................. 55 
5.1.7 
Overdose ..................................................................................................................... 55 
5.2 
Investigational Product Accountability Procedures ................................................... 56 
6 
STUDY ASSESSMENTS .......................................................................................... 56 
6.1 
Remote Assessments or Visits .................................................................................... 57 
6.2 
Screening Assessments ............................................................................................... 57 
6.2.1 
Demography ............................................................................................................... 57 
6.2.2 
Medical and Psychiatric History ................................................................................ 57 


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6.2.3 
Schizophrenia Disease History ................................................................................... 57 
6.2.4 
Structured Clinical Interview for DSM-5, Clinical Trials Version (SCID-5-CT 
customized module) ................................................................................................... 57 
6.2.5 
Interview by an Independent Clinician ...................................................................... 58 
6.2.6 
Confirmation of Main Antipsychotic ......................................................................... 58 
6.3 
Efficacy Scales ........................................................................................................... 58 
6.3.1 
Negative Symptom Assessment–16 ........................................................................... 58 
6.3.2 
Clinical Global Impression of Schizophrenia Scale–Severity ................................... 58 
6.3.3 
Personal and Social Performance Scale ..................................................................... 58 
6.3.4 
Clinical Global Impression of Schizophrenia Scale–Improvement ........................... 58 
6.3.5 
Positive and Negative Syndrome Scale ...................................................................... 59 
6.3.6 
Informant Questionnaire for the Positive and Negative Syndrome Scale .................. 59 
6.3.7 
Brief Assessment of Cognition in Schizophrenia ....................................................... 59 
6.3.8 
Calgary Depression Scale for Schizophrenia ............................................................. 59 
6.3.9 
Work Readiness Questionnaire................................................................................... 59 
6.4 
Safety Scales .............................................................................................................. 60 
6.4.1 
Abnormal Involuntary Movement Scale .................................................................... 60 
6.4.2 
Barnes Akathisia Rating Scale ................................................................................... 60 
6.4.3 
Simpson-Angus Extrapyramidal Side Effects Scale .................................................. 60 
6.4.4 
Columbia–Suicide Severity Rating Scale................................................................... 60 
6.5 
Safety Measures ......................................................................................................... 61 
6.5.1 
Medical and Psychiatric History ................................................................................ 61 
6.5.2 
Medication History ..................................................................................................... 61 
6.5.3 
Physical Examination ................................................................................................. 61 
6.5.4 
Vital Sign Measurements............................................................................................ 61 
6.5.5 
Height and Weight ...................................................................................................... 61 
6.5.6 
Electrocardiograms ..................................................................................................... 61 
6.5.7 
Laboratory Evaluations .............................................................................................. 62 
6.6 
Pharmacokinetic Assessments .................................................................................... 64 
6.6.1 
Remote Pharmacokinetic Assessments ...................................................................... 65 
6.7 
Safety Follow-up ........................................................................................................ 65 
6.8 
Unscheduled Visits ..................................................................................................... 65 
7 
ADVERSE EVENTS ................................................................................................. 65 


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7.1 
Specification of Safety Parameters ............................................................................ 65 
7.1.1 
Definition of Adverse Event ....................................................................................... 65 
7.1.2 
Definition of Serious Adverse Event .......................................................................... 66 
7.2 
Classification of an Adverse Event ............................................................................ 68 
7.2.1 
Severity of Event ........................................................................................................ 68 
7.2.2 
Relationship to Study Drug ........................................................................................ 68 
7.2.3 
Duration ...................................................................................................................... 68 
7.2.4 
Frequency ................................................................................................................... 68 
7.2.5 
Action Taken with Study Drug ................................................................................... 69 
7.2.6 
Therapy ....................................................................................................................... 69 
7.2.7 
Outcome ..................................................................................................................... 69 
7.2.8 
Seriousness ................................................................................................................. 69 
7.2.9 
Definition of Unexpectedness .................................................................................... 69 
7.3 
Time Period and Frequency for Event Assessment and Follow-up ........................... 69 
7.4 
Reporting Procedures ................................................................................................. 70 
7.4.1 
Adverse Event Reporting ........................................................................................... 70 
7.4.2 
Serious Adverse Event Reporting............................................................................... 70 
7.4.3 
Reporting of Pregnancy .............................................................................................. 71 
7.4.3.1 Reporting Paternal Study Drug Exposure .................................................................. 72 
7.4.4 
Reporting of Overdose ............................................................................................... 72 
8 
MONITORING .......................................................................................................... 72 
9 
STATISTICAL METHODS AND DATA ANALYSIS .............................................. 72 
9.1 
Statistical and Analytical Plans .................................................................................. 72 
9.2 
Statistical Hypotheses ................................................................................................ 72 
9.3 
Sample Size Determination ........................................................................................ 73 
9.4 
Subject Populations for Analysis ................................................................................ 73 
9.5 
Statistical Analyses ..................................................................................................... 74 
9.5.1 
Primary Analyses ........................................................................................................ 74 
9.5.2 
Secondary Analyses .................................................................................................... 74 
9.5.2.1 Key Secondary Endpoint ............................................................................................ 74 
9.5.2.2 Other Secondary Endpoints ........................................................................................ 75 
9.5.3 
Exploratory Analyses ................................................................................................. 76 


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9.5.4 
Safety Analyses .......................................................................................................... 76 
9.5.4.1 Adverse Events ........................................................................................................... 76 
9.5.4.2 Clinical Laboratory Values ......................................................................................... 77 
9.5.4.3 Vital Signs and Body Weight ..................................................................................... 77 
9.5.4.4 Electrocardiogram ...................................................................................................... 77 
9.5.4.5 Physical Examinations ............................................................................................... 77 
9.5.4.6 Columbia Suicide Severity Rating ............................................................................. 77 
9.5.4.7 Extrapyramidal Symptom Measures .......................................................................... 77 
9.5.5 
Confirmation of Main Antipsychotic ......................................................................... 78 
9.5.6 
Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analyses ........................ 78 
9.5.7 
Subgroup Analyses ..................................................................................................... 78 
9.6 
Interim Analyses ......................................................................................................... 78 
9.7 
Data and Safety Monitoring Board ............................................................................ 78 
9.8 
Measures to Minimize Bias ........................................................................................ 78 
9.8.1 
Enrollment/Randomization/Masking Procedures....................................................... 78 
9.9 
Breaking the Study Blind/Subject Code ..................................................................... 78 
10 
STUDY MANAGEMENT AND DATA COLLECTION .......................................... 79 
10.1 
Data Collection and Management Responsibilities ................................................... 79 
10.2 
Source Documents ...................................................................................................... 79 
10.3 
Case Report Forms ..................................................................................................... 80 
10.4 
Confidentiality ............................................................................................................ 80 
10.5 
Study Records Retention ............................................................................................ 80 
10.6 
Protocol Exceptions and Deviations .......................................................................... 81 
10.7 
Protocol Amendments ................................................................................................ 81 
11 
QUALITY MANAGEMENT .................................................................................... 81 
11.1 
Risk Management ....................................................................................................... 81 
11.2 
Quality Control and Quality Assurance ..................................................................... 82 
12 
ETHICAL CONSIDERATIONS ................................................................................ 83 
12.1 
Ethical Standard ......................................................................................................... 83 
12.2 
Institutional Review Board/Ethics Committee ........................................................... 83 
12.3 
Informed Consent Process .......................................................................................... 83 
12.3.1 Consent and Other Informational Documents Provided to Subjects .......................... 84 


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12.3.2 Consent Procedures and Documentation .................................................................... 84 
12.3.2.1 Remote Consent Procedures and Documentation ...................................................... 84 
13 
PUBLICATION PLAN .............................................................................................. 85 
14 
CONFLICT OF INTEREST POLICY ....................................................................... 85 
14.1 
Finance, Insurance, and Indemnity ............................................................................ 85 
15 
LITERATURE REFERENCES .................................................................................. 86 
16 
APPENDICES ............................................................................................................ 89 
Appendix A Prohibited and Restricted Medications ............................................................. 89 
Appendix B Prohibited and Restricted Concomitant Medications: Inhibitors and 
Inducers of Cytochrome P450 Enzyme 3A4 ..................................................... 93 
 


Study: ACP-103-064 
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LIST OF TABLES 
Table S-1 
Schedule of Events and Assessments for ACP-103-064 .................................. 19 
Table 6–1 
Safety Laboratory Evaluations......................................................................... 64 
 
LIST OF FIGURES 
Figure S–1 
Schematic of Study Design for ACP-103-064 ................................................. 18 
 


Study: ACP-103-064 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
5-HT 
5-hydroxytryptamine (serotonin) 
5-HT2A 
5-hydroxytryptamine (serotonin) 2A 
5-HT2C 
5-hydroxytryptamine (serotonin) 2C 
AC-279 
N-desmethyl-pimavanserin, major metabolite 
AE 
adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
BACS 
Brief Assessment of Cognition in Schizophrenia 
BARS 
Barnes Akathisia Rating Scale 
CDSS 
Calgary Depression Scale for Schizophrenia 
CFR 
Code of Federal Regulations 
CGI-S 
Clinical Global Impression–Severity 
CGI-SCH-I 
Clinical Global Impression of Schizophrenia Scale–Improvement 
CGI-SCH-S 
Clinical Global Impression of Schizophrenia Scale–Severity 
CI 
confidence interval 
CNS 
central nervous system 
CSR 
clinical study report 
C-SSRS 
Columbia–Suicide Severity Rating Scale 
CYP 
cytochrome P450 
CYP3A4 
CYP 3A4 enzyme 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
DSMB 
data and safety monitoring board 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOT 
end of treatment 
ER 
extended release 
ET 
early termination 
EU GDPR 
European Union General Data Protection Regulation 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HbA1c 
glycosylated hemoglobin 
HIV-AIDS 
human immunodeficiency virus–acquired immunodeficiency syndrome 
ICF 
informed consent form 


Study: ACP-103-064 
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Abbreviation 
Definition 
ICH 
International Council for Harmonisation 
IQ-PANSS 
Informant Questionnaire for the Positive and Negative Syndrome Scale 
IR 
immediate release 
IRB 
institutional review board 
MMRM 
mixed-effect model repeated measures 
NSA-16 
Negative Symptom Assessment–16  
PANSS 
Positive and Negative Syndrome Scale 
PDP 
Parkinson’s disease psychosis 
PK 
pharmacokinetic(s) 
PK/PD 
pharmacokinetic/pharmacodynamic 
PSP 
Personal and Social Performance  
QRS interval 
QRS interval of ECG 
QT interval 
QT interval for heart rate of ECG 
QTc interval 
corrected QT interval 
QTcF 
corrected QT interval using Fridericia’s formula 
QTcLD 
QT interval corrected for heart rate using the population specified linear 
derived method 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
Simpson-Angus Extrapyramidal Side Effects Scale 
SCID-5-CT 
Structured Clinical Interview for DSM-5, Clinical Trials Version 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
UDS 
urine toxicity (drug) screen 
US 
United States 
WoRQ 
Work Readiness Questionnaire 


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1 INTRODUCTION 
This document is a research protocol and the described study will be conducted in 
compliance with the protocol, the International Council for Harmonisation (ICH) 
Good Clinical Practice (GCP) Guideline, and applicable regulatory requirements.  
1.1 
Background Information 
Schizophrenia is a chronic and debilitating disease that affects approximately 2.4 million 
adults in the United States. The lifetime prevalence is about 1% worldwide (McGrath et al. 
2008). The onset of symptoms generally occurs among people 16 to 30 years of age. Positive 
symptoms of psychosis are necessary to establish a diagnosis; however, other symptom 
clusters, including negative, cognitive, and general psychopathology symptoms, are also 
highly prevalent and contribute significantly to the disability and functional impairment of 
people with the disease. Throughout life the course of the symptoms fluctuate, with acute 
exacerbations being treated and followed by maintenance periods until a relapse occurs. The 
chronic nature of schizophrenia and enduring positive and negative symptoms pose a 
significant need for safe and effective long-term treatment. 
According to the World Health Organization, schizophrenia is included as one of the seven 
most disabling diseases in adults aged between 20 and 45 years, surpassing diabetes, 
cardiovascular disease, and HIV-AIDS (Ebdrup et al. 2011). Indeed, 40% to 80% of patients 
with schizophrenia have a reduced capability for learning and working, performing self-care, 
and maintaining interpersonal relationships and general living skills (Ebdrup et al. 2011). 
Schizophrenia is characterized by positive symptoms, negative symptoms, and cognitive 
impairment. Comorbid sleep disorders may also present in this disease. Negative symptoms 
of schizophrenia include blunted affect, alogia, avolition, asociality, and anhedonia) 
(Alphs et al. 1989; Andreasen 1982; Kay et al. 1988; Kirkpatrick et al. 1989). In contrast to 
positive symptoms, negative symptoms are relatively enduring, constant, and more predictive 
of psychosocial impairment (Tamminga et al. 1998; Peralta et al. 2000). Persistent negative 
symptoms are present in more than 25% of patients with a first episode of psychosis 
(Hovington et al. 2012). 
1.2 
Investigational Product 
Pimavanserin is an atypical antipsychotic that is present in the investigational product as 
pimavanserin tartrate salt with the chemical name, urea, N-[(4-fluorophenyl)methyl]-N-(1-
methyl-4-piperidinyl)-N’-[[4-(2-methylpropoxy)phenyl]methyl]-, (2R,3R)-2,3-
dihydroxybutanedioate (2:1). In April 2016, pimavanserin was approved in the United States 
for the treatment of hallucinations and delusions associated with Parkinson’s disease 
psychosis (PDP). 


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Pimavanserin is a novel small molecule designed to specifically block serotoninergic 
neurotransmission mediated by the 5-hydroxytryptamine (serotonin) receptor subtype 2A 
(5-HT2A receptor). At higher doses, pimavanserin may block 5-HT2C receptors (Vanover et al. 
2006). Pimavanserin shows no appreciable activity at dopaminergic, adrenergic, 
histaminergic, or muscarinic receptors. Activity at these receptors has been implicated in a 
range of dose-limiting side effects associated with existing antipsychotic drugs including 
cognitive dulling (Saeedi et al. 2006; Mehta et al. 2004; Peretti et al. 1997) and an increased 
risk of mortality in elderly patients with dementia (Wang et al. 2005). On the basis of its 
novel receptor binding profile, pimavanserin may have benefits with regard to overall 
tolerability relative to other antipsychotic agents. 
1.3 
Previous Clinical Experience 
Always refer to the latest version of the pimavanserin Investigator’s Brochure for the overall 
benefit/risk assessment and the most accurate and current information regarding nonclinical 
data, drug metabolism, pharmacokinetics, efficacy, and safety. 
The clinical pharmacokinetics, pharmacodynamics, efficacy, and safety of pimavanserin have 
been evaluated in a total of 40 completed studies, 2 studies in reporting, 6 otherwise ongoing 
studies, and 1 completed expanded-access program (EAP). As of 28 April 2021, an estimated 
3689 subjects had been exposed to pimavanserin, including 552 healthy subjects, 12 renally 
impaired subjects, 25 hepatically impaired subjects, 34 adolescents with psychiatric 
disorders, 726 subjects with Parkinson’s disease/PDP (of which 632 had PDP, including 15 in 
the EAP), 90 subjects with Alzheimer’s disease psychosis, 96 subjects with agitation and 
aggression in Alzheimer’s disease, 392 subjects with dementia-related psychosis, 
435 subjects in additional studies in frail subjects with neurodegenerative disease and 
neuropsychiatric symptoms, 979 subjects diagnosed with schizophrenia, and 348 subjects 
with major depressive disorder. 
Total exposure of subjects with PDP exceeds 1040 person-years. The longest single exposure 
is in a subject with 12.3 years of continuous treatment with pimavanserin. 
Pimavanserin is considered to be generally safe and well tolerated. In single and multiple 
dose studies in healthy subjects, the highest doses administered were 255 mg and 
136 mg/day, respectively. Across all clinical studies of pimavanserin, the most frequently 
reported adverse events (AEs) were in the central nervous system (CNS), gastrointestinal, 
and psychiatric systems. Most AEs were mild to moderate in intensity. The most common 
CNS treatment-emergent AEs (TEAEs) included dizziness (including postural), headache, 
and somnolence (drowsiness). Common gastrointestinal disturbances included dyspepsia, 
nausea, constipation, and vomiting; severe nausea and vomiting were dose limiting in a few 


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cases. Reported psychiatric conditions included such events as agitation, insomnia, and 
confusional state. 
A Phase 2 study (ACP-103-007) was conducted in subjects with schizophrenia experiencing 
haloperidol-induced akathisia. Sixteen subjects received 51 mg/day of pimavanserin in 
addition to their regular dosage of haloperidol (≤20 mg/day) and 18 subjects received placebo 
in addition to their haloperidol dose (≤20 mg/day) for a 5-day treatment period. The primary 
efficacy measure was the change from Baseline in the Barnes Akathisia Rating Scale 
(BARS), Part 4 (global clinical assessment of akathisia score). The results of this study 
supported the potential for efficacy of pimavanserin in the reduction of haloperidol-induced 
akathisia. This effect was most prominent at Day 3. Pharmacokinetic results indicated that 
coadministration of pimavanserin at 51 mg once daily did not affect haloperidol 
concentrations. 
The antipsychotic efficacy of adjunctive pimavanserin was evaluated in a Phase 2 study 
(ACP-103-008) (Meltzer et al. 2012) and a Phase 3 study (ACP-103-034) conducted in 
subjects with schizophrenia. ACP-103-008 was a 6-week study where the primary objective 
was to determine whether a combination of pimavanserin (17 mg once daily) with either 
low-dose haloperidol (2 mg once daily) or low-dose risperidone (2 mg; 1 mg twice daily) 
administered to subjects with schizophrenia would demonstrate antipsychotic efficacy, as 
measured by the Positive and Negative Syndrome Scale (PANSS). 
It was observed that pimavanserin 17 mg plus 2 mg risperidone was significantly more 
efficacious than 2 mg risperidone plus placebo (p≤0.01 starting at Day 15, Intent-to-treat 
[ITT] last observation carried forward [LOCF]) and similar in efficacy to a standard dose 
(6 mg) of risperidone (treatment differences not statistically significant). Efficacy advantages 
of the pimavanserin plus risperidone group over the 2 mg risperidone plus placebo group 
were demonstrated in the PANSS total score (p=0.007), PANSS negative symptom score 
(p=0.018), PANSS ≥20% (p=0.001) and ≥50% (p=0.039) responder analysis, and the Clinical 
Global Impression–Severity (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%). 
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. 
 


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The Phase 3 ENHANCE study (ACP-103-034) was a global six-week, randomized, 
double-blind, placebo-controlled, multicenter, outpatient study designed to examine the 
efficacy and safety of adjunctive use of pimavanserin in patients with schizophrenia who had 
not achieved an adequate response to their current antipsychotic treatment. A total of 
396 subjects were randomized (1:1) to receive either pimavanserin, orally, once daily, in a 
flexible dosing regimen as an adjunctive treatment with a background antipsychotic or 
placebo, orally, once daily, with a background antipsychotic. The starting daily dose of 20 mg 
of pimavanserin or matching placebo at baseline could be adjusted to 34 mg or 10 mg during 
the first three weeks of treatment. The majority of subjects completed the study at the highest 
dose-level (55%). Baseline characteristics were similar across two treatment arms. The most 
prevalent background antipsychotics in the study included risperidone (39.1%), olanzapine 
(35.7%), and aripiprazole (21.3%). The average age of subjects in the study was 37.2 years. 
The primary objective was to evaluate the efficacy of adjunctive pimavanserin versus 
placebo. The primary efficacy measure was the 6-week change from Baseline in PANSS total 
score, the key secondary measure was CGI-S, and other secondary and exploratory measures 
included change from baseline in PANSS factor subscores, and Marder factor scores.  
A consistent improvement of symptoms was observed in the pimavanserin group, but 
improvement on the primary endpoint, the PANSS total score, was not statistically significant 
(p=0.0940) relative to placebo at Week 6. Analysis of the key secondary endpoint, 
CGI-S score, showed improvement consistent with the primary result (unadjusted p=0.0543). 
Secondary and exploratory analyses showed an effect on negative symptoms: 
PANSS Negative Symptoms subscore (unadjusted p=0.0474) and PANSS Marder Negative 
Factor score (unadjusted p=0.0362). 
Study completion was achieved by 88% of pimavanserin and 96% of placebo subjects. 
Pimavanserin was well tolerated, with a treatment-emergent adverse event (TEAE) rate 
(39.9%) similar to that for placebo (36.4%), and few subjects in either group discontinuing 
due to a TEAE (pimavanserin 2.5%, placebo 0%). Serious adverse events were reported in 
1% of subjects in each arm. Use of adjunctive pimavanserin did not result in clinically 
significant differences from placebo in vital signs, body weight metabolic syndrome), or 
extrapyramidal symptoms. 
The Phase 2 ADVANCE study (ACP-103-038) was a 26-week, randomized, double-blind, 
placebo-controlled, multi-center, international study designed to examine the efficacy and 
safety of pimavanserin in patients with schizophrenia who have predominant negative 
symptoms while on a stable background antipsychotic therapy. A total of 403 subjects were 
randomized to receive once-daily pimavanserin (n=201) or placebo (n=202) as an adjunct 
treatment to their ongoing antipsychotic in a flexible dosing regimen. The starting daily dose 


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of 20 mg of pimavanserin at baseline could have been adjusted to 34 mg or 10 mg during the 
first eight weeks of treatment. 53.8% of subjects who were randomized to receive 
pimavanserin completed the trial on 34 mg, 44.7% on 20 mg, and 1.5% on 10 mg. The 
primary endpoint of the study was the change from baseline to Week 26 on the Negative 
Symptom Assessment-16 (NSA-16) total score. 
Baseline characteristics were similar across two treatment arms. The most prevalent 
background antipsychotics in the study included risperidone (38.5%), aripiprazole (32.5%), 
and olanzapine (28.0%). The average age of subjects in the study was 37.2 years. 
Pimavanserin demonstrated a statistically significant improvement on the study’s primary 
endpoint, the change from baseline to Week 26 on the NSA-16 total score, compared to 
placebo (-10.4 vs. -8.5; p=0.043; effect size = 0.21). A greater improvement in the NSA-16 
total score compared to placebo was observed in the 53.8% of subjects (n=107) who received 
the highest pimavanserin dose of 34 mg (-11.6 vs.-8.5; unadjusted p=0.0065, effect 
size = 0.34). 
Improvement in the NSA-16 total score was observed at each postbaseline visit, achieving 
nominal statistical significance at Week 4 (unadjusted p=0.0334) and Week 20 (unadjusted 
p=0.0067), in addition to Week 26 (the primary endpoint). Improvement of negative 
symptoms of schizophrenia was independent of treatment impact on depression, cognition, or 
positive symptoms of schizophrenia. More subjects in the pimavanserin group were 
responders, and change in NSA-16 domain scores was numerically greater with pimavanserin 
for each domain score, with nominally statistically significant improvement in the social 
involvement domain at Week 26 (unadjusted p=0.0111). 
In the study, pimavanserin was well-tolerated with high completion rates of approximately 
86% in both the pimavanserin and placebo treatment groups and similar rates of adverse 
events between pimavanserin (39.8%) and placebo (35.1%). Additionally, no clinically 
significant differences in vital signs, weight, metabolic syndrome or extrapyramidal 
symptoms were observed in the pimavanserin group compared to placebo. Serious adverse 
events were reported in 2.0% of subjects on pimavanserin and 0.5% of subjects on placebo 
and discontinuations due to adverse events were also low, 5.0% for pimavanserin and 3.0% 
for placebo. 
Additional information on previous pimavanserin clinical studies is provided in the 
pimavanserin Investigator’s Brochure and in the US Package Insert for NUPLAZID® 
(pimavanserin) tablets for oral use. 


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1.4 
Study Rationale 
At the National Institute of Mental Health (NIMH)-supported consensus meeting on negative 
symptoms, experts agreed that treatments for persistent and clinically signiﬁcant negative 
symptoms are an unmet therapeutic need (Kirkpatrick et al. 2006). Atypical antipsychotics 
are currently the standard of treatment for schizophrenia. While the effectiveness of 
antipsychotics has been established, a good proportion of patients do not achieve full control 
of their symptoms, including negative symptoms. 
Despite the clinical importance of negative symptoms, these symptoms remain inadequately 
addressed by current pharmacology with only limited evidence for minor symptom 
improvement (Blanchard et al. 2011). Thus, the adequate treatment of negative symptoms 
remains an unmet therapeutic need in this patient population. There is evidence that 
ritanserin, another selective 5-HT2A/2C inverse agonist/antagonist has efficacy against 
negative symptoms of schizophrenia both as monotherapy (Duinkerke et al. 1993) and when 
added to risperidone (Akhondzadeh et al. 2008). These data support the use of 5-HT2A 
receptor inverse agonists as adjunctive therapy for psychosis and negative symptoms of 
schizophrenia. 
In light of demonstrated antipsychotic efficacy and a well-defined safety profile, and on the 
basis of preclinical and clinical data suggesting potentiation of antipsychotic efficacy in 
coadministration with currently approved antipsychotics, Acadia Pharmaceuticals Inc. 
(Acadia) is currently pursuing additional studies on pimavanserin as adjunctive treatment of 
negative symptoms of schizophrenia. 
1.5 
Benefit/Risk Assessment 
1.5.1 
Known Potential Risks 
The Prescribing Information for NUPLAZID® (pimavanserin) tablets for oral use 
(Acadia Pharmaceuticals Inc. 2020) includes the following Boxed Warning: 
“WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH 
DEMENTIA-RELATED PSYCHOSIS” 
The increased mortality warning in elderly patients with dementia-related psychosis is based 
on information regarding antipsychotic drugs in general, rather than specific pimavanserin 
data. It should be noted that this study will not be recruiting any subjects older than 55 years 
(see Section 4.1, inclusion criterion #1). 
NUPLAZID is contraindicated in patients with a history of a hypersensitivity reaction to 
pimavanserin or any of its components. Rash, urticaria, and reactions consistent with 
angioedema (e.g., tongue swelling, circumoral edema, throat tightness, and dyspnea) have 


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been reported. To mitigate this risk, this study will not be recruiting any subjects who have a 
significant sensitivity or allergic reaction to pimavanserin or its excipients (see Section 4.2, 
exclusion criterion #25). 
The Warnings and Precautions section of the Prescribing Information for pimavanserin also 
includes information about QT interval prolongation. Pimavanserin prolongs the QT interval. 
The use of pimavanserin should be avoided in patients with known QT prolongation or in 
combination with other drugs known to prolong QT interval including Class 1A 
antiarrhythmics (e.g., quinidine, procainamide) or Class 3 antiarrhythmics (e.g., amiodarone, 
sotalol), certain antipsychotic medications (e.g., ziprasidone, chlorpromazine, thioridazine), 
and certain antibiotics (e.g., gatifloxacin, moxifloxacin). Pimavanserin should also be 
avoided in patients with a history of cardiac arrhythmias, as well as other circumstances that 
may increase the risk of the occurrence of torsade de pointes and/or sudden death, including 
symptomatic bradycardia, hypokalemia or hypomagnesemia, and the presence of congenital 
prolongation of the QT interval. To mitigate this risk, this study has strict exclusion criteria 
covering subjects who have a known personal or family history of long QT syndrome; risk 
factors for torsade de pointes and/or sudden death, including symptomatic bradycardia, 
hypokalemia or hypomagnesemia; the presence of congenital prolongation of the QT interval 
or prolonged QTcF values detected by ECG at Screening or Baseline visits; moderate to 
severe congestive heart failure; or a history of myocardial infarction within 6 months prior to 
enrollment (see Section 4.2, exclusion criteria # 13, 14, 16, and 17). In addition, the study has 
prohibitions or restrictions on the concomitant use of drugs known to prolong QT interval 
(Appendix A).  
1.5.2 
Known Potential Benefits 
There are currently no well-established potential benefits of pimavanserin in subjects with 
negative symptoms of schizophrenia. Pimavanserin has to date been tested in one study for 
its effects on positive and negative symptoms (ACP-103-034, primary endpoint PANSS) and 
in one study for its effects on negative symptoms of schizophrenia (ACP-103-038, primary 
endpoint NSA-16) (see Section 1.3 for summaries of results).  
A detailed summary of the potential risks and benefits is available in the pimavanserin 
Investigator’s Brochure. 
2 STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objective 
• To evaluate the efficacy of pimavanserin compared with placebo in the adjunctive 
treatment of the negative symptoms of schizophrenia 


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2.1.1 
Primary Endpoint 
• Change from Baseline to Week 26 in the Negative Symptom Assessment–16 (NSA-16) 
total score 
2.2 
Secondary Objective 
• To evaluate the effect of adjunctive pimavanserin compared with adjunctive placebo on 
global impression of severity of illness, global improvement of symptoms of illness, 
personal and social performance, and response to treatment in adults experiencing 
negative symptoms of schizophrenia 
2.2.1 
Secondary Endpoints 
2.2.1.1 
Key Secondary Endpoint 
• Change from Baseline to Week 26 in the Clinical Global Impression of Schizophrenia 
Scale–Severity (CGI-SCH-S) of negative symptoms score 
2.2.1.2 
Other Secondary Endpoints 
• Clinical Global Impression of Schizophrenia Scale–Improvement (CGI-SCH-I) of 
negative symptoms score at Week 26 
• Proportion of CGI-SCH-I of negative symptoms responders (CGI-SCH-I of negative 
symptoms score of 1 or 2) at Week 26 
• Change from Baseline to Week 26 in the Personal and Social Performance (PSP) scale 
score 
• Proportion of NSA-16 responders (≥20% and ≥30% reduction in NSA-16 total score) at 
Week 26 
• Change from Baseline to Week 26 in the Positive and Negative Syndrome Scale (PANSS) 
total score 
• Change from Baseline to Week 26 in PANSS negative subscores 
• Change from Baseline to Week 26 in PANSS Marder factor (negative symptoms) score 
2.3 
Exploratory Objective 
• To evaluate the effect of adjunctive pimavanserin compared with adjunctive placebo in 
adults experiencing negative symptoms of schizophrenia with respect to change in 
symptom domains, readiness to work, cognition, and depression 
2.3.1 
Exploratory Endpoints 
• Change from Baseline to Week 26 in PANSS subscores (positive and general) 


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• Change from Baseline to Week 26 in PANSS Marder factor (positive symptoms, 
disorganized thought, uncontrolled hostility/excitement, depression/anxiety) scores 
• Change from Baseline to Week 26 in Work Readiness Questionnaire (WoRQ) total score 
• Change from Baseline to Week 26 in Work Readiness Questionnaire (WoRQ) readiness to 
work question (item 8) 
• Change from Baseline to Week 26 in Brief Assessment of Cognition in Schizophrenia 
(BACS) score 
• Change from Baseline to Week 26 in Calgary Depression Scale for Schizophrenia 
(CDSS) score 
2.4 
Safety Objectives 
• To evaluate the safety and tolerability of pimavanserin compared with placebo in the 
adjunctive treatment of the negative symptoms of schizophrenia 
2.4.1 
Safety Endpoints 
Safety will be evaluated by analyses of the following: 
• Treatment-emergent adverse events 
• Vital signs 
• ECGs 
• Physical examination results 
• Clinical laboratory tests (including urinalysis) 
• Abnormal Involuntary Movement Scale (AIMS) 
• Barnes Akathisia Rating Scale (BARS) 
• Simpson-Angus Extrapyramidal Side Effects Scale (SAS) 
• Columbia–Suicide Severity Rating Scale (C-SSRS). 
The schedule of safety laboratory evaluations is included in Table 6–1. 
2.5 
Pharmacokinetic Objectives 
• To characterize the pharmacokinetics (PK) and pharmacodynamics of pimavanserin in the 
adjunctive treatment of the negative symptoms of schizophrenia 
2.5.1 
Pharmacokinetic Endpoints 
• Plasma concentration of pimavanserin, AC-279 (N-desmethyl-pimavanserin, major 
metabolite), and the main antipsychotic 
• Pimavanserin pharmacokinetic parameters using a population pharmacokinetic approach 


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• Pharmacokinetics/pharmacodynamics (PK/PD) using appropriate PK/PD analysis 
methods 
3 STUDY DESCRIPTION 
3.1 
Overview of Study Design 
This study will be conducted as a Phase 3, 26-week, randomized, double-blind, 
placebo-controlled, multicenter, multinational outpatient study in subjects with schizophrenia 
who have predominant negative symptoms while on adequate treatment with an 
antipsychotic. Schizophrenia is defined by the Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition (DSM-5), confirmed by a customized module of the Structured 
Clinical Interview for DSM-5, Clinical Trials Version (SCID-5-CT). Negative symptoms are 
considered predominant when other symptoms of schizophrenia, particularly positive 
symptoms such as delusions and hallucinations, are relatively mild and well controlled 
(Marder et al. 2013). 
This study will screen approximately 692 subjects and randomize approximately 426 subjects 
(213 subjects per treatment group) with predominant negative symptoms of schizophrenia 
across approximately 88 study sites in 12 countries. On the first day of the randomized 
treatment phase (Baseline), eligible subjects will be randomly assigned to receive 
pimavanserin 34 mg or placebo daily in a 1:1 ratio, according to a computer-generated 
randomization schedule. The randomization will be stratified according to geographic region 
(North America, Europe, or rest of world). The daily dose of the main antipsychotic must 
remain stable and may not be changed from Screening through the duration of the study. 
Subjects will participate in the study for up to 36 weeks, including a Screening Period of up 
to 6 weeks, a 26-week Treatment Period, and a 30 (+4) day safety follow-up (telephone call 
visit) 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). 
The study start date is defined as the date the first subject is enrolled, which is the date the 
first subject is randomized. 
The primary completion date is the last date that subject data was collected for the primary 
outcome measure. 
The study completion date is defined as the last date that subject data was collected, which 
includes the safety follow-up telephone call visit. Procedures for when a subject is lost to 
follow-up are provided in Section 4.5. 


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3.1.1 
Screening Period (up to 42 Days) 
During the Screening Period, subjects will be assessed for study eligibility and prohibited 
medications will be discontinued if medically appropriate. Subject eligibility will be assessed 
by the site and the Sponsor through an eligibility review process. 
Investigators should not withdraw a subject’s prohibited medication for the purpose of 
enrolling them into the study. Medications should only be discontinued if it is deemed 
clinically appropriate to do so and in consultation with the treating physician. 
Only outpatients with stable living conditions and a reliable informant may enter the study. 
Although subjects who are ≥18 and ≤55 years old are allowed to participate, in order to 
provide appropriate age representation, Investigators are encouraged to enroll an equal 
number of subjects who are ≤35 and who are >35 years old. 
Subjects who are deemed eligible for inclusion at the initial screening visit are scheduled to 
have a structured telemedicine (i.e., live unrecorded video) interview by an independent 
clinician to confirm that the subject has schizophrenia with predominant negative symptoms 
while on adequate treatment with an antipsychotic. 
Subjects must be taking only one antipsychotic, which will be continued throughout the 
subject’s participation in this study (see inclusion criterion #12 in Section 4.1). 
In order to provide appropriate representation of all antipsychotics in the study, Investigators 
are encouraged to enroll subjects with a range of allowable antipsychotics (see 
inclusion criterion #13 in Section 4.1). The objective is that at any given site no more than 
one-third of total subjects enrolled are on the same antipsychotic. 
Subjects who meet the criteria for study eligibility will continue to receive their antipsychotic 
at a stable dose for the duration of the study and will be randomly assigned to receive either 
pimavanserin 34 mg or matching placebo in a 1:1 ratio.   
3.1.2 
Double-Blind Treatment Period (26 Weeks) 
The Baseline visit (Day 1) may occur after all screening procedures are completed and 
subject eligibility is confirmed. The Baseline visit must occur within 6 weeks [42 days] after 
Screening. Subjects will be randomly assigned in a 1:1 ratio to receive either pimavanserin 
34 mg or matching placebo. The randomization will be stratified according to geographic 
region (North America, Europe, or rest of world). 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. 
Clinic visits occurring after Baseline will be conducted at Weeks 2, 4, 8, 14, 20, and 26 
(end of treatment [EOT]/early termination [ET] visit). 


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3.1.3 
Safety Follow-up Period (30 Days) 
Subjects who successfully complete the 26-week Treatment Period may enroll in a 52-week, 
open-label extension study (Study ACP-103-035) if they qualify and if the subjects have 
presented to the clinic in person to sign the ACP-103-035 informed consent form (ICF) and 
have all ACP-103-064 end of treatment procedures. For subjects who discontinue 
prematurely from the study or who do not enroll in the extension study (Study ACP-103-
035), in addition to the EOT or ET visit performed at time of discontinuation, a safety 
follow-up visit will occur 30 (+4) days after the last dose of study drug. For these subjects 
who discontinue prematurely or who do not continue into the extension study, the 
Investigator must ensure that the subject is appropriately transitioned to standard of care 
and/or followed for additional care per the Investigator or physician’s clinical judgment. 
Figure S–1 illustrates the study design. 
4 SUBJECT ELIGIBILITY AND WITHDRAWAL CRITERIA 
To be eligible for this study, subjects must meet all of the inclusion criteria and none of the 
exclusion criteria. 
Subjects are not to be dosed until all Baseline test results that are considered in inclusion and 
exclusion criteria are reviewed and determined to be consistent with enrollment. Some 
inclusion and exclusion criteria involve testing at Baseline where local/central testing results 
will not be available at the time of randomization. For these tests (e.g., urine toxicity [drug] 
screen and ECG), the Investigator should consider all available information (e.g., Screening 
test results, substance use history, concomitant medications, medical history, and local ECG 
reading) before determining eligibility. The subject may then be randomized prior to 
receiving local/central test results. If any information received post-randomization indicates 
that the subject was not eligible at the time of randomization, the subject will be discontinued 
as described in Section 10.6. 
4.1 
Inclusion Criteria 
A subject must meet all of the following inclusion criteria to be eligible for participation in 
the study: 
1. Male or female, ≥18 and ≤55 years of age at the time of Screening 
2. Able to understand and provide signed informed consent 
3. Able to sign and date a request for medical records and/or subject privacy form if 
applicable according to local regulations 


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4. In the Investigator’s opinion, is able to understand the nature of the trial, follow 
protocol requirements, be willing to comply with study drug administration, and 
discontinue prohibited concomitant medications 
5. Has a caregiver or some other identified responsible person (e.g., family member, 
social worker, caseworker, or nurse) considered reliable by the Investigator in 
providing support to the subject to help ensure compliance with study treatment, study 
visits, and protocol procedures, and who is also able to provide input helpful for 
completing study rating scales 
6. Able to complete subject-reported outcome measures, can be reliably rated on 
assessment scales, and is willing to participate in audio recording of assessment scales 
and in an unrecorded telemedicine interview  
7. Diagnosis of schizophrenia according to Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition (DSM-5) criteria (confirmed using a customized module of 
the Structured Clinical Interview for DSM-5, Clinical Trials Version [SCID -5-CT]) 
8. Diagnosis of schizophrenia made ≥1 year prior to Screening 
9. Score ≥20 on the sum of the 7 PANSS Marder negative factor items at Screening and 
Baseline 
AND 
Score ≥4 on at least 3, or ≥5 on at least 2, of the 7 PANSS Marder negative factor 
items 
10. Score ≤22 on the sum of the 8 PANSS Marder positive factor items 
AND 
PANSS score where no more than two of the following items have a score of 4 and 
none of the following items has a score ≥5 at both Screening and Baseline: 
• P1 (delusions) 
• P3 (hallucinatory behavior) 
• P4 (excitement) 
• P6 (suspiciousness/persecution) 
• P7 (hostility) 
11. A Clinical Global Impression of Schizophrenia Scale–Severity (CGI-SCH-S) for the 
negative symptoms of schizophrenia score ≥4 (moderately ill or worse) at Screening 
and Baseline 


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12. Has been treated with an adequate dose of an antipsychotic within the dose range 
recommended according to the local prescribing information for at least 8 weeks prior 
to Screening and remaining at the same dose during the Screening Period  
13. The antipsychotic with which the subject is being treated must be one of the 
antipsychotics listed below: 
• Aripiprazole 
• Aripiprazole long-acting injectables 
o Abilify Maintena® 
o Aristada® 
• Asenapine 
• Brexpiprazole 
• Cariprazine 
• Lurasidone 
• Olanzapine 
• Paliperidone extended release (ER) (≤9 mg) 
• Paliperidone palmitate 
o Invega Sustenna® (≤156 mg) 
o Invega Trinza® (≤546 mg) 
o Trevicta® (≤350 mg) 
o Xeplion® (≤100 mg) 
• Risperidone 
• Risperidone long-acting injection 
14. If taking an oral antipsychotic, no dose change within 4 weeks prior to Screening or 
during the Screening Period 
15. If taking a long-acting injectable antipsychotic, no dose change within 16 weeks prior 
to Screening or during the Screening Period 
16. If taking an antidepressant medication or an anxiolytic medication, no dose change 
within 4 weeks of Screening or during the Screening Period (see also Appendix A for 
restrictions/prohibitions during the study) 


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17. Must be medically stable (including no recent hospitalization for exacerbation of 
psychiatric disorder) and has been medically stable for at least 12 weeks prior to 
Screening, in the opinion of the Investigator 
18. If the subject is female, she must not be pregnant or breastfeeding. She must also be of 
non-childbearing potential (defined as either surgically sterilized or at least 1 year 
postmenopausal) OR must agree to use TWO clinically acceptable methods of 
contraception, or be abstinent, for at least 1 month prior to Visit 2 (Baseline), during 
the study, and for 41 days following completion of the study. Abstinence as a method 
of contraception is defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments. This option is usually made 
for a specific moral, religious, legal, or health reason. If heterosexual intercourse does 
occur, two acceptable methods of birth control are required. 
Acceptable methods of contraception include the following: 
a. A barrier method (condom, diaphragm, or cervical cap) with spermicide 
b. Hormonal contraception, including oral, injectable, transdermal, or 
implantable methods 
c. Intrauterine device (IUD) 
Only one of the two clinically acceptable methods can be a hormonal method. 
All female subjects of childbearing potential must have a negative serum human 
chorionic gonadotropin (hCG) pregnancy test at Screening and a negative urine 
pregnancy test at Baseline. 
Note: Specific contraceptive methods are not required for male subjects with partners 
of childbearing potential, but may be used as a general precaution. 
4.2 
Exclusion Criteria 
A subject must meet none of the following exclusion criteria to be eligible for the study: 
1. Based on the SCID-5-CT, has a current comorbid psychiatric disorder other than 
schizophrenia (e.g., bipolar disorder, obsessive compulsive disorder, substance abuse) 
or a disorder that would interfere with the ability to complete study assessments 
(e.g., intellectual disability) 
2. Score ≥2 for two or more movements or a score of 3 or 4 for any single movement on 
the Abnormal Involuntary Movement scale (AIMS) 
3. Total score ≥2 on the Barnes Akathisia Rating Scale (BARS) 
4. Total score ≥5 on the Simpson-Angus Extrapyramidal Side Effects Scale (SAS) 


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5. Calgary Depression Scale for Schizophrenia (CDSS) score ≥9 at both Screening and 
Baseline 
6. Is at a significant risk of suicide (e.g., answers “Yes” to suicidal ideation question 4 or 
5 [current or over last 6 months] or answers “Yes” to suicidal behavior questions on 
the C-SSRS [over last 6 months]), in the opinion of the Investigator 
7. Has a significant risk of violent behavior in the opinion of the Investigator 
8. Has met DSM-5 criteria for substance use disorders within the last 6 months prior to 
randomization (other than caffeine and/or nicotine) 
9. A confirmed urine toxicity (drug) screen result at Screening or Baseline that indicates 
the presence of any tested prohibited substance of potential abuse, including marijuana 
10. Subject was treated with two or more antipsychotics, for any indication, within 
8 weeks prior to Screening 
11. Laboratory testing confirms the absence of the main antipsychotic 
12.  Is taking a medication or drug or other substance that is prohibited according to this 
protocol, including medications that prolong the QT interval, strong cytochrome P450 
(CYP) 3A4 enzyme (CYP3A4) inhibitors and inducers (see Appendix A and 
Appendix B) 
13. Known family or personal history or symptoms of long QT syndrome or risk factors 
for torsade de pointes and/or sudden death, including symptomatic bradycardia, 
hypokalemia or hypomagnesemia, and the presence of congenital prolongation of the 
QT interval 
14. Has an ECG result at Screening or Baseline that meets one of the following 
exclusionary conditions: 
• If QRS interval <120 ms then a QTcF ≥460 ms is exclusionary 
• If QRS interval ≥120 ms then a QTcF ≥480 ms is exclusionary 
15. Current evidence, or history within the previous 12 weeks prior to Screening, of a 
serious and/or unstable psychiatric, neurologic, cardiovascular, respiratory, 
gastrointestinal, renal, hepatic, hematologic, or other medical disorder, including 
cancer or malignancies that in the judgment of the Investigator would jeopardize the 
safe participation of the subject in the study 
16. Has moderate to severe congestive heart failure (New York Heart Association [NYHA] 
class III and class IV) 
17. Has a history of myocardial infarction within 6 months prior to enrollment 
18. Has a history of uncontrolled diabetes mellitus (DM), Type 1 or 2 DM requiring 
insulin treatment, or glycosylated hemoglobin (HbA1c) >7% at Screening 


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19. Has a clinically significant thyroid function test result at Screening as defined by 
abnormal thyroid stimulating hormone (TSH) with abnormal reflex thyroxine (T4). If 
TSH is abnormal and the reflex free T4 is normal, the subject may be enrolled. 
20. Has clinically significant laboratory abnormalities that in the judgment of the 
Investigator or Medical Monitor would jeopardize the safe participation of the subject 
in the study 
21. Known to be positive for hepatitis C virus (HCV) or human immunodeficiency virus 
(HIV) 
22. Has a body mass index (BMI) <19 or ≥35 at Screening 
23. Has a history of neuroleptic malignant syndrome 
24. Is breastfeeding or lactating 
25. Has a significant sensitivity or allergic reaction to pimavanserin or its excipients 
26. Has previously been randomized in any prior clinical study with pimavanserin, and/or 
received any other investigational (either approved or unapproved) drug within 
30 days or 5 half-lives (whichever is longer) prior to Screening 
27. Has any condition that, in the opinion of the Investigator, would interfere with the 
ability to comply with study instructions, or that might confound the interpretation of 
the study results or put the subject at undue risk 
28. Is an employee of Acadia, or has a family member who is an employee of Acadia 
29. Has participated in >2 pharmaceutical clinical research studies within the previous 
2 years 
30. Subject is judged by the Investigator or the Medical Monitor to be inappropriate for 
the study 
31. Subject has had a social hospitalization, defined as admission to the hospital as a result 
of inadequate family support or care at the subject’s primary residence, during the 
8 weeks prior to Screening 
4.3 
Subject Withdrawal of Consent 
In accordance with the Declaration of Helsinki and other applicable regulations, a subject has 
the right to withdraw from the study at any time, and for any reason, without prejudice to his 
or her future medical care. 
If the subject (and/or legally acceptable representative/caregiver) decides to withdraw 
consent from all components in the study, this must be documented and no additional 
assessments will be performed. The Sponsor may retain and continue to use any data 
collected before such a withdrawal of consent. The subject may request destruction of any 


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samples taken and not tested, prior to their withdrawal of consent, and the Investigator must 
document this in the site study records. 
If the subject (and/or legally acceptable representative/caregiver) wants to discontinue 
treatment and agrees to the evaluations specified at the EOT/ET visit and/or at safety follow 
up (whichever is applicable), as outlined in Table S-1, the agreed assessments should be 
conducted. The subject’s reason for wanting to discontinue treatment and the agreement to 
continue with the applicable assessments for study termination must be documented. 
4.4 
Subject Discontinuation 
Subjects may be discontinued from the study for a number of reasons, including, but not 
limited to, those listed below: 
• Adverse event 
• Death 
• Failure to meet randomization criteria 
• Lack of efficacy 
• Lost to follow-up (Section 4.5) 
• Non-compliance with study drug 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Study terminated by Sponsor 
• Use of prohibited medication 
• Withdrawal of consent by subject  
• Investigator determines that continuation in the study would be detrimental to a subject’s 
well-being (e.g., safety or tolerability concerns due to an adverse event; a clinically 
significant risk of suicidality is identified for a subject or a subject’s clinical symptoms 
significantly worsen or relapse which in the opinion of the Investigator required the 
subject to be withdrawn). 
• Subject has a confirmed ECG measurement of QTcF interval >500 ms or a change from 
baseline in the QTcF interval >60 ms concurrently with a QTcF interval >470 ms. 
• Other 


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A subject is considered to have completed planned participation in the study if all treatment 
visits including the EOT visit have been completed. 
A single documented social hospitalization (see Section 7.1.2) for a maximum duration of 
2 weeks may be allowed over the course of the study provided that the subject has the 
opportunity to engage in social and functional activities, as required for PSP assessment. 
4.4.1 
Guidance for Investigators on Suicidality, Symptom Worsening, and Relapse 
The decision to withdraw a subject due to suicidality, symptom worsening, or relapse is a 
clinical judgment made by the Investigator. Below are some potential signs of suicidality, 
symptom worsening, or relapse that Investigators may choose to use to inform this decision: 
• Subject answers “Yes” to suicidal ideation question 4 or 5 (since previous visit) or 
answers “Yes” to suicidal behavior questions on the C-SSRS 
• An increase in the level of psychiatric care required by the subject (e.g., significant 
crisis intervention needed to avert hospitalization or clinically notable increases in the 
frequency or intensity of subject contact required to maintain outpatient status) 
• Deliberate self-injury, suicidal, or homicidal ideation that is clinically significant as 
determined by the Investigator, or violent behavior resulting in clinically significant 
injury to another person or property damage 
• Increase in main antipsychotic dose of more than 25% of the current stable dose 
(Note: any change to main antipsychotic dose during the study is prohibited and will 
result in the subject being withdrawn from the study) or addition or dose increase of 
another psychotropic medication to prevent symptom exacerbation, including 
additional antipsychotics, mood stabilizers, or benzodiazepines (see Appendix A and 
Appendix B for medications and changes to medications that are prohibited and will 
result in the subject being withdrawn from the study) 
• Substantial clinical deterioration, as indicated by a score of 6 (“much worse”) or 
7 (“very much worse”) on the CGI-SCH-I of negative symptoms scale 
4.4.2 
Handling of Subject Discontinuation During the Treatment Period 
Unless the subject has withdrawn consent from all components of the study, every reasonable 
effort should be made to complete Visit 8/ ET and the safety follow-up visit (as outlined in 
Table S-1) if a subject discontinues prematurely during the Treatment Period of the study. All 
information will be reported on the applicable pages of the eCRF. 
If a subject is discontinued from the study because of an AE, every reasonable attempt should 
be made to follow and appropriately treat (or refer for treatment) the subject until the AE 
resolves or until the Investigator deems the AE to be chronic or stable. For subjects who 


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continue to be followed for safety, SAEs should continue to be reported as described in 
Section 7.4.2. All SAEs will continue to be followed and appropriately treated until such 
events have resolved or the Investigator deems them to be chronic or stable. 
4.5 
Subject Lost to Follow-up 
A subject will be considered lost to follow-up if they fail to attend a scheduled visit 
(including the safety follow-up visit) and the study subject or caregiver (if applicable) is 
unable to be contacted by the study site after repeated attempts.  
Every reasonable effort should be made to contact the subject and caregiver (if applicable) 
and will include a minimum of 3 documented phone calls (each performed at different times 
of the day) and, if necessary, a certified letter to the subject’s last known mailing address or 
local equivalent methods. All contact attempts are to be documented in the source documents. 
4.6 
Study Discontinuation 
The Sponsor reserves the right to discontinue the study at any time for any reason. Such 
reasons may be any of, but not limited to, the following: 
• Occurrence of AEs unknown to date in respect of their nature, severity, and duration 
or the unexpected incidence of known AEs 
• Medical, ethical, or business reasons affecting the continued performance of the study 
Regulatory authorities also have the right to terminate the conduct of the study in their region 
for any reason. 
The Sponsor reserves the right to stop a site from further participation due to issues of 
quality, conduct or unresponsiveness. 
4.7 
Prior and Concomitant Therapy 
All medications used from study screening until completion of the safety follow-up visit are 
to be recorded. 
4.7.1 
Prior Medication 
Prior medication is defined as any medication with a stop date prior to the date of the first 
dose of study drug. 
4.7.2 
Concomitant Medication 
Concomitant medication is defined as any medication that is ongoing at the first dose of 
study drug or with a start date between the dates of the first dose and last dose of study drug, 
inclusive (this includes vaccines). 


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In order to ensure that appropriate concomitant therapy is administered, it is essential that 
subjects be instructed not to take any medication without prior consultation with the 
Investigator (unless the subject is receiving treatment for a medical emergency). 
The Investigator may prescribe appropriate medication to treat AEs. 
4.7.2.1 
Permitted, Restricted, and Prohibited Medications 
Prohibitions and restrictions for concomitant medications should be followed between the 
initial screening visit and Visit 8/EOT/ET as specified in Appendix A and Appendix B. These 
appendices do not constitute an exhaustive list and any questions regarding prohibited and 
restricted medications should be discussed with the Medical Monitor or designee. 
Medications that can prolong QT interval are prohibited (or restricted if approved by the 
Medical Monitor) as specified in Appendix A.  
Permitted concomitant medications should remain at a stable dose throughout the study.  
If a subject is on a medication restricted by the protocol, the medication should be adjusted if 
it is determined by the Investigator to be clinically appropriate (e.g., if the subject's 
symptoms are not well-controlled or if the subject cannot tolerate the current medication) in 
consultation with the treating physician. 
Subjects who require current treatment with a prohibited medication will be withdrawn from 
the study. 
Subjects who have taken a prohibited medication during the study will be withdrawn from 
the study unless: 
• the prohibited medication has been discontinued, AND 
• withdrawal from the study presents an unacceptable medical risk to the subject 
The justification to allow the subject who has taken a prohibited medication to continue in 
the trial will be made by the Sponsor/Medical Monitor, with medical input from the 
Investigator, and will be documented. If a subject is allowed to remain in the trial, this will be 
reported as a major protocol deviation and not a waiver. 
4.7.2.1.1 
Rationale for Including Paliperidone Extended Release (≤9 mg/day) 
Formulations as Allowed Antipsychotics 
As part of Study ACP-103-064 Protocol Amendment 2, paliperidone (9-OH-risperidone, the 
main active metabolite of risperidone) extended release (ER) drug formulations have been 
added as allowed antipsychotics with a maximum dose of 9 mg/day (or equivalents for depot 
formulations). 


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Data from clinical studies conducted by both Acadia and others support the inclusion of 
paliperidone ER (≤9 mg/day) as an allowed antipsychotic:  
Acadia Studies 
Review of data from recently completed and ongoing Acadia studies in patients with 
schizophrenia, in which pimavanserin was used as adjunctive treatment with various 
antipsychotics, showed no evidence of significant QTc prolongation when pimavanserin was 
used with oral risperidone or risperidone long-acting injection, relative to that observed when 
pimavanserin was used with aripiprazole or olanzapine. 
Specifically, 
• in Study ACP-103-034 (6 weeks of double-blind adjunctive treatment; 73 subjects 
treated with risperidone, 37 subjects with aripiprazole, and 69 subjects with 
olanzapine), there were no postbaseline QTcF values ≥481 ms, and one subject in 
each of the risperidone and aripiprazole groups had a change from baseline to 
postbaseline maximum of >60 ms. More subjects had a change from baseline to 
postbaseline maximum of 31 to 60 ms in the risperidone plus adjunctive placebo 
group than in the risperidone plus adjunctive pimavanserin group. 
• in Study ACP-103-038 (26 weeks of double-blind adjunctive treatment; 83 subjects 
treated with risperidone, 60 subjects with aripiprazole, and 47 subjects with 
olanzapine), one subject treated with aripiprazole had a postbaseline QTcF maximum 
of 481 to 500 ms, and one subject treated with aripiprazole had a change from 
baseline to postbaseline maximum of >60 ms. Of note, more subjects had a change 
from baseline to postbaseline maximum between 31 to 60 ms in each of the groups 
treated with aripiprazole or olanzapine than in the group treated with risperidone. 
• in Study ACP-103-035 (currently ongoing; 52 weeks of open-label adjunctive 
treatment; exposure ranges from 52 to 78 weeks in those subjects who have 
completed the study; 253 subjects on risperidone, 171 subjects on aripiprazole, and 
214 subjects on olanzapine), one subject treated with aripiprazole had a postbaseline 
QTcF maximum of 481 to 500 ms, and one subject in each of the groups treated with 
aripiprazole and risperidone had a double-blind baseline to post double-blind baseline 
maximum of >60 ms. Similar proportions of subjects had changes from double-blind 
baseline to post double-blind baseline maximum between 31 to 60 ms across 
treatments. 
In these studies, subjects received doses of risperidone from 1 mg once daily to 6 mg three 
times daily, with over 85% of subjects on a dose of >4 mg/day. Of note, 6 weeks of treatment 


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with approximately 5 mg oral risperidone (Riedel et al. 2005) resulted in similar exposure to 
paliperidone as compared with 12 mg paliperidone ER.  
Invega® Study 
In a thorough QT study testing various doses of immediate release (IR) oral formulation of 
paliperidone, a 4 mg dose with peak plasma concentration at steady state (Cmax,ss) of 
35 ng/mL showed an increased placebo-subtracted QTcLD of 6.8 ms (90% CI: 3.6, 10.1). 
In the same study, an 8 mg paliperidone IR dose showed a mean placebo-subtracted increase 
from Baseline in QTcLD of 12.3 ms (90% CI: 8.9, 15.6). The mean Cmax,ss for this 8 mg dose 
of paliperidone IR was more than twice the exposure observed with the maximum 12 mg 
dose of paliperidone ER recommended by the manufacturer (113 ng/mL and 45 ng/mL, 
respectively). None of the subjects had a change exceeding 60 ms or a QTcLD exceeding 
500 ms at any time during this study (Janssen Pharmaceuticals Inc. 2019).  
Study Precautions 
In light of these findings, study precautions include a maximum dose of 9 mg paliperidone 
ER (i.e., a similar plasma concentration to a 4 mg dose of the IR oral formulation of 
paliperidone) and eligibility review of each potential subject taking into account medical 
history and ECG data (i.e., a QRS interval <120 ms and a QTcF ≥460 ms, OR a QRS interval 
≥120 ms and a QTcF ≥480 ms, at Screening or Baseline is exclusionary). Subjects on high 
doses of paliperidone ER (12 and 18 mg) and paliperidone palmitate will be excluded. In 
addition, ongoing study safety data monitoring will include regular data and safety 
monitoring board (DSMB) reviews and discontinuing subjects who have a QTcF interval 
>500 ms, or an increase of >60 ms from Baseline concurrently with a QTcF interval >470 ms. 
5 INVESTIGATIONAL PRODUCT 
5.1 
Investigational Product Description 
The investigational product will be pimavanserin 17 mg tablets or matching placebo tablets. 
Placebo tablets will be size- and color-matched to the pimavanserin tablets. Tablets will be 
administered orally as a single dose once daily. 
Pimavanserin doses to be studied: 
• Pimavanserin 34 mg (provided as 2 × 17 mg tablets) 
• Placebo (provided as 2 × placebo tablets). 


St u d y: A C P -1 0 3 -0 6 4  
Fi nal Versi o n 1. 0  
Cli nical St u d y Pr ot oc ol A me n d me nt 3  
Date: 0 5 Oct o ber 2 0 2 2  
C o nfi de ntial a n d Pr o prietar y I nf or mati o n of Aca dia P har mace uticals I nc.  
Pa ge 5 4  of 9 4  
5. 1. 1  
F or m ul ati o n, A p pe ar a nce, P ac k a gi n g, a n d L a beli n g 
T he S p o ns or will s u p pl y pi ma va nseri n 1 7 m g  ta bl ets a n d matc hi n g place b o ta blets pac ka g e d 
i n blister car ds eac h c o nt ai ni n g 2 0 ta blets. Pac ka gi n g will be la bele d per a p plica ble c o u ntr y 
re g ulati o ns. 
Pi ma va nseri n tartrat e is a w hite t o off -w hite p o w d er. Pi ma va nseri n ta blets i ncl u de t he acti ve 
c o m p o u n d ( pi ma va nseri n tartrate) a n d t he f oll o wi n g e xci pie nts: pre gel ati nize d starc h, 
ma g nesi u m stearate, a n d micr ocr ystalli ne cell ul ose, a n d t he ta blet c oati n g is O pa dr y ®  t m 
0 7 F 2 8 5 8 8 w hite. T he dr u g pr o d uct is f or m ulate d wit h sta n dar d p har mace utical e xci pie nts at 
1 7 m g stre n gt h ( 2 0 m g of pi ma va nseri n tartrate ) I R ta blets f or o nce-d ail y oral a d mi nistrati o n.  
Place b o ta blets c o ntai n all of t he sa me e x ci pie nts as pi ma va nseri n 1 7 m g ta blets b ut d o n ot 
c o ntai n a n y pi ma va nseri n tartrate. 
Pi ma va nseri n a n d place b o ta blets are ma n ufact ure d u n der c urre nt G o o d Ma n ufact uri n g 
Practice s ( c G M P) b y 
 
D uri n g t he T reat me nt Peri o d, st u d y dr u g will be distri b ute d i n a q ua ntit y s ufficie nt t o e ns ure 
t he s u bject has a n a de q uate s u p pl y of st u d y dr u g bet wee n st u d y visits. I n a d diti o n t o t he st u d y 
dr u g dis pe nse d at t he site, i n vesti gati o nal pr o d uct ma y be deli vere d directl y t o t he s u bject’s 
place of resi de nce; relat e d pr oce d ur es will be descri b e d i n t he st u d y-s pecifi c p har mac y 
ma n ual.  
5. 1. 2  
Pr o d uct St or a ge a n d St a bilit y  
I n vesti gati o nal pr o d uct m ust be st ore d bet wee n 1 5° C a n d 3 0° C ( 5 9° F a n d 8 6° F) in a sec ure 
area wit h restricte d access a n d acc or di n g t o l ocal a n d nati o nal re g ulati o ns.  Neit her t he 
I n vesti gat or, n or t he p h ar macist, n or a n y of his or her desi g nees ma y pr o vi de st u d y dr u g t o 
a n y pers o n n ot partici pati n g i n t he st u d y. 
5. 1. 3  
D osi n g a n d A d mi nistr ati o n 
T he first d ose of st u d y dr u g ( pi ma va nseri n 3 4 m g  or matc hi n g place b o) will be ta ke n at t he  
Baseli ne v isit, after all baseli ne assess me nts ha ve bee n c o m plete d. St u d y dr u g will c o nti n ue 
dail y at t his d ose le vel f or t he rest of t he st u d y. 
Eac h dail y d ose c o nsists of t w o i n di vi d ual ta blets t hat s h o ul d be ta ke n t o get her. S u bject s 
s h o ul d be i nstr ucte d t o ta ke t w o w h ole ta blets, orall y, o nce dail y. S u bjects s h o ul d be 
i nstr ucte d t o n ot cr us h t he ta blets. T he ta blets ma y be ta ke n wit h or wit h o ut f o o d. 
S u bjects s h o ul d ta ke t he st u d y dr u g at a p pr o xi mat el y t he sa me ti me eac h d a y u ntil Wee k 2 6 
(E O T / E T), e x ce pt f or Da y 1 ( Visit 2) w he n t he d ose is ta ke n at t he st u d y ce nter. S u bjects 
s h o ul d ta ke t he dail y d ose of st u d y dr u g at t he sa me ti me as t he y n or mall y ta ke t heir mai n 
C CI


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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 kits will be dispensed to the subject to take home. 
Subjects will take study drug adjunctively to their main antipsychotic throughout the 
Treatment Period. Adjustments in the dose of the main antipsychotic are not permitted after 
Screening. 
5.1.4 
Method of Assigning Subjects to Treatment Groups 
At the Baseline visit (Day 1/Visit 2), eligible subjects who meet inclusion and do not meet 
exclusion criteria will be randomized in a 1:1 ratio to receive either pimavanserin 34 mg or 
placebo. The randomization will be stratified according to geographic region (North America, 
Europe, or rest of world).   
5.1.5 
Blinding 
Treatment assignments will be blinded to all study subjects, study caregivers, Investigators, 
raters, site personnel, and Sponsor personnel. In the event of a potential suspected unexpected 
serious adverse reaction (SUSAR), in accordance with current health authority guidance, 
treatment assignments for the affected subject may be unblinded to a controlled group of the 
Sponsor’s Safety and/or Regulatory personnel for reporting purposes.  
Details regarding medical emergency unblinding procedures are provided in Section 9.9. 
5.1.6 
Study Drug Compliance 
The Investigator or designated study center personnel will maintain a log of all study drug 
dispensed and returned during the study. Study drug supplies for each subject will be 
inventoried and accounted for throughout the study to verify the subject’s compliance with 
the dosage regimen. Subjects will be counseled regarding compliance at every visit. Subjects 
who have <80% or>120% compliance may be discontinued from the study. If a subject 
shows significant undercompliance (<80%) between any two scheduled visits, the Medical 
Monitor should be notified to determine if the subject remains eligible for the study and 
whether the incident should be considered a protocol deviation. 
If a subject misses one dose of study drug, he or she should not take an extra dose the next 
day. 
5.1.7 
Overdose 
An overdose is a deliberate or inadvertent administration of a treatment at a dose higher than 
the maximum recommended dose per protocol. It must be reported using the Sponsor’s 


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Overdose Reporting form, irrespective of outcome, even if toxic effects were not observed 
(Section 7.4.4). All events of overdose are to be captured as protocol deviations. 
An overdose is considered an AE only if there are symptoms associated with the event. 
5.2 
Investigational Product 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 regulatory authority and the 
Sponsor that the study drug is being handled appropriately. Subjects should be instructed to 
return all packaging and unused study drug to the Investigator at regularly scheduled clinic 
visits and ET visits. Any study drug supplied is for use in this study only and should not be 
used for any other purpose. 
At appropriate intervals during the study, study drug reconciliation will be performed by the 
Sponsor (or designee) who may return appropriate unused study drug and used and unused 
packaging to the Sponsor’s designee for destruction. 
At the conclusion of the study, final study drug reconciliation will be conducted at the site. 
Final study drug accountability documentation will be maintained at both the site and at the 
Sponsor. Any remaining unused study drug and all used and unused packaging will be sent 
back to the Sponsor’s designee for destruction. Documentation of study drug destruction will 
be recorded and maintained by both the Sponsor and the Sponsor’s designee. 
6 STUDY ASSESSMENTS 
Study specific assessments are detailed below. All assessments will be completed according 
to the schedule described in Table S-1. Every effort should be made to complete the required 
procedures and evaluations at the designated visits and times. It is mandatory that the 
caregiver/responsible person attend every visit with the subject. If a caregiver/responsible 
person misses 2 or more visits, the subject may be discontinued. 
The Screening Period will be up to 42 days in duration.  
It is required that trained and experienced clinicians administer the efficacy and safety scales 
for this protocol. Training, certification, and materials for rating will be provided by Acadia 
or its designee. 
The NSA-16 is only to be administered by site personnel certified as qualified to administer 
the scale. All administrations of the NSA-16 will be audio-recorded for quality control, 
training, and calibration purposes. Personnel will also be trained in the administration of the 
other efficacy and safety assessment scales prior to administration of assessment scales to 
subjects. Changes in personnel administering scales (e.g., different site personnel 


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administering assessments for the same subject at different visits) are strongly discouraged 
and will be monitored by the Sponsor. 
6.1 
Remote Assessments or Visits 
Circumstances may arise (e.g., pandemic, natural disaster, or political upheaval) when on-site 
assessments of efficacy and/or safety may not be possible. In those cases, assessments may 
be performed at the subject’s place of residence by raters either in person, or via video 
technology or telephone where possible. The Investigator must contact the Medical Monitor 
for approval with the plan. Sites must keep a log to identify details of all visits that are 
administered remotely. For some remote efficacy assessments (i.e., NSA-16, PANSS, CGI), 
the vendor will provide additional training to ensure calibration to reduce discrepancy 
between on-site and remote assessments.   
6.2 
Screening Assessments 
6.2.1 
Demography 
Demographic information, including date of birth, age at Screening, gender, race, and 
ethnicity will be recorded. 
6.2.2 
Medical and Psychiatric History 
A complete medical history will be obtained from each potential subject. Any new medical 
condition beginning after the ICF has been signed will be captured as an AE. Subjects may be 
asked to provide pharmacy or medical records to substantiate the medication history. Details 
of the subject’s psychiatric history and treatment will also be collected. 
6.2.3 
Schizophrenia Disease History 
Details of the subject’s schizophrenia history and treatment will be collected. 
6.2.4 
Structured Clinical Interview for DSM-5, Clinical Trials Version (SCID-5-CT 
customized module) 
The Structured Clinical Interview for DSM-5 (SCID-5) is a semi-structured interview guide 
for making the major DSM-5 diagnoses. It is administered by a clinician or trained mental 
health professional who is familiar with the DSM-5 classification and diagnostic criteria. The 
Clinical Trials Version (SCID-5-CT) is an adaptation that has been reformatted, streamlined, 
and optimized for use in clinical trials that incorporate typical inclusion and exclusion 
criteria. The customized version is tailored to conform to the specific diagnostic inclusion 
and exclusion criteria of the protocol. 


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6.2.5 
Interview by an Independent Clinician 
A structured telemedicine interview of the subject by an independent clinician will be 
performed during the Screening Period. The interview will be conducted by video and will 
not be recorded. 
6.2.6 
Confirmation of Main Antipsychotic 
The presence or absence of the main antipsychotic in the plasma will be assessed at 
Screening. 
6.3 
Efficacy Scales 
6.3.1 
Negative Symptom Assessment–16 
The NSA-16 is a 16-item scale that can be completed in approximately 20 to 30 minutes for 
most subjects, but may take longer (i.e., based on effort and/or response of the subject) 
(Axelrod et al. 1993). The NSA-16 has been validated for the assessment of the negative 
symptoms of schizophrenia and assesses 5 domains of negative symptoms: 
(1) communication, (2) emotion/affect, (3) social involvement, (4) motivation, and 
(5) retardation. 
6.3.2 
Clinical Global Impression of Schizophrenia Scale–Severity 
The CGI-SCH-S is a clinician-rated, 7-point scale that is designed to evaluate positive, 
negative, depressive, cognitive symptoms, and overall severity in schizophrenia 
(Haro et al. 2003). For the purposes of this study, only the negative symptoms will be 
evaluated. 
6.3.3 
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). 
6.3.4 
Clinical Global Impression of Schizophrenia Scale–Improvement 
The CGI-SCH-I is a clinician-rated, 7-point scale that is designed to evaluate change in 
positive, negative, depressive, cognitive symptoms, and overall severity in schizophrenia 
(Haro et al. 2003). For the purposes of this study, only the negative symptoms will be 
evaluated. 


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6.3.5 
Positive and Negative Syndrome Scale 
The PANSS is a 30-item scale used to evaluate the presence, absence, and severity of 
schizophrenia symptoms (Kay et al. 1988). The 30 items are arranged as 7 positive symptom 
items, 7 negative symptom items, and 16 general psychopathology symptom items. The 
PANSS total score can range from a minimum of 30 to a maximum of 210. 
6.3.6 
Informant Questionnaire for the Positive and Negative Syndrome Scale 
The Informant Questionnaire for the Positive and Negative Syndrome Scale (IQ-PANSS) is a 
14-item informant questionnaire designed to obtain input from the informant on each of the 
items by evaluating the presence, absence, and severity of schizophrenia symptoms as they 
relate to the subject (Opler and Ramirez 2009). Behaviors observed by the informant about 
the subject are captured verbatim in notes below each PANSS item. 
While two PANSS items, Passive/apathetic social withdrawal (N4) and Active social 
avoidance (G16), are scored exclusively based on information obtained from the informant, 
information reported on the other items included in the IQ-PANSS is to be used in 
conjunction with data obtained during the Structured Clinical Interview for the PANSS 
(SCI-PANSS). 
6.3.7 
Brief Assessment of Cognition in Schizophrenia 
The BACS is a performance-based assessment that measures treatment-related changes in 
cognition and assesses six cognitive domains, including verbal memory and learning (verbal 
memory task), working memory (digit sequencing), motor function (token motor task), verbal 
fluency (semantic and letter fluency), speed of processing (symbol coding), and executive 
function (Tower of London) (Keefe et al. 2004). The BACS takes approximately 30 minutes 
to administer, and incorporates alternative forms for repeated testing. 
6.3.8 
Calgary Depression Scale for Schizophrenia 
The CDSS is a 9-item scale that was developed specifically to assess the level of depression 
in schizophrenia. It was originally developed to differentiate depressive symptoms from 
negative symptoms (Addington et al. 1990; Addington et al. 1992). 
6.3.9 
Work Readiness Questionnaire 
The WoRQ (Potkin et al., 2016) consists of 7 statements that the Investigator rates on a 
4-point scale (“strongly agree” [1 point] to “strongly disagree” [4 points], with “strongly 
agree” being the most indicative of work readiness). Using the ratings of these 7 statements 
as an aid, the Investigator provides a global yes/no judgment about the subject’s readiness to 
work. The WoRQ total score is calculated by adding scores for the 7 statements.  


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6.4 
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), Barnes Akathisia 
Rating Scale (BARS), and the Simpson-Angus Extrapyramidal Side Effects Scale (SAS). 
In addition, the Columbia–Suicide Severity Rating Scale (C-SSRS) will be used to assess 
suicidal ideations and behaviors. 
6.4.1 
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. 
6.4.2 
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. 
6.4.3 
Simpson-Angus Extrapyramidal Side Effects Scale 
The SAS is a 10-item physician-administered scale commonly used for the assessment of 
parkinsonian movement disorder related to psychiatric drug treatment (Simpson and Angus 
1970). One item on the SAS measures gait (hypokinesia); six items measure rigidity; and 
three items measure glabella tap, tremor, and salivation, respectively. The grade of severity of 
each item is rated using a 5-point scale and individual scores are combined to obtain a total 
score. 
6.4.4 
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 


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Investigator should discontinue the subject and implement appropriate treatment 
(Sections 4.3 and 3.1.3). 
6.5 
Safety Measures 
Circumstances may arise (e.g., pandemic, natural disaster, or political upheaval) when on-site 
assessments of safety measures may not be possible. In those cases, assessments may be 
performed at the subject’s place of residence either in person or via video technology or 
telephone, where possible. If a subject is unable to come to the site for lab draws and the site 
is unable to travel to the subject’s place of residence, the subject may visit a local lab to 
obtain all safety labs. The Investigator must contact the Medical Monitor for approval with 
the plan. Sites must keep a log to identify details of all visits that are administered remotely. 
6.5.1 
Medical and Psychiatric History 
A thorough medical and psychiatric history, including schizophrenia history, will be obtained 
by interviewing each subject at the Screening visit. 
6.5.2 
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. 
6.5.3 
Physical Examination 
A complete physical examination should be performed at Screening, Baseline, and Week 26 
(EOT/ET); symptom-directed examinations will be performed at Weeks 2 and 14. Pelvic 
and/or urogenital examination may be deferred, unless the Investigator deems this to be 
clinically indicated. 
6.5.4 
Vital Sign Measurements 
Vital signs, including sitting (at least 3 minutes) blood pressure, pulse rate, respiratory rate, 
and temperature, should be performed at Screening, Baseline (Day 1), and Weeks 2, 4, 8, 14, 
20, and 26 (EOT/ET). At Baseline, vital signs must be measured before study drug is given. 
6.5.5 
Height and Weight 
Height will be measured at Screening only. Weight will be measured at Screening, Baseline 
(Day 1), and Week 26 (EOT/ET). 
6.5.6 
Electrocardiograms 
A 12-lead ECG will be performed in triplicate at Screening. Single 12-lead ECG recordings 
will be performed at Baseline, Week 14, and at the Week 26 (EOT/ET) visit. If possible, ECG 


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recordings should be performed prior to any blood sampling procedures (e.g., PK or 
laboratory evaluations) and can be performed any time before blood sampling. If an ECG is 
conducted after blood sampling, the ECG must be conducted at least 30 minutes after blood 
sampling. 
At Screening, if the set of triplicate ECGs has a prolonged QTcF due to an identifiable cause, 
and it is medically appropriate to address that cause, a repeat set of triplicate ECGs may be 
performed during Screening at the discretion of the Medical Monitor. 
At Baseline, a subject may be enrolled based on the machine read of the locally completed 
Baseline ECG. If the interpretation of the ECG by the central cardiologist indicates QTcF 
outside of the allowable range, the subject will be discontinued from the study (see 
Section 4.4), but this will not be considered a protocol deviation. 
6.5.7 
Laboratory Evaluations 
Clinical laboratory sample collection (including HbA1c at Screening only) is encouraged, but 
not required, to be completed under fasting conditions. The laboratory evaluations will 
include, but are not limited to, the following: 
• Clinical chemistry serum tests 
o Sodium (Na), potassium (K), chloride (Cl), phosphorus (P), calcium (Ca), 
magnesium (Mg), carbon dioxide (CO2), blood urea nitrogen (BUN), creatinine 
(CR), uric acid 
 Mg should only be performed at Visit 1 (Screening) 
o Alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), total 
bilirubin (TBIL), lactate dehydrogenase (LDH) 
o Vitamin B12 
 Vitamin B12 should only be performed at Visit 1 (Screening) 
o HbA1c 
 HbA1c should only be performed at Visit 1 (Screening) 
o Glucose 
o Albumin (ALB), total protein 
o Prolactin 
o Thyroid stimulating hormone (TSH) and free T4 


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o Creatine kinase (CK)/creatine phosphokinase (CPK) 
o Lipid panel 
 Total cholesterol, HDL-cholesterol, triglycerides, LDL-cholesterol, 
cholesterol/HDL ratio, non-HDL cholesterol 
• Pregnancy test 
o A serum pregnancy test should only be performed at Visit 1 (Table 6–1) for 
women of childbearing potential 
o A urine pregnancy test should be performed at all designated visits after Visit 1 
(Table 6-1) for women of child-bearing potential 
 If urine cannot be obtained in women of childbearing potential, a serum 
pregnancy test should be done in its place 
• Hematology tests 
o Complete blood count (CBC) including: 
 White blood cell (WBC) count 
 Complete differential (relative and absolute) 
 Hematocrit (Hct), hemoglobin, red blood cells (RBC), platelets 
 Reticulocyte count 
• Urinalysis 
o Blood, leukocyte esterase (plus reflexed microscopic analysis if test is positive), 
protein, glucose, ketones, specific gravity, pH 
• Urine toxicity (drug) screen 
o The urine toxicity (drug) screen (UDS) will include testing for the following 
substances: tetrahydrocannabinol (THC), benzodiazepines, barbiturates, cocaine, 
amphetamine, methamphetamine, ecstasy, opiates, methadone, oxycodone, 
buprenorphine, and phencyclidine.  
o At Baseline, a subject may be enrolled based on local testing of the drug urine 
sample. If the result of the central laboratory indicates the presence of a prohibited 
substance, the subject will be withdrawn from the study (see Section 4.4), but this 
will not be considered a protocol deviation. 
o A positive UDS for benzodiazepines will be evaluated by the Investigator in the 
context of allowed anxiolytics. 


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o Additional UDS tests (apart from scheduled timepoints) may be repeated at any 
time throughout the study, at the discretion of the Investigator.  
Laboratory evaluations will be completed according to the schedule presented in Table 6–1 
and procedures detailed in the study laboratory manual. Additional safety testing may be 
performed at the discretion of the Investigator or designee.  
Table 6–1 
Safety Laboratory Evaluations 
Visit 
Tests 
Visit 1 (Screening) 
CHEM, CBC, UA, urine toxicity (drug) screen, confirmation of 
main antipsychotic, and serum pregnancy test 
Visit 2 (Baseline) 
CHEM, CBC, UA, urine toxicity (drug) screen, urine pregnancy 
test and PK blood draws 
Visit 3 (Week 2) 
Urine pregnancy test and PK blood draws 
Visit 4 (Week 4) 
Urine pregnancy test 
Visit 5 (Week 8) 
Urine pregnancy test and PK blood draws 
Visit 6 (Week 14) 
Urine pregnancy test and PK blood draws 
Visit 7 (Week 20) 
Urine pregnancy test 
Visit 8 (ET/EOT)  
CHEM, CBC, UA, urine toxicity (drug) screen, urine pregnancy 
test and PK blood draws 
Abbreviations: CBC=complete blood count; CHEM=clinical chemistry serum tests; EOT=end of treatment; 
ET=early termination; PK=pharmacokinetic; UA=urinalysis 
6.6 
Pharmacokinetic Assessments 
Blood samples for measurements of concentrations in plasma (PK samples) of pimavanserin, 
the metabolite AC-279, and the main antipsychotic will be collected at the timepoints 
identified in Table 6-1. The blood draw at Baseline should be completed before the first dose 
of study medication (pre-dose). 
When possible, an additional PK sample will be collected from subjects who experience an 
SAE or AE leading to discontinuation, as soon as possible after experiencing that event. 
For all PK samples (scheduled and unscheduled), the dates and times of administration of the 
last 3 doses of both study drug and the main antipsychotic should be recorded. For samples 
collected from subjects who experience an SAE or an AE leading to discontinuation, the date 
and time of the last dose prior to the SAE or AE should also be recorded. 
Pimavanserin plasma concentration data will remain blinded to the Investigators and the 
Sponsor until the unblinding of the clinical database at the end of the study. 


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6.6.1 
Remote Pharmacokinetic Assessments 
Circumstances may arise (e.g., pandemic, natural disaster, or political upheaval) when on-site 
assessment of PK is not possible. In those cases, PK assessments may be performed at the 
subject’s place of residence by study staff. The Investigator must contact the Medical 
Monitor for approval with the plan. Sites must keep a log to identify details of all visits that 
are administered remotely. 
6.7 
Safety Follow-up 
In addition to the EOT/ET visit, a 30-day safety follow-up telephone contact is to be 
completed for subjects who complete the Treatment Period of 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. For these subjects who discontinue prematurely 
or who do not continue into the extension study, the follow-up Investigator must ensure that 
the subject is appropriately transitioned to standard of care treatment and/or followed for 
additional care per the Investigator or physician’s clinical judgment. Subjects should have the 
following completed at least 30 days after last dose of study drug: 
• Assessment of concomitant medications/treatments 
• Assessment of AEs  
6.8 
Unscheduled Visits 
Unscheduled visits may occur as determined by the Investigator. The following safety 
assessments generally should be recorded at each unscheduled safety 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. 
Investigators may conduct unscheduled telephone contacts with the subject/caregiver for 
administrative purposes such as upcoming visit reminders or eligibility status updates during 
the screening period. 
7 ADVERSE EVENTS 
7.1 
Specification of Safety Parameters 
7.1.1 
Definition of Adverse Event 
An AE is defined as “any untoward medical occurrence in a patient or clinical study 
participant, temporally associated with the use of study drug, whether or not considered 
related to study drug”. 


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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) or 
scheduled surgery/procedure. The condition that leads to the procedure is an AE if not 
present at time of consent. 
• Overdose of concomitant medication without any signs or symptoms will not be 
considered an AE, but if a subject is hospitalized or has other serious criteria, the 
overdose will be considered an AE and shall be reported on the Sponsor’s Overdose 
Reporting form.  
• Hospitalization for elective surgery planned prior to study (situation where an untoward 
medical occurrence has not occurred) 
• Pregnancy will not be considered an AE, but if it occurs, it will be reported on a 
pregnancy form. 
7.1.2 
Definition of Serious Adverse Event 
In addition to the severity rating, each AE will be classified by the Investigator as “serious” 
or “not serious.” The seriousness of an event will be defined according to the applicable 
regulations and generally refers to the outcome of an event. An SAE is one that meets one or 
more of the following: 
• Is fatal 
• Is life threatening 
• Results in disability or permanent damage 
• Requires hospitalization (initial or prolonged) 
• Results in congenital anomaly or birth defect  
• Other serious event (medically significant/important medical event) 


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Definition of Life Threatening 
A life threatening event places the subject at immediate risk of death from the event as it 
occurred. This does not include an AE, which, had it occurred in a more severe form, might 
have caused death. 
Definition of Hospitalization 
Hospitalization is defined by the Sponsor as a full admission to the hospital for diagnosis and 
treatment. This includes prolongation of an existing inpatient hospitalization.  
Examples of visits to a hospital facility that do not meet the serious criteria for 
hospitalization include: 
• Emergency room visits (that do not result in a full hospital admission) 
• Outpatient surgery 
• Preplanned or elective procedures 
• Protocol procedures 
• Social hospitalization, defined as admission to the hospital as a result of inadequate 
family support or care at the subject’s primary residence  
Definition of Disability or Permanent Damage 
Disability is defined as a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions. 
Definition of Medically Significant 
Important medical events (medically significant events) that may not result in death, be life 
threatening, or require hospitalization may be considered to be an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject or may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. Examples of 
such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias, 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. 


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7.2 
Classification of an Adverse Event 
7.2.1 
Severity of Event 
The severity of each AE will be assessed as described below 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 drug cessation (de-challenge) or re-challenge 
• Compatibility with known class effect 
• Known effects of concomitant medications 
• Pre-existing risk factors 
• A plausible mechanism 
• Concurrent illnesses 
• Past medical history 
7.2.3 
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 worsening in severity 
• Stop: Date when AE recovered or resolved, recovered or resolved with sequelae, or 
worsened in severity 
7.2.4 
Frequency 
The frequency of the AE should be indicated according to the following definitions: 


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• Single: Experienced once, without recurrence at same severity 
• Recurrent: More than one discrete episode with the same severity 
7.2.5 
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 
• Not applicable 
• Unknown 
7.2.6 
Therapy 
• None: No new treatment instituted 
• Medication: New treatment initiated as a direct result of AE 
• Other: Other action required 
7.2.7 
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 due to an AE 
• Unknown: Unknown 
7.2.8 
Seriousness 
• Not serious 
• Serious (see Section 7.1.2) 
7.2.9 
Definition of Unexpectedness 
An AE, the nature or severity of which is not consistent with the information provided in the 
Reference Safety Information section of the current pimavanserin Investigator’s brochure. 
7.3 
Time Period and Frequency for Event Assessment and Follow-up 
Adverse events will be recorded from the time informed consent is obtained through the 
study safety follow-up period. If an AE is ongoing at the end of the study safety follow-up 


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period, every reasonable attempt should be made to follow and appropriately treat the subject 
until the AE resolves or until the Investigator deems the AE to be chronic or stable. 
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 through the Safety follow-up Period for 
30 days after last dose of study drug. 
In the event that a subject discontinues from the study and has an ongoing AE at the time of 
discontinuation (Section 4.4.2), the subject should be followed and appropriately treated until 
the AE resolves or until the Investigator deems the AE to be chronic or stable. If a subject 
withdraws consent from the study because of an AE, no additional assessments may be 
performed (Section 4.3). 
7.4 
Reporting Procedures 
7.4.1 
Adverse Event Reporting 
The Investigator must record all observed AEs and all reported AEs. At each visit, the 
Investigator should ask the subject a nonspecific question (e.g., “Have you noticed anything 
different since your last visit?”) to assess whether any AEs have been experienced since the 
last report or visit. 
Note that any use of medication (and specifically any newly prescribed medication) during 
the course of a study may indicate the occurrence of an AE that may need to be recorded on 
both the AE and the concomitant medication page. 
All AEs, serious and not serious, will be recorded on the AE eCRF page using appropriate 
medical terminology. Severity and relationship to study drug will be assessed by the 
Investigator. 
When possible, clinical AEs should be described by diagnosis and not by symptoms 
(e.g., “cold” or “seasonal allergies” instead of “runny nose”). 
All AEs, whether or not related to the study drug, must be fully and completely documented 
on the AE eCRF and in the subject’s notes. 
7.4.2 
Serious Adverse Event Reporting 
The reporting of SAEs by the Sponsor or designee to the regulatory authorities is a regulatory 
requirement. Each regulatory authority has established a timetable for reporting SAEs based 
upon established criteria. 


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Serious AEs must be reported within 24 hours of discovery to the Sponsor or its designee; 
both using the SAE form for initial and/or follow-up reporting and entering in the electronic 
data capture (EDC) system.  
At a minimum, events identified by the Sponsor to require expedited reporting as serious, 
unexpected, and related to study drug must be brought to the attention of the responsible 
institutional review board/ethics committee (IRB/EC), as per applicable regulations. These 
will be provided by the Sponsor after their assessment. For European Union member states, 
the Sponsor or its designee will provide reports of SUSARs directly to the ECs, as required 
by local legislation. In all other countries, it is the Investigator’s responsibility to provide 
these expedited reports to the responsible IRB/EC. It is also the Investigator’s responsibility 
to notify the responsible IRB/EC regarding any new and significant safety information. 
When an SAE occurs, Investigators will review all documentation related to the event and 
will complete the paper SAE form, as well as enter the SAE into the EDC system, with all 
required information (for initial and/or follow-up information) and fax or email (within 
24 hours of discovery) to the contact information provided on the SAE form. 
Subjects who are early terminated or do not enroll in the open-label study, ACP-103-035, will 
be followed through the Safety follow-up Period (i.e., 30 [+4] days after last dose of study 
drug) for any SAEs and/or other reportable information until such events have resolved or the 
Investigator deems them to be chronic or stable. 
In the event of any SAE (other than death), the study subject will be instructed to contact the 
Investigator (or designee) using the telephone number provided in the ICF. All subjects 
experiencing an SAE will be seen by the Investigator or designee as soon as is feasible 
following the report of the SAE. 
Serious AEs occurring after the Safety follow-up Period (i.e., 30 [+4] days after the last dose 
of study drug) should be reported if in the judgment of the Investigator there is “a reasonable 
possibility” that the event may have been caused by the product. 
SAEs should also be reported to the IRB/EC according to local regulations. 
7.4.3 
Reporting of Pregnancy 
Any female subject who becomes pregnant during the study (with or without AEs) must be 
discontinued from the study. If the pregnancy occurred after exposure to the study drug, it 
must be reported on the Pregnancy form within 24 hours of discovery to the Sponsor or its 
designee. Any female subject who becomes pregnant during the study will be followed 
through the pregnancy outcome. 


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If pregnancy occurs during the study, the pregnant subject should be unblinded so that 
counseling may be offered based on whether the fetus was exposed to the active drug, or 
placebo. 
Any AEs that are the consequence of pregnancy and which meet the criteria for serious 
should also be reported via the SAE form. 
7.4.3.1 
Reporting Paternal Study Drug Exposure 
Paternal study drug exposure is defined as a father’s exposure to a medicinal product before 
or during his partner’s pregnancy. Any paternal study drug exposure cases must be reported 
to the Sponsor within 24 hours of discovery via the Pregnancy form. Any AEs that are the 
consequence of paternal study drug exposure and which meet the criteria for serious must 
also be reported to the Sponsor within 24 hours of discovery via the SAE form. 
7.4.4 
Reporting of Overdose 
An overdose is a deliberate or inadvertent administration of a treatment at a dose higher than 
the maximum recommended dose per protocol. It must be reported to the Sponsor or 
designee on the Sponsor Overdose Reporting form within 24 hours of discovery. In addition, 
all events of overdose are to be captured as protocol deviations (see Section 5.1.7). 
8 MONITORING  
Routine monitoring of study sites is described in Section 11. 
Clinical site monitoring is conducted to ensure that the rights and well-being of human 
subjects are protected, that the reported study data are accurate, complete, and verifiable, and 
that the conduct of the study is in compliance with the currently approved protocol and 
amendment(s) as applicable, with GCP, and with applicable regulatory requirements. Details 
of the study site monitoring process are described in a separate clinical monitoring plan 
document. 
9 STATISTICAL METHODS AND DATA ANALYSIS 
9.1 
Statistical and Analytical Plans 
Statistical methods will be documented in detail in a statistical analysis plan (SAP) to be 
approved by the Sponsor prior to database lock. Deviations from the approved SAP will be 
described and justified in the final clinical study report. 
9.2 
Statistical Hypotheses 
The hypotheses for the primary endpoint are the following: 


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• The null hypothesis is that there is no difference in the mean change from Baseline to 
Week 26 in the NSA-16 total score between the pimavanserin and placebo treatment 
groups. 
o The alternative hypothesis is that there is a difference in the mean change 
from Baseline to Week 26 NSA-16 total score between the pimavanserin 
and placebo treatment groups. 
The hypotheses for the key secondary endpoint are the following: 
• The null hypothesis is that there is no difference in the mean change from Baseline to 
Week 26 CGI-SCH-S of negative symptoms score between the pimavanserin and placebo 
treatment groups. 
o The alternative hypothesis is that there is a difference in the mean change 
from Baseline to Week 26 CGI-SCH-S of negative symptoms score 
between the pimavanserin and placebo treatment groups. 
9.3 
Sample Size Determination 
The planned sample size is approximately 426 (213 subjects per treatment group). 
Assuming the true difference in the mean change in the NSA-16 total score from Baseline to 
Week 26 is 3.00 points between the pimavanserin group and the placebo group, and the 
common standard deviation is 9 points, 191 subjects who complete the study per treatment 
group will provide 90% power to detect a difference between the pimavanserin group and the 
placebo group at a significance level of 0.05, using a 2-sided t-test. 
Adjusting for a potential discontinuation rate of up to 10%, approximately 426 subjects 
(213 subjects per treatment group) will be randomized. 
9.4 
Subject Populations for Analysis 
The Safety Analysis Set includes all randomized subjects who received at least one dose of 
study drug (pimavanserin or placebo). Subjects will be analyzed based on the treatment that 
they actually received. The Safety Analysis set will be used for all safety analyses. 
The Full Analysis Set includes all randomized subjects who received at least one dose of 
study drug and who have both a baseline value and at least one post-baseline value for the 
NSA-16 total score. Subjects will be analyzed based on their randomized treatment. The Full 
Analysis Set will be used for the analysis of all efficacy endpoints. 
The Per protocol (PP) Analysis Set will consist of those subjects in the Full Analysis Set 
without any protocol deviations that could potentially have a substantial impact on the 
primary efficacy outcome. The precise reasons for excluding subjects from the PP Analysis 


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Set will be fully defined and documented prior to the clinical database lock. Subjects will be 
analyzed based on their randomized treatment assignment. The PP Analysis Set will be used 
for sensitivity analyses of selected efficacy endpoints. 
For pimavanserin and AC-279 plasma concentration summaries, the Pharmacokinetics 
Analysis Set will consist of subjects with at least one measurable pimavanserin plasma 
concentration. 
9.5 
Statistical Analyses 
9.5.1 
Primary Analyses 
The primary endpoint is the change from Baseline to Week 26 in the NSA-16 total score. The 
primary analysis will be based on the Full Analysis Set. The PP Analysis Set will be used for 
sensitivity analyses. 
The NSA-16 total score will be analyzed using mixed-effect model repeated measures 
(MMRM). The model will include effects for treatment group (pimavanserin or placebo), 
visit (Week 2, Week 4, Week 8, Week 14, Week 20, and Week 26), the treatment-by-visit 
interaction, geographic region (North America, Europe, or rest of world), the Baseline 
NSA-16 total score, and the Baseline-by-visit interaction. The treatment comparison will be 
based on the difference in least squares means at Week 26 and will be tested at an alpha level 
of 0.05 (2-sided) using the Full Analysis Set. 
In addition to the primary treatment comparisons for the Week 26 timepoint, the treatment 
groups will also be compared at each of the other timepoints (Weeks 2, 4, 8, 14, and 20) 
using the same MMRM model described above. These other comparisons will be considered 
exploratory. 
Handling of missing values will be described in detail in the SAP. Sensitivity analyses will be 
performed to assess the impact of missing data, including analyses based on a missing not at 
random assumption. 
A hierarchical testing procedure will be used to control the Type 1 error rate across the 
primary and key secondary endpoint. Details will be provided in the SAP. 
9.5.2 
Secondary Analyses 
9.5.2.1 
Key Secondary Endpoint 
The key secondary endpoint is the change from Baseline to Week 26 in the CGI-SCH-S of 
negative symptoms score. The change from Baseline in the CGI-SCH-S of negative 
symptoms score will be analyzed using an MMRM model. The model will include effects for 
treatment group, visit, the treatment-by-visit interaction, geographic region, the Baseline 


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CGI-SCH-S of negative symptoms total score, and the Baseline-by-visit interaction. The 
treatment comparison will be based on the difference in least squares means at Week 26 and 
will be tested at an alpha level of 0.05 (2-sided) using the Full Analysis Set. 
9.5.2.2 
Other Secondary Endpoints 
Other secondary endpoints are the following: 
• CGI-SCH-I of negative symptoms score at Week 26 
• Proportion of CGI-SCH-I of negative symptoms responders (CGI-SCH-I of negative 
symptoms score of 1 or 2) at Week 26 
• Change from Baseline to Week 26 in PSP scale score 
• Proportion of NSA-16 responders (≥20% and ≥30% reduction in NSA-16 total score) at 
Week 26 
• Change from Baseline to Week 26 in the PANSS total score 
• Change from Baseline to Week 26 in PANSS subscores (negative scale) 
• Change from Baseline to Week 26 in PANSS Marder factor (negative symptoms) score 
The change from Baseline to each post-Baseline timepoint in the PSP score, PANSS total 
score, the PANSS subscores (negative scale), and the PANSS Marder factor (negative 
symptoms) score will be analyzed using an MMRM model. The model will include effects 
for treatment group, visit, the treatment-by-visit interaction, geographic region, the Baseline 
value of the endpoint being analyzed, and the Baseline-by-visit interaction.  
The CGI-SCH-I of negative symptoms score at each post-Baseline timepoint will be analyzed 
using an MMRM model. The model will include effects for treatment group, visit, the 
treatment-by-visit interaction, geographic region, the Baseline CGI-SCH-S of negative 
symptoms score, and the Baseline-by-visit interaction. 
The proportion of subjects with ≥20% reduction in the NSA-16 total score, the proportion of 
subjects with ≥30% reduction in the NSA-16 total score, and the proportion of subjects with a 
CGI-SCH-I of negative symptoms score of 1 or 2 will be summarized at each timepoint and 
the treatment comparison will be performed. Details will be provided in the SAP. Since 
NSA-16 is an interval scale that lacks a natural zero point, the percent change in NSA-16 
total score will be calculated based on corrected scores after subtracting 16 points from the 
raw scores. 


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9.5.3 
Exploratory Analyses 
Exploratory endpoints are the following: 
• Change from Baseline to Week 26 in PANSS subscores (positive scale and general 
psychopathology scale) 
• Change from Baseline to Week 26 in PANSS Marder factor scores (positive symptoms, 
disorganized thought, uncontrolled hostility/excitement, and anxiety/depression factors) 
• Change from Baseline to Week 26 in Work Readiness Questionnaire (WoRQ) total score 
• Change from Baseline to Week 26 in Work Readiness Questionnaire (WoRQ) readiness to 
work question (item 8) 
• Change from Baseline to Week 26 in Brief Assessment of Cognition in Schizophrenia 
(BACS) score 
• Change from Baseline to Week 26 in CDSS score 
The change from Baseline to each post-Baseline timepoint in the PANSS subscores (positive 
scale and general psychopathology scale), PANSS Marder factor (positive symptoms, 
disorganized thought, uncontrolled hostility/excitement, and anxiety/depression factors) 
score, WoRQ total score, and CDSS score will be analyzed using an MMRM model. The 
model will include effects for treatment group, visit, the treatment-by-visit interaction, 
geographic region, the Baseline value of the endpoint being analyzed, and the 
Baseline-by-visit interaction. 
The proportion of subjects who are rated as ready for work in the WoRQ readiness to work 
question (item 8) will be summarized at each timepoint. In addition, the treatment 
comparison at Week 26 will be performed. 
The change from Baseline to Week 26 in the BACS score will be analyzed using an 
ANCOVA model with effects for treatment group (pimavanserin or placebo), geographic 
region, and the Baseline BACS score. 
9.5.4 
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. 
9.5.4.1 
Adverse Events 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
coding dictionary. All adverse events will be listed and TEAEs will be summarized by system 
organ class and preferred term. A TEAE is defined as an AE that started after the first dose of 


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study drug. Summaries by maximum severity and by relationship will also be provided. 
Serious adverse events, fatal TEAEs, and TEAEs leading to discontinuation will also be 
summarized. Other TEAEs of special interest may also be summarized. 
9.5.4.2 
Clinical Laboratory Values 
The serum clinical chemistry, hematology, and urinalysis results at Baseline and at Week 26 
will be summarized by treatment group. Change from Baseline values will also be 
summarized. 
The number and percentage of subjects with potentially clinically important post-baseline 
laboratory values will be summarized by treatment group at Week 26 for selected parameters. 
The criteria for potentially clinically important values will be specified in the SAP. 
9.5.4.3 
Vital Signs and Body Weight 
Vital signs will be measured at Screening, Baseline, and each post-baseline visit and will be 
summarized by treatment group. Body weight only will be measured at Screening, Baseline, 
and Week 26 and will be summarized by treatment group. Change from baseline values will 
also be summarized. The number and percentage of subjects with changes from baseline 
(increases and decreases separately) in body weight of 7% or more will also be provided. 
9.5.4.4 
Electrocardiogram 
ECG parameters at Baseline and Weeks 14 and 26 will be summarized by treatment group. 
Change from Baseline values will also be summarized. Categorical analyses will be 
conducted on the incidence of subjects with prolonged QTc intervals and changes in QTc 
intervals in accordance with International Council for Harmonisation (ICH) guidelines and 
based on the FDA E14 Guidance Document. 
9.5.4.5 
Physical Examinations 
The results of the physical examinations at Screening, Baseline, Weeks 2, 14, and 26 will be 
tabulated by treatment group. A complete physical examination should be performed at 
Screening, Baseline, and Week 26; symptom-directed examinations will be performed at 
Weeks 2 and 14. 
9.5.4.6 
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. 
9.5.4.7 
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. 


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9.5.5 
Confirmation of Main Antipsychotic 
Presence or absence of the main antipsychotic will be listed and summarized using standard 
summary statistics. 
9.5.6 
Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analyses 
Plasma concentration data for pimavanserin and its major metabolite (AC-279), as well as for 
antipsychotics, will be listed and summarized using standard summary statistics. 
If data allow, population PK and PK/PD analyses will be performed to further characterize 
the PK profile and exposure response relationship of pimavanserin and its metabolite using 
measures of safety, and efficacy parameters. The results of population PK and PK/PD 
modeling will be presented in a separate report. Pimavanserin plasma concentration data will 
remain blinded to the Investigators and the Sponsor until unblinding of the clinical database 
at the end of the study. 
9.5.7 
Subgroup Analyses 
Selected analyses will be performed in subgroups defined in the SAP. 
9.6 
Interim Analyses 
No interim analyses are planned for this study. 
9.7 
Data and Safety Monitoring Board 
An independent DSMB will review interim safety data including data on AEs and SAEs. 
9.8 
Measures to Minimize Bias 
9.8.1 
Enrollment/Randomization/Masking Procedures 
Eligible subjects will be randomized into one of two treatment groups (pimavanserin or 
placebo) in a 1:1 ratio using an interactive response technology (IRT) system. The 
randomization will be stratified according to 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 matching tablets 
and packaging for the pimavanserin and placebo treatments. 
9.9 
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. 


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For DSMB safety reviews, the treatment codes will be released to an independent 
statistician/programmer to produce unblinded statistical outputs. The Sponsor and the 
Investigators will remain blinded. 
Unblinding of individual treatment assignment during the study is discouraged. The 
Investigator at a site may break the blind for a given subject in the event of a medical 
emergency, where knowledge of the subject’s treatment assignment (pimavanserin or 
placebo) must be known in order to facilitate appropriate emergency medical treatment.  
In case of an emergency, the Investigator has the sole responsibility for determining if 
unblinding of a subject’s intervention assignment is warranted. Subject safety must always be 
the first consideration in making such a determination. If the Investigator decides that 
unblinding is warranted, the Investigator should make every effort to contact the Sponsor 
prior to unblinding a subject’s intervention assignment unless this could delay emergency 
treatment of the subject. If a subject’s intervention assignment is unblinded, the Sponsor must 
be notified within 24 hours after breaking the blind. 
If pregnancy occurs during the study, the pregnant subject should be discontinued and 
unblinded so that counseling may be offered based on whether the fetus was exposed to the 
active drug or placebo (Section 7.4.3). 
Details of the process to be followed are provided in a separate IRT manual. 
10 STUDY MANAGEMENT AND DATA COLLECTION 
10.1 Data Collection and Management Responsibilities 
All documents required for the conduct of the study as specified in the ICH GCP guidelines 
will be maintained by the Investigator in an orderly manner and made available for 
monitoring and/or auditing by the Sponsor and regulatory authorities. 
The Investigator and institution must permit authorized representatives of the Sponsor or 
designees (including monitors and auditors), regulatory authorities (including inspectors), 
and the IRB/EC direct or remote access to source documents (such as original medical 
records) as allowed by local regulations. Direct or remote access includes permission to 
examine, analyze, verify, and reproduce any records and reports that are needed for the 
evaluation of the study either in person or through a remote video/electronic medium (such as 
email). The Investigator must ensure the reliability and availability of source documents from 
which the information on the eCRF was derived. 
10.2 Source Documents 
All study specific information obtained at each study visit must be recorded in the subject’s 
record (source documentation) and then entered into a validated EDC database by trained site 


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personnel and/or transferred electronically. The source documentation may consist of source 
notes captured by site personnel as well as laboratory reports, ECG reports, and electronic 
source data. 
10.3 Case Report Forms 
Subject data required by this protocol are to be recorded in an EDC system on eCRFs and/or 
transferred electronically and securely for data review. The Investigator and his or her site 
personnel will be responsible for completing the eCRFs. The Investigator is responsible for 
the accuracy and reliability of all the information recorded on the eCRFs. All information 
requested on the eCRFs needs to be supplied, including subject identification data, visit 
date(s), assessment values, etc., and any omission or discrepancy will require explanation. All 
information on eCRFs must be traceable to source documentation (unless eCRF is considered 
the source) 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 control review and statistical analysis. A 
copy of the final eCRFs will be retained by the Investigator, who must ensure that the copy is 
stored in a secure place. 
10.4 Confidentiality 
The Investigator must ensure that each subject’s anonymity is maintained as described below. 
On the eCRFs, medical records, or other documents submitted to the Sponsor or designees, 
subjects must be identified by a subject identification number only. Subject identifiers 
uniquely identify subjects within the study and do not identify any person specifically. 
Documents that are not for submission to the Sponsor or designees (e.g., signed ICFs) should 
be kept in strict confidence by the Investigator in compliance with Federal regulations or 
other applicable laws or ICH guidance on GCP. Data collection and handling should comply 
with the European Union General Data Protection Regulation (EU GDPR) and other relevant 
regulations concerning data privacy, where applicable. Acadia has assigned a Data Protection 
Officer (DPO) as per the EU GDPR. 
10.5 Study Records Retention 
Investigators are required to maintain all essential study documentation as per ICH GCP 
guidelines. This includes, but is not limited to, copies of signed, dated and completed eCRFs, 
documentation of eCRF corrections, signed ICFs, audio recordings, subject-related source 
documentation, and adequate records for the receipt and disposition of all study drug. 
Investigators should maintain all essential study documentation, for a period of at least 


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2 years following the last approval of marketing application in an ICH region (US, Europe, 
and Japan), or until at least 2 years after the drug investigational program is discontinued, 
unless a longer period is required by applicable law or regulation. Only the Sponsor can 
notify an Investigator or vendor when any records may be discarded. Investigators should 
contact the Sponsor before destroying any files. 
10.6 Protocol Exceptions and Deviations 
No prospective entry criteria protocol deviations are allowed; all subjects must meet all 
eligibility criteria in order to participate in the study. 
Protocol waivers for eligibility will not be granted by the Sponsor under any circumstances. 
If, during the course of a subject’s post-enrollment participation in the trial it is discovered 
that the subject did not meet all eligibility criteria (excluding central laboratory and ECG 
results), this will be reported as a major protocol deviation and not a waiver. In this situation, 
the subject will be discontinued, unless the discontinuation presents an unacceptable medical 
risk. The justification to allow the subject to continue in the trial will be made by the 
Sponsor, with medical input from the Investigator, and will be documented. If discontinuation 
occurs based on central results that were not available to the Investigator at the time of 
randomization, then this will not be considered a protocol deviation. All follow-up safety 
assessments must be completed and documented as outlined in the protocol (Section 6.7). 
The Investigator must report any protocol deviation to the Sponsor and, if required, to the 
IRB/EC in accordance with local regulations, within reasonable time. 
10.7 Protocol Amendments 
Changes to the protocol may be made only by the Sponsor (with or without consultation with 
the Investigator). All protocol modifications must be submitted to the site IRB/EC in 
accordance with local requirements and, if required, to regulatory authorities, as either an 
amendment or a notification. Approval for amendments must be awaited before any changes 
can be implemented, except for changes necessary to eliminate an immediate hazard to trial 
subjects, or when the changes involve only logistical or administrative aspects of the trial. 
No approval is required for notifications. 
11 QUALITY MANAGEMENT 
11.1 Risk Management 
The Sponsor utilizes the ICH E6 (GCP) Revision 2 risk management approach that includes 
methods to assure and control the quality of the trial proportionate to the risks inherent in the 
trial and the importance of the information collected. The intent is that all aspects of this trial 
are operationally feasible and that any unnecessary complexity, procedures, and data 


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collection are avoided. The Sponsor’s risk management approach includes the following 
documented activities:  
• Critical Process and Data Identification: during protocol development, risks of processes 
and data that are critical to ensure human subject protection and the reliability of trial 
results are identified and assessed. 
• Risk Identification: risks to critical trial processes, governing systems, investigational 
product, trial design, data collection, and recording are identified. 
• Risk Evaluation: identified risks are evaluated by considering the following factors: 
(a) likelihood of occurrence, (b) impact on human subject protection and data integrity, 
and (c) detectability of errors. 
• Risk Control: risks that can be avoided, reduced (i.e., mitigated), or accepted are 
differentiated. Risk mitigation activities are incorporated in protocol design and 
implementation, study plans, training, processes, and other documents governing the 
oversight and execution of study activities. Where possible, predefined quality tolerance 
limits are defined to identify systematic issues that can impact subject safety or data 
integrity and deviations from the predefined quality tolerance limits will trigger an 
evaluation and possibly an action. Contingency plans are developed for issues with a high 
risk factor that cannot be avoided. 
• Periodic risk review, communication, and escalation of risk management activities during 
trial execution and risk outcome reporting in the clinical study report (CSR). 
11.2 Quality Control and Quality Assurance 
The Sponsor or designees and regulatory authority inspectors are responsible for contacting 
and visiting the Investigator for the purpose of inspecting the facilities and, upon request, 
inspecting the various records of the trial (e.g., eCRFs and other pertinent data) provided that 
subject confidentiality is respected. 
The Sponsor’s or designee’s monitor is responsible for inspecting the eCRFs at regular 
intervals throughout the study to verify adherence to the protocol; completeness, accuracy, 
and consistency of the data; and adherence to local regulations on the conduct of clinical 
research. The monitor should have access to subject medical records and other study-related 
records needed to verify the entries on the eCRFs. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in 
the course of these monitoring visits are resolved. 
In accordance with ICH guidance on GCP and the Sponsor’s audit plans, sites participating in 
this study may be audited. These audits may include a review of site facilities (e.g., 


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pharmacy, drug storage areas, and laboratories) and review of study-related records may 
occur in order to evaluate the trial conduct and compliance with the protocol, ICH guidance 
on GCP, and applicable regulatory requirements. 
The Sponsor’s or designee’s representatives, regulatory authority inspectors and IRB/EC 
representatives who obtain direct access to source documents should also respect subject 
confidentiality, taking all reasonable precautions in accordance with applicable regulatory 
requirements to maintain the confidentiality of subjects’ identities. 
12 ETHICAL CONSIDERATIONS 
12.1 Ethical Standard 
The study will be conducted in compliance with the protocol, the Declaration of Helsinki, 
ICH GCP, and other applicable regulatory requirements (e.g., Serious Breach reporting, 
urgent safety measures, and EU GDPR). 
The study will be performed in accordance with current US Health Insurance Portability and 
Accountability Act (HIPAA) regulations, US FDA GCP Regulations (US CFR 21 parts 50, 
54, 56, and 312), and ICH guidance on GCP (E6) and clinical safety data management (E2A). 
In accordance with Directive 75/318/EEC, as amended by Directive 91/507/EEC, the final 
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, any subject information or advertising materials, and 
any other requested information. 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 any 
screening procedures. The subject’s caregiver must also provide written consent prior to any 
screening procedures. 


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The informed consent must, at a minimum, include the elements of consent described in the 
ICH guidance on GCP and the US CFR 21 part 50.25. A copy of the ICF planned for use will 
be reviewed by the Sponsor or designee for acceptability and must be submitted by the 
Investigator or designee together with the protocol, to the appropriate IRB/EC for review and 
approval prior to the start of the study at that investigational site. Consent forms must be in a 
language fully comprehensible to the prospective subject. The Investigator must provide the 
Sponsor or designee with a copy of the IRB/EC letter approving the protocol and the ICF 
before the study drug supplies will be shipped and the study can be initiated. 
The consent form must be revised if new information becomes available during the study that 
may be relevant to the subject’s willingness to continue participation. Any revision must be 
submitted to the appropriate IRB/EC for review and approval in advance of use. 
12.3.1 
Consent and Other Informational Documents Provided to Subjects 
The subject and caregiver must be given a copy of the signed informed consent and the 
original maintained in the designated location at the site. 
12.3.2 
Consent Procedures and Documentation 
It is the Investigator or designee’s responsibility to obtain written informed consent from the 
subject after adequate explanation of the aims, methods, anticipated benefits, and potential 
hazards of the study. The subject must be given ample time to decide about study 
participation and opportunity to inquire about details of the study. The IRB/EC-approved 
consent form must be personally signed 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’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 
consent prior to any screening visit procedures being performed indicating their agreement to 
participate in the study in the caregiver role. 
Records related to a study subject’s participation will be maintained and processed according 
to local laws, and where applicable, the EU GDPR. The consent and study information 
documentation will include statements describing local and regional requirements concerning 
data privacy, and who to contact for questions. 
12.3.2.1 
Remote Consent Procedures and Documentation 
Investigators may also need to obtain informed consent from a potential trial participant or their 
caregiver when these individuals are unable to travel to the site where the Investigator is 
located due to extenuating circumstances (e.g., pandemic, natural disaster, or political 


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upheaval). The consent form may be sent to the subject or the subject’s caregiver by facsimile 
or e-mail, and the consent interview may then be conducted by telephone when the subject or 
subject’s caregiver can read the consent form during the discussion. After the consent 
discussion, the subject or the subject’s caregiver can sign and date the consent form. Options 
for returning the document to the clinical investigator may include facsimile, scanning the 
consent form and returning it through a secure e-mail account, or posting it to a secure internet 
address. Alternatively, the subject or caregiver may bring the signed and dated consent form to 
his/her next visit to the clinical site, if restrictions on traveling to the clinical trial site are 
alleviated, or mail it to the clinical investigator. The case history for each subject must 
document that informed consent was obtained prior to participation in the trial. In addition, the 
person signing the consent form must receive a copy of the consent form.  
If concerns exist about having subjects mail to the Investigator potentially contaminated 
consent documents from the subject’s location, the Investigator may employ the procedures 
described above for enrolling patients in isolation through the use of a photographic image of 
the signed consent form transmitted through electronic means.  
The subject or the subject’s caregiver must sign and date the informed consent form before the 
Investigator may conduct any study-related procedures involving the subject. Where it is not 
feasible for Investigators to receive the signed consent form prior to beginning study-related 
procedures, the Investigators should have the subject or caregiver confirm verbally during the 
consent interview that the subject or caregiver has signed and dated the form. In addition, the 
overseeing IRB must review and approve the planned informed consent process. 
13 PUBLICATION PLAN 
All publication rights are delineated in the Clinical Study Agreement and/or other separate 
agreements with the Investigator and/or Institution, as applicable. 
14 CONFLICT OF INTEREST POLICY 
14.1 Finance, Insurance, and Indemnity 
Arrangements for finance, insurance, and indemnity are delineated in the Clinical Study 
Agreement and/or other separate agreements with the Investigator and/or Institution, as 
applicable. 
 


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15 LITERATURE REFERENCES 
Acadia Pharmaceuticals Inc. NUPLAZID® [package insert]. San Diego, CA, November 
2020. 
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. 
Addington D, Addington J, Schissel B. A depression rating scale for schizophrenics. 
Schizophr Res. 1990; 3(4):247-251. 
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. 
Alphs LD, Summerfelt A, Lann H, Muller RJ. The negative symptom assessment: a new 
instrument to assess negative symptoms of schizophrenia. Psychopharmacol Bull. 
1989;25(2):159-163. 
Andreasen NC. Negative symptoms in schizophrenia. Definition and reliability. Arch Gen 
Psychiatry. 1982;39(7):784-788. 
Awad AG. Subjective response to neuroleptics in schizophrenia. Schizophr Bull. 
1993;19(3):609-618. 
Axelrod BN, Goldman RS, Alphs LD. Validation of the 16-item Negative Symptom 
Assessment. J Psychiatr Res. 1993;27(3):253-258. 
Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989;154:672-676. 
Blanchard JJ, King AM, Horan WP, Gur R. Toward the next generation of negative symptom 
assessments: the collaboration to advance negative symptom assessment in schizophrenia. 
Schizophr Bull. 2011;37(2):291-299. 
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. 
Haro JM, Kamath SA, Ochoa S, et al. The Clinical Global Impression – Schizophrenia scale: 
a simple instrument to measure the diversity of symptoms present in schizophrenia. Acta 
Psychiatr Scand. 2003; 107(suppl. 416):16-23. 


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Hovington CL, Bodnar M, Joober R, Malla AK, Lepage M. Identifying persistent negative 
symptoms in first episode psychosis. BMC Psychiatry. 2012;12:224. 
Janssen Pharmaceuticals Inc. INVEGA® [package insert]. Titusville, NJ, January 2019. 
Kay SR, Opler LA, Lindenmayer JP. Reliability and validity of the positive and negative 
syndrome scale for schizophrenics. Psychiatry Res. 1988;23(1):99-110. 
Keefe RS, Goldberg TE, Harvey PD, Gold JM, Poe MP, Coughenour L. The Brief 
Assessment of Cognition in Schizophrenia: reliability, sensitivity, and comparison with a 
standard neurocognitive battery. Schizophr Res. 2004; 68(2-3):289-297. 
Kirkpatrick B, Buchanan RW, McKenney PD, Alphs LD, Carpenter WT Jr. The Schedule for 
the Deficit syndrome: an instrument for research in schizophrenia. Psychiatry Res. 
1989;30(2):119-23. 
Kirkpatrick B, Fenton WS, Carpenter WT Jr, Marder SR. The NIMH-MATRICS Consensus 
Statement on Negative Symptoms. Schizophr Bull. 2006;32(2):214-219. 
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. 
Marder S, Alphs L, Anghelescu IG, et al. Issues and perspectives in designing clinical trials 
for negative symptoms in schizophrenia. Schizophr Res. 2013;150(2-3):328-333. 
McGrath J, Saha S, Chant D, et al. Schizophrenia: a concise overview of incidence, 
prevalence, and mortality. Epidemiol Rev. 2008;30:67-76. 
Mehta MA, Manes FF, Magnolfi G, Sahakian BJ, Robbins TW. Impaired set-shifting and 
dissociable effects on tests of spatial working memory following the dopamine D2 receptor 
antagonist sulpiride in human volunteers. Psychopharmacology (Berl). 2004;176(3-4):331-
342. 
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. 


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Opler LA, Ramirez PM. Informant Questionnaire for the Positive and Negative Syndrome 
Scale (IQ-PANSS). North Tonawanda, NY: Multi-Health Systems Publications, Inc. 2009. 
Peralta V, Cuesta MJ, Martinez-Larrea A, Serrano JF. Differentiating primary from secondary 
negative symptoms in schizophrenia: a study of neuroleptic-naïve patients before and after 
treatment. Am J Psychiatry. 2000;157(9):1461-1466. 
Peretti CS, Danion JM, Kauffmann-Muller F, Grangé D, Patat A, Rosenzweig P. Effects of 
haloperidol and amisulpride on motor and cognitive skill learning in healthy volunteers. 
Psychopharmacology (Berl). 1997;131(4):329-338. 
Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry. 2011;168(12):1266-1277. 
Potkin SG, Bugarski-Kirola D, Edgar CJ, Soliman S, Le Scouiller S, Kunovac J, Miguel 
Velasco E, Garibaldi GM. Psychometric evaluation of the Work Readiness Questionnaire in 
schizophrenia. CNS Spectr. 2016;21:199–206. 
Riedel M, Schwarz MJ, Strassnig M, et al. Risperidone plasma levels, clinical response and 
side-effects. Eur Arch Psychiatry Clin Neurosci. 2005;255(4):261-268. 
Saeedi H, Remington G, Christensen BK. Impact of haloperidol, a dopamine D2 antagonist, 
on cognition and mood. Schizophr Res. 2006;85(1-3):222-231. 
Simpson GM, Angus JW. A rating scale for extrapyramidal side-effects. Acta Psychiatr Scand 
Suppl. 1970;212:11-19. 
Tamminga CA, Buchanan RW, Gold JM. The role of negative symptoms and cognitive 
dysfunction in schizophrenia outcome. Int Clin Psychopharmacol. 1998;13(suppl 3):S21-
S26. 
Vanover KE, Weiner DM, Makhay M, et al. Pharmacological and behavioral profile of N-(4-
fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl) 
carbamide (2R,3R)-dihydroxybutanedioate (2:1) (ACP-103), a novel 5- 
hydroxytryptamine(2A) receptor inverse agonist. J Pharmacol Exp Ther. 2006;317(2):910-
918. 
Wang PS, Schneeweiss S, Avorn J, et al. Risk of death in elderly users of conventional vs 
atypical antipsychotic medications. N Engl J Med. 2005;353(22):2335-2341. 
 


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


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Medication Class 
Examplesa 
Prohibitions/Restrictions 
Anticonvulsants and mood 
stabilizers 
• 
carbamazepine  
• 
lamotrigine 
• 
lithium 
• 
phenytoin 
• 
valproate 
• 
Must be washed out 5 half-lives 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. 
o 
If lorazepam is not available, 
another benzodiazepine may be 
used at doses equivalent to 
lorazepam 
• 
May not be used within 12 hours prior to 
an assessment visit 
Stimulants 
• methylphenidate 
• 
Prohibited at study entry and throughout 
the study 
Non-stimulant attention 
deficit/hyperactivity disorder 
medications 
• atomoxetine 
• 
Prohibited at study entry and throughout 
the study 
Serotonin antagonists 
• cyproheptadine 
• fluvoxamine 
• mianserin 
• 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 
• 
Prohibited at study entry and throughout 
the study 


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Medication Class 
Examplesa 
Prohibitions/Restrictions 
• propafenone 
• quinidine 
• sotalol, d-sotalol 
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: 
o 
Prohibited at Baseline but may be 
used during the course of the study 
to treat a bacterial infection (e.g., 
urinary tract infection, respiratory 
infection), post-Baseline at the 
discretion of the Investigator 
• 
Artenimol/piperaquine, bedaquiline, 
gemifloxacin, norfloxacin, ofloxacin, 
quinine, and roxithromycin are allowed 
under the following conditions: 
o 
The subject has a Baseline ECG 
with a QTcF <425 ms OR 
o 
The subject has a QTcF <450 ms at 
Baseline AND QRS duration 
≥120 ms 
Antidepressants 
PROHIBITED 
•   esketamine 
• 
Prohibited at study entry and throughout 
the study 
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 
• venlafaxine 
• 
If subject is remaining on these 
medications, the dose of the permitted 
antidepressants on the left must be 
unchanged for at least 4 weeks prior to 
Baseline and is expected to remain 
unchanged until completion of the EOT 
visit. If the medication is being 
discontinued, it must be discontinued at 
least 2 weeks or 5 half-lives (whichever 
is longer) prior to the Baseline visit. 


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Medication Class 
Examplesa 
Prohibitions/Restrictions 
o 
Citalopram is restricted to a 
maximum dose of 20 mg/day. 
o 
Escitalopram is restricted to a 
maximum dose of 10 mg/day. 
o 
Venlafaxine is restricted to a 
maximum dose of 225 mg/day  
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  
a 
Medications within each class include but are not limited to the examples listed in this table. 


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Appendix B Prohibited and Restricted Concomitant Medications: Inhibitors and 
Inducers of Cytochrome P450 Enzyme 3A4 
The information presented here is intended to provide guidance and does not constitute an 
exhaustive list of strong CYP 3A4 enzyme (CYP3A4) inhibitors and inducers. Any questions 
should be discussed with the Medical Monitor or appropriate designee.  
Subjects who require current treatment with a prohibited medication will be withdrawn from 
the study. 
Subjects who have previously taken a prohibited medication during the study will be 
withdrawn from the study unless:  
• the prohibited medication has been discontinued AND  
• withdrawal from the study presents an unacceptable medical risk to the subject 
The justification to allow the subject to continue in the study will be made by the 
Sponsor/Medical Monitor with medical input from the Investigator, and will be documented. 
If allowed to remain in the study, this will be reported as a major protocol deviation and not a 
waiver. 
The metabolism of pimavanserin is affected by strong CYP3A4 inhibitors, resulting in an 
increase in maximum plasma concentration (Cmax) and area under the plasma 
concentration-time curve (AUC) of approximately 3-fold.  
Strong inhibitors of CYP3A4 are to be stopped at least 7 days or 5 half-lives prior to 
investigational product administration, whichever is longer. Strong inducers of CYP3A4 are 
to be stopped 30 days or 5 half-lives prior to investigational product administration, 
whichever is longer. Moderate inhibitors and inducers of CYP3A4 are allowed but should be 
used with caution. 
STRONG 
INHIBITORS 
grapefruit juicea  
boceprevir (Victrelis®) 
clarithromycin (Biaxin®)  
cobicistat (part of Stribild®) 
indinavir (Crixivan®)  
itraconazole (Sporanox®)  
ketoconazole (Nizoral®)  
lopinavir and ritonavir (Kaletra®) 
mibefradil (Posicor®) 
nefazodone (Serzone®)  
nelfinavir (Viracept®)  
posaconazole (Noxafil®) 
quinupristin (Synercid®) 
MODERATE 
INHIBITORS 
grapefruit juicea 
amprenavir (Agenerase®) 
aprepitant (Emend®) 
atazanavir (Reyataz®) 
ciprofloxacin (Cipro®) 
conivaptan (Vaprisol®) 
crizotinib 
cyclosporine 
darunavir/ritonavir 
(Prezista®/Ritonavir) 
diltiazem 
dronedarone 
erythromycin (Erythrocin® 


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ritonavir (Norvir®, part of 
Viekira Pak™) 
− combination treatments 
including ritonavir, such as: 
danoprevir and ritonavir 
elvitegravir and ritonavir 
indinavir and ritonavir 
lopinavir and ritonavir 
paritaprevir and ritonavir and 
ombitasvir (and/or dasabuvir) 
saquinavir and ritonavir 
tipranavir and ritonavir 
saquinavir (Invirase®)  
telaprevir (Incivek®) 
telithromycin (Ketek®) 
troleandomycin  
voriconazole (Vfend®) 
Lactobionate) 
fluconazole (Diflucan®) 
fluvoxamine (Luvox®) 
fosamprenavir (Lexiva®) 
imatinib (Gleevec®) 
isavuconazole 
tofisopam 
verapamil (Calan®) 
STRONG 
INDUCERS 
Apalutamide 
avasimibe 
carbamazepine (Tegretol®) 
enzalutamide 
ivosidenib 
lumacaftor 
mitotane 
phenytoin (Dilantin®)  
rifampin (Rifadin®, Rifadin IV®, 
Rimactane®) 
St. John's Wort 
MODERATE 
INDUCERS 
bosentan (Tracleer®) 
cenobamate 
dabrafenib 
efavirenz (Sustiva®) 
etravirine (Intelence®) 
lorlatinib 
modafinil (Provigil®) 
nafcillin (Unipen®, Nallpen®) 
pexidartinib 
phenobarbital (Luminal®, 
Solfoton®) 
primidone 
sotorasib 
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). 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
Protocol No.: 
ACP-103-064 
Protocol Title: 
A Phase 3, Randomized, Double-Blind, Placebo-
Controlled Study to Evaluate the Efficacy and Safety of 
Pimavanserin as Adjunctive Treatment for the Negative 
Symptoms of Schizophrenia (ADVANCE-2) 
Drug: 
Pimavanserin 
Sponsor: 
Acadia Pharmaceuticals Inc. 
Version No. and Date 
Version 4.0, January 11, 2024 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc. 


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Protocol ACP-103-064 
Version 4.0 
Statistical Analysis Plan 
11 JAN 2024 
TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF TABLES ...........................................................................................................................7 
LIST OF FIGURES .........................................................................................................................7 
ABBREVIATIONS .........................................................................................................................8 
1.
INTRODUCTION ......................................................................................................10 
2.
OBJECTIVES .............................................................................................................10 
2.1. 
Primary Objective .......................................................................................................10 
2.2. 
Secondary Objective ...................................................................................................10 
3.
STUDY DESIGN .......................................................................................................11 
3.1. 
General Study Design .................................................................................................11 
3.2. 
Schedule of Assessments ............................................................................................13 
3.3. 
Randomization ............................................................................................................13 
3.4. 
Blinding ......................................................................................................................13 
3.5. 
Determination of Sample Size ....................................................................................13 
3.6. 
Coronavirus Disease 2019 ..........................................................................................14 
4.
ANALYSIS SETS ......................................................................................................14 
5.
DATA HANDLING CONVENTIONS ......................................................................15 
5.1. 
General Data Reporting Conventions .........................................................................15 
5.2. 
Derived Variables .......................................................................................................15 
5.2.1. 
Negative Symptom Assessment-16 (NSA-16) ...........................................................16 
5.2.2. 
Clinical Global Impression of Schizophrenia Scale – Severity (CGI-SCH-S) ...........17 
5.2.3. 
Clinical Global Impression of Schizophrenia Scale – Improvement 
(CGI-SCH-I) ...............................................................................................................17 
5.2.4. 
Positive and Negative Syndrome Scale (PANSS) ......................................................18 
5.2.5. 
Personal and Social Performance Scale (PSP) ...........................................................20 
5.2.6. 
Brief Assessment of Cognition in Schizophrenia (BACS) .........................................20 
5.2.7. 
Work Readiness Questionnaire (WoRQ) ....................................................................21 
5.2.8. 
Calgary Depression Scale for Schizophrenia (CDSS) ................................................22 
5.2.9. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................22 
5.2.10. 
Abnormal Involuntary Movement Scale (AIMS) .......................................................23 
5.2.11. 
Barnes Akathisia Scale (BARS) .................................................................................23 
5.2.12. 
Simpson Angus Extrapyramidal Side Effect Scale (SAS) .........................................24 
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Protocol ACP-103-064 
Version 4.0 
Statistical Analysis Plan 
11 JAN 2024 
5.3. 
Data Presentation Conventions ...................................................................................24 
5.4. 
Study Day ...................................................................................................................24 
5.5. 
Baseline Definition .....................................................................................................24 
5.6. 
Analysis Visit Windows .............................................................................................25 
5.6.1. 
Unscheduled Assessments ..........................................................................................25 
5.6.2. 
Multiple Measurements within Visit Windows ..........................................................25 
5.7. 
Missing or Incomplete Date for Last Dose of Study Drug .........................................26 
5.8. 
Missing or Incomplete Dates for Prior or Concomitant Medications .........................26 
5.9. 
Missing or Incomplete Dates for Adverse Events ......................................................26 
5.10. 
Missing Severity Assessment for Adverse Events .....................................................27 
5.11. 
Missing Relationship to Study Drug for Adverse Events ...........................................27 
5.12. 
Character Values of Clinical Laboratory Variables ....................................................27 
5.13. 
Duplicate Subjects ......................................................................................................27 
6.
SUBJECT DISPOSITION ..........................................................................................27 
7.
PROTOCOL DEVIATIONS ......................................................................................28 
8.
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ...................29 
9.
MEDICAL HISTORY ................................................................................................30 
10.
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE ...........................30 
10.1. 
Exposure to Study drug ..............................................................................................30 
10.2. 
Measurement of Treatment Compliance ....................................................................31 
11.
PRIOR, CONCOMITANT AND POST-TREATMENT MEDICATION .................31 
12.
EFFICACY ANALYSES CONSIDERATIONS .......................................................31 
12.1. 
Efficacy Variables ......................................................................................................32 
12.2. 
Adjustment for Covariates ..........................................................................................33 
12.3. 
Handling of Missing Data ...........................................................................................33 
12.4. 
Multiple Comparisons / Multiplicity ..........................................................................33 
12.5. 
Examination of Subgroups .........................................................................................33 
13.
METHODS OF EFFICACY ANALYSES .................................................................34 
13.1. 
Primary Efficacy Endpoints ........................................................................................34 
13.1.1. 
Primary Analysis ........................................................................................................34 
13.1.2. 
Sensitivity Analysis with MNAR Using Multiple Imputation (MI) ...........................37 
13.1.3. 
Supportive Analysis ....................................................................................................39 
13.2. 
Key Secondary Efficacy Analysis ..............................................................................39 
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Protocol ACP-103-064 
Version 4.0 
Statistical Analysis Plan 
11 JAN 2024 
13.3. 
Other Secondary Efficacy Analyses ...........................................................................39 
13.3.1. 
Responder Analysis ....................................................................................................39 
13.3.2. 
Other Secondary Efficacy Analysis for Continuous Variables ..................................40 
13.4. 
Exploratory Efficacy Analyses ...................................................................................41 
14.
SAFETY ANALYSES ...............................................................................................41 
14.1. 
Adverse Events ...........................................................................................................41 
14.2. 
Clinical Laboratory Variables .....................................................................................42 
14.3. 
Vital Signs ..................................................................................................................47 
14.4. 
Electrocardiogram (ECG) ...........................................................................................48 
14.5. 
Physical Examination .................................................................................................49 
14.6. 
Other Safety Variables ................................................................................................50 
14.6.1. 
Suicidality ...................................................................................................................50 
14.6.2. 
Extrapyramidal Symptom Measures ...........................................................................50 
15.
CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC
ANALYSES ...............................................................................................................52 
16.
UNBLINDED INTERIM ANALYSIS .......................................................................52 
17.
DATA MONITORING/REVIEW COMMITTEE .....................................................52 
18.
COMPUTER METHODS ..........................................................................................53 
19.
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL .....................................53 
20.
REFERENCES ...........................................................................................................54 
21.
APPENDICES ............................................................................................................55 
21.1. 
Appendix A Schedule of Events and Assessments.....................................................56 
21.2. 
Appendix B Composite z score and T-score Transformation for Brief 
Assessment of Cognition in Schizophrenia (BACS) ..................................................59 
21.3. 
Appendix C Sample SAS Codes.................................................................................66 
21.4. 
Summary of Version Changes ....................................................................................68 
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Protocol ACP-103-064 
Version 4.0 
Statistical Analysis Plan 
11 JAN 2024 
LIST OF TABLES 
Table 1 
Analysis Visit Windows .............................................................................................25 
Table 2 
Criteria for Potentially Clinically Important Laboratory Values – 
Hematology and Chemistry ........................................................................................46 
Table 3 
Criteria for Potentially Clinically Important Laboratory Values - Urinalysis ............47 
Table 4 
Criteria for Potentially Clinically Important Vital Signs ............................................48 
Table 5 
Criteria for Potentially Clinically Important ECG Values .........................................49 
 
LIST OF FIGURES 
Figure 1 
Schematic of Study Design .........................................................................................12 
 
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Protocol ACP-103-064 
Version 4.0 
Statistical Analysis Plan 
11 JAN 2024 
ABBREVIATIONS 
AE 
adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
ANCOVA 
analysis of covariance 
ATC 
Anatomical Therapeutic Chemical 
BACS 
Brief Assessment of Cognition in Schizophrenia 
BARS 
Barnes Akathisia Rating Scale 
BLQ 
below the limit of quantification 
BMI 
body mass index 
CDSS 
Calgary Depression Scale for Schizophrenia 
CGI-SCH-I 
Clinical Global Impression – Improvement scale 
CGI-SCH-S 
Clinical Global Impression – Severity scale 
CMH 
Cochran-Mantel-Haenszel 
COVID-19 
coronavirus disease 2019 
C-SSRS
Columbia-Suicide Severity Rating Scale 
DSMB 
Data and Safety Monitoring Board 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EOT 
End-of-Treatment 
ET 
Early Termination 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GSD 
Guidance for Site Documentation and Data Management Querying of Data 
Impacted by COVID-19 
ICE 
Intercurrent event 
LOE 
lack of efficacy 
MAR 
missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
MMRM 
mixed model for repeated measures 
MNAR 
missing not at random 
Msec 
Milliseconds 
NSA-16 
Negative Symptom Assessment-16 
OC 
observed cases 
PANSS 
Positive and Negative Syndrome Scale 
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Protocol ACP-103-064 
Version 4.0 
Statistical Analysis Plan 
11 JAN 2024 
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 
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 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
WoRQ 
Work Readiness Questionnaire 
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Protocol ACP-103-064 
Version 4.0 
Statistical Analysis Plan 
11 JAN 2024 
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 3 dated 
05OCT2022. 
For Argentina, a country-specific protocol amendment (Amendment 2-AR finalized 19 March 
2021) specifies additional hepatitis C virus (HCV) and human immunodeficiency virus (HIV) 
testing at Screening and additional pregnancy tests at Week 12, 18 and 24 for all female subjects 
of childbearing potential to be conducted only for subjects enrolled in Argentina.  
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. 
This plan should be read in conjunction with the study protocol and the electronic case report 
forms (eCRFs). 
2.
OBJECTIVES
2.1. 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of pimavanserin compared with 
placebo in the adjunctive treatment of the negative symptoms of schizophrenia. 
2.2. 
Secondary Objective 
The secondary objectives of the study are to evaluate the effect of adjunctive pimavanserin 
compared with adjunctive placebo on  
•
Global impression of severity of negative symptoms of schizophrenia
•
Global improvement of symptoms of negative symptoms of schizophrenia
•
Personal and social performance
•
Response to treatment in adults experiencing negative symptoms of schizophrenia
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Protocol ACP-103-064 
Version 4.0 
Statistical Analysis Plan 
11 JAN 2024 
3.
STUDY DESIGN
3.1. 
General Study Design 
This study will be conducted as a Phase 3, 26-week, randomized, double-blind, placebo-
controlled, multicenter, multinational outpatient study in subjects with schizophrenia who have 
predominant negative symptoms while on adequate treatment with an antipsychotic. 
Schizophrenia is defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition (DSM-5), confirmed by a customized module of the Structured Clinical Interview for 
DSM-5, Clinical Trials Version (SCID-5-CT). Negative symptoms are considered predominant 
when other symptoms of schizophrenia, particularly positive symptoms such as delusions and 
hallucinations, are relatively mild and well controlled. 
This study will screen approximately 692 subjects and randomize approximately 426 subjects 
(213 subjects per treatment group) with predominant negative symptoms of schizophrenia across 
approximately 88 study sites in 12 countries. The daily dose of the main antipsychotic must 
remain stable and may not be changed from Screening through the duration of the study. Subjects 
will participate in the study for up to 36 weeks, including a Screening Period of up to 6 weeks, a 
26-week Treatment Period, and a 30 (+4) day safety follow-up (telephone visit) 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 be administered under double-blind conditions throughout the Treatment Period. 
Clinic visits occurring after Baseline will be conducted at Weeks 2, 4, 8, 14, 20, and 26 (End-of-
Treatment [EOT]/Early Termination [ET] visit). 
Figure 1 illustrates the study design. 
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Protocol ACP-103-064 
Version 4.0 
Statistical Analysis Plan 
5 JAN 2024 
Figure 1 
Schematic of Study Design 
Subjects with 
predominant negative 
symptoms of 
schizophrenia while on 
adequate treatment with 
an antipsychotic 
Main antipsychotic + placebo 
Double-Blind Treatment Period 
26 weeks 
1:1 Randomization 
Main antipsychotic + pimavanserin 34 mg 
Screening Period 
Up to 6 weeks 
Follow-up Period 
30 (+4) days 
EOT/ET* 
30 (+4) day follow-up 
(telephone call visit) 
*Subjects who complete the 26-week Treatment Period may be eligible to enroll in a 52-week, open-label extension study (Study ACP-103-035).
Subjects entering ACP-103-035 will not complete a follow-up telephone call visit as they will be immediately enrolled in ACP-103-035. 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc.
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Protocol ACP-103-064 
Version 4.0 
Statistical Analysis Plan 
11 JAN 2024 
3.2. 
Schedule of Assessments 
The schedule of events and assessments for the study is presented in Appendix A. 
3.3. 
Randomization 
Eligible subjects will be randomized into 1 of 2 treatment groups (pimavanserin or placebo) in a 
1:1 ratio using an interactive response technology (IRT) system. The randomization will be 
stratified by geographic region (North America, Europe, or rest of world). The assignments will 
be based on a pre-generated permuted-block randomization schedule. 
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 pimavanserin and 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 26 in the Negative Symptom 
Assessment-16 (NSA-16) total score. 
Let Δ be the difference in the mean change from Baseline to Week 26 in the NSA-16 total score 
between the pimavanserin and the 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 NSA-16 total score from Baseline to 
Week 26 is 3.0 points between the pimavanserin group and the placebo group, and the common 
standard deviation is 9 points, 191 subjects who complete the study per treatment group will 
provide at least 90% power to detect a difference between the pimavanserin group and the 
placebo group at a significance level of 0.05, using a 2-sided t-test. 
Acadia used a dropout rate of 10% to calculate the sample size for this study. This dropout rate 
was informed based on the whole Full Analysis Set (FAS) dropout rate of 13.5% and the dropout 
rate of 8.8% based on the last dose of 34 mg in FAS observed in the recently completed study 
ACP-103-038 (ADVANCE). Adjusting for a potential dropout rate of up to 10%, approximately 
426 subjects (213 subjects per treatment group) will be randomized. 
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Protocol ACP-103-064 
Version 4.0 
Statistical Analysis Plan 
11 JAN 2024 
 
3.6. 
Coronavirus Disease 2019  
In the context of the global COVID-19 pandemic or other natural disaster, the mechanisms to 
record information on the potential impact of the COVID-19 pandemic on data itself, as well as 
data collection and integrity, will be implemented (as detailed in the “Guidance for Site 
Documentation and Data Management Querying of Data Impacted by COVID-19” [GSD] of the 
Data Management Plan). The impact of COVID-19 on the statistical analysis is discussed in each 
of the relevant sections of this SAP. 
4. 
ANALYSIS SETS 
Randomized Analysis Set 
The Randomized Analysis Set will consist of all unique subjects who were randomized. 
Note that if there are duplicate subjects (see Section 5.13 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 all subjects who were randomized and 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 Randomized Analysis Set who 
receive at least one dose of study drug, and have both a Baseline value and at least one post-
Baseline value for the NSA-16 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 without 
any protocol deviation that could potentially have a substantial impact on the primary efficacy 
outcome. The precise reasons for excluding subjects from the Per-protocol Analysis Set will be 
fully defined and documented prior to the clinical database lock. 
Subjects will be classified according to the randomized treatment assignment. 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc.
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Protocol ACP-103-064 
Version 4.0 
Statistical Analysis Plan 
11 JAN 2024 
 
Pharmacokinetics Analysis Set 
For pimavanserin and AC-279 plasma concentration summaries, the Pharmacokinetics Analysis 
Set will consist of subjects with at least one measurable pimavanserin 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 standard deviations and standard 
errors will be presented to 2 more decimal places than the raw data. Unless otherwise specified, 
the maximum number of decimal places is 4 and values will be truncated to 4 decimal places in 
situations where there are more than 4 decimal places. Wherever possible data will be decimal 
aligned. 
For categorical variables, summaries will include the number and percentage of subjects in each 
category. For demographic and baseline characteristics, the number of subjects and the 
percentage of subjects with missing data will be summarized (if applicable), and the denominator 
for percentages will be the total number of subjects in the given treatment group. Categories with 
zero counts will not have zero percentages displayed. Percentages will be presented to 1 decimal 
place. 
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. 
Values that are collected with “<” or “>” signs will generally be analysed as the numerical value 
without the sign in tables and figures. In listings, these data will be reported as collected with the 
sign. 
5.2. 
Derived Variables 
In general, the assessment scale total scores and subscores will be derived within the analysis 
datasets. In the event that total scores and/or subscores are also collected on the electronic case 
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Confidential and Proprietary Information of Acadia Pharmaceuticals Inc.
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Confidential and Proprietary Information of Acadia Pharmaceuticals Inc.
Page 17 of 68


Protocol ACP-103-064 
Version 4.0 
Statistical Analysis Plan 
11 JAN 2024 
The CGI-SCH-I is a clinician-rated, 7-point scale that is designed to evaluate change from 
Baseline in positive, negative, depressive, cognitive symptoms and overall severity in 
schizophrenia. For purpose of this study, only the changes in negative symptoms from Baseline 
are evaluated. 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 of negative symptoms in schizophrenia. 
Missing CGI-SCH-I scores will not be imputed. 
5.2.4. 
Positive and Negative Syndrome Scale (PANSS) 
The PANSS is assessed at Screening, Baseline, Week 14 and Week 26/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 
•
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 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc.
Page 18 of 68


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Page 19 of 68


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Confidential and Proprietary Information of Acadia Pharmaceuticals Inc.
Page 20 of 68


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Confidential and Proprietary Information of Acadia Pharmaceuticals Inc.
Page 21 of 68


Protocol ACP-103-064 
Version 4.0 
Statistical Analysis Plan 
11 JAN 2024 
more than 1 score is missing, then the total score will be missing. If there is only 1 missing item 
score, the total score will be calculated by the arithmetic mean of non-missing items for that 
subject and timepoint multiplied by 7, rounded to the nearest integer. 
5.2.8. 
Calgary Depression Scale for Schizophrenia (CDSS) 
The CDSS is assessed at Screening, Baseline, Week 14 and Week 26/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. 
5.2.9. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is assessed at Screening, Baseline, Weeks 2, 4, 8, 14, 20, and Week 26/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. 
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. 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc.
Page 22 of 68


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Confidential and Proprietary Information of Acadia Pharmaceuticals Inc.
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Confidential and Proprietary Information of Acadia Pharmaceuticals Inc.
Page 24 of 68


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Confidential and Proprietary Information of Acadia Pharmaceuticals Inc.
Page 25 of 68


Protocol ACP-103-064 
Version 4.0 
Statistical Analysis Plan 
11 JAN 2024 
 
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. 
5.7. 
Missing or Incomplete Date for Last Dose of Study Drug 
In the Safety Analysis Set, if the last dose date of study drug is missing for a subject who 
completed or early terminated from the study, then the missing last dose date of study drug will 
be imputed using the last expected dosing date which is defined as the minimum of the 
non-missing drug return date of the last dispensed drug kits, the last drug dispensed date plus the 
number of days that the dosing would continue per protocol or the end-of-treatment/early 
termination visit (EOT/ET) date, whichever occurs earlier. For the incomplete last dose date of 
the study drug, the imputation will be compared against the last expected dosing date defined as 
above. Detailed algorithms will be documented in a separate specifications document. The 
missing or incomplete dates will be displayed in the data listings as reported on the eCRF rather 
than the imputed dates. 
For data summarization before final database lock, if a subject is still ongoing, then this subject’s 
last dose date will be imputed using the database extract date. 
5.8. 
Missing or Incomplete Dates for 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 a separate specification document. The missing or 
incomplete dates will be displayed in the data listings as reported on the eCRF rather than the 
imputed dates. 
5.9. 
Missing or Incomplete Dates for Adverse Events  
Missing or incomplete adverse event (AE) start dates will be imputed for the purpose of 
determining whether the AEs are treatment-emergent (see Section 14.1 for definition). When the 
chronological order of an AE onset relative to the study drug treatment period is unclear due to 
missing or incomplete date(s), the AE will be considered as treatment-emergent. The imputation 
algorithms will be detailed in a separate specification document. The missing or incomplete dates 
will be displayed in the data listings as reported on the eCRF rather than the imputed dates. 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc.
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Protocol ACP-103-064 
Version 4.0 
Statistical Analysis Plan 
11 JAN 2024 
 
5.10. 
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. 
5.11. 
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. 
5.12. 
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 determined 
coded value will be used in the statistical analysis. The coding algorithms will be detailed in a 
separate specification document. The actual values as reported in the database will be presented 
in data listings. 
5.13. 
Duplicate Subjects  
Duplicate-subject check will be performed throughout study to identify whether there are 
individuals who are randomized more than once into ACP-103-064 study. Confirmed duplicates 
will only be included for efficacy analyses under the subject number to which they were first 
randomized in ACP-103-064. In the event of the confirmed duplicate subjects, additional details 
for handling the duplicates in the efficacy and safety analyses will be provided in a separate 
document prior to the final database lock. Data collected under other subject number(s) 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 including the reason 
due to coronavirus disease 2019 [COVID-19]) 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 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc.
Page 27 of 68


Protocol ACP-103-064 
Version 4.0 
Statistical Analysis Plan 
11 JAN 2024 
 
reasons are reported will also be summarized. Note that one subject may be deemed ineligible for 
multiple inclusion/exclusion criteria. If the screen failure was due to a temporary condition that 
subsequently resolved, it may be allowed to rescreen with the permission of the Medical 
Monitor. 
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. 
For Randomized Analysis Set, Safety Analysis Set, Full Analysis Set, and Per-protocol Analysis 
Set, the number and percentage of subjects who completed the study or discontinued (all 
discontinued and by discontinuation reason including the reason due to COVID-19) will also be 
summarized by treatment group and overall. The number and percentage of subjects completed 
by visit will be summarized by visit and treatment group.  
7. 
PROTOCOL DEVIATIONS 
Protocol deviations will be reviewed regularly 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 Management Plan. Protocol deviations will also be assessed 
with respect to relationship to COVID-19. 
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 in three ways: all protocol 
deviations, COVID-19 related protocol deviations, and non COVID-19 related protocol 
deviations. 
Three listings of protocol deviations will be provided: all deviations, COVID-19 related protocol 
deviations and non COVID-19 related protocol deviations. 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc.
Page 28 of 68


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Page 29 of 68


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Confidential and Proprietary Information of Acadia Pharmaceuticals Inc.
Page 30 of 68


Protocol ACP-103-064 
Version 4.0 
Statistical Analysis Plan 
11 JAN 2024 
10.2. 
Measurement of Treatment Compliance 
Study drug dosing compliance (in percentage) for a subject is defined as the total number of 
tablets actually taken divided by the number of tablets expected to be taken and then multiplied 
by 100. The total number of tablets actually taken is calculated by the total number of tablets 
dispensed minus the total number of tablets returned. The number of tablets expected to be taken 
is calculated as the duration of exposure multiplied by 2 (the planned number of tablets taken per 
day). Additional details for handling missing number of tablets returned will be provided in a 
separate specification document. 
Compliance will be summarized as both continuous and categorical variables 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 stop date prior to the date of the 
first dose of study drug. Concomitant medication is defined as any medication that is ongoing at 
the first dose of study drug or with a start date between the dates of the first and last doses of 
study rug, inclusive.  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 2021 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. 
Relationship to COVID-19 will be assessed for selected medications as detailed in the GSD. 
Concomitant and post-treatment medication analyses described above will also be summarized 
and listed by relationship to COVID-19 (Not related to COVID-19 vs. Related to COVID-19). 
12.
EFFICACY ANALYSES CONSIDERATIONS
All efficacy analyses will be performed using the planned treatment assignments based on the 
randomization schedule for the Full Analysis Set 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc.
Page 31 of 68


Protocol ACP-103-064 
Version 4.0 
Statistical Analysis Plan 
11 JAN 2024 
12.1. 
Efficacy Variables 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from Baseline to Week 26 in the NSA-16 total 
score. 
Key Secondary Efficacy Endpoint 
The key secondary efficacy endpoint is the change from Baseline to Week 26 in the CGI-SCH-S 
of negative symptoms score.   
Other Secondary Efficacy Endpoints 
Other secondary efficacy endpoints are the following: 
•
CGI-SCH-I of negative symptoms score at Week 26
•
Proportion of CGI-SCH-I of negative symptoms responders (CGI-SCH-I of negative
symptoms score of 1 or 2) at Week 26
•
Change from Baseline to Week 26 in PSP scale score
•
Proportion of NSA-16 responders (≥20% and ≥30% reduction in NSA-16 total score) at
Week 26
•
Change from Baseline to Week 26 in the PANSS total score
•
Change from Baseline to Week 26 in PANSS negative subscores
•
Change from Baseline to Week 26 in PANSS Marder factor (negative symptoms) score
Exploratory endpoints are the following: 
•
Change from Baseline to Week 26 in PANSS subscores (positive scale and general
psychopathology scale)
•
Change from Baseline to Week 26 in PANSS Marder factor scores (positive symptoms,
disorganized thought, uncontrolled hostility/excitement, and anxiety/depression factors)
•
Change from Baseline to Week 26 in Work Readiness Questionnaire (WoRQ) total score
•
Change from Baseline to Week 26 in Work Readiness Questionnaire (WoRQ) readiness to
work question (item 8)
•
Change from Baseline to Week 26 in Brief Assessment of Cognition in Schizophrenia
(BACS) score
•
Change from Baseline to Week 26 in CDSS score
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc.
Page 32 of 68


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Protocol ACP-103-064 
Version 4.0 
Statistical Analysis Plan 
11 JAN 2024 
Population-level summary: difference (pimavanserin 34 mg vs. placebo) in the mean changes 
from Baseline to Week 26 in the NSA-16 total score. 
Hypotheses 
Let Δ be the difference in the mean change from Baseline to Week 26 in the NSA-16 total score 
between the pimavanserin and placebo groups: 
The null hypothesis for the primary efficacy endpoint is:  
Δ = 0 
The alternative hypothesis for the primary efficacy endpoint is: 
Δ ≠ 0 
Primary Estimator 
The hypothesis testing will be performed for Full Analysis Set using the direct likelihood 
MMRM method assuming missing data are missing at random (MAR). The dependent variable 
will be the change from Baseline in the NSA-16 total score. The independent variables in the 
model will include the following:  treatment group (pimavanserin or placebo), visit (Week 2, 
Week 4, Week 8, Week 14, Week 20, or Week 26), treatment-by-visit interaction, Baseline-by-
visit interaction, geographic region (North America, Europe, or rest of world), and the Baseline 
NSA-16 total score. 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. Sample SAS® code for MMRM analysis is provided in Appendix C. 
In the event that the model fails to converge using the unstructured  covariance matrix, the 
following alternative covariance structures will be modeled in the order given: heterogeneous 
Toeplitz, heterogeneous compound symmetry, heterogeneous autoregressive(1), Toeplitz, 
compound symmetry, autoregressive(1), variance components. The first alternative covariance 
structure that allows for convergence will be selected for the final model and the sandwich 
estimator will be used to estimate the standard errors of the fixed-effect parameters. 
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 NSA-16 total score (observed and change from baseline) will be 
presented for all visits from Baseline through Week 26. For change from Baseline values at each 
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Protocol ACP-103-064 
Version 4.0 
Statistical Analysis Plan 
11 JAN 2024 
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 26 and 
will be tested at an alpha level of 0.05 (2-sided). The treatment-group comparisons at each of the 
other timepoints (Weeks 2, 4, 8, 14, or 20) using the same MMRM model will be considered 
exploratory. 
The LS mean differences with corresponding 95% CIs from the primary analysis will also be 
graphically presented in a forest plot. 
13.1.2. 
Sensitivity Analysis with MNAR Using Multiple Imputation (MI)  
MMRM assumes data are MAR, which is a reasonable assumption in longitudinal clinical trials. 
However, the possibility of missing not at random (MNAR) data can never be ruled out. In order 
to further evaluate robustness of the primary results to deviations from MAR assumptions, 
additional sensitivity analyses may be conducted. Sensitivity analyses based on pattern-mixture 
model (PMM) will be performed in order to explore data missing mechanisms of MNAR and 
investigate the response profile of dropout reasons. 
PMM based on MI with mixed missing data mechanisms will be used to investigate the response 
profile of dropout subjects by dropout reason under MNAR mechanism for the following 
scenarios: 
1)
Dropout reason due to Adverse Event (AE) as MNAR
2)
Dropout reasons due to AE, lack of efficacy (LOE), subject withdraw consent,
COVID-19, use of prohibited medication or change background therapy as MNAR
3)
All dropouts not due to COVID-19 as MNAR
4)
All dropouts as MNAR
Delta Adjustment Imputation Methods (Tipping Point Analyses)  
This sensitivity analysis will be implemented for Full Analysis Set using delta adjustment 
imputation. This MNAR sensitivity analysis is to departure from MAR assumption by 
progressively increasing the delta until conclusion from the primary analysis is overturned. The 
delta is 0%, 5%, 10%, 15%,  .., 100% of the observed treatment difference between pimavanserin 
and placebo from the primary analysis of MMRM model until conclusion of the primary analysis 
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Protocol ACP-103-064 
Version 4.0 
Statistical Analysis Plan 
11 JAN 2024 
is overturned. When delta = 0 the missing data are assumed to be MAR. When delta > 0, the 
missing data are assumed to be MNAR.  
1) Using Monte Carlo Markov Chain (MCMC) methodology from PROC MI to impute the
intermittent missing data to a monotone missing pattern
2) Using a standard MAR-based multiple imputation approach from PROC MI to impute the
monotone missingness data
3) For subjects in the pimavanserin group with a dropout reason due to AE, LOE, subject
withdraw consent, COVID-19, use of prohibited medication or change background
therapy, a delta will be added for all the values after the dropout time
4) Using MMRM model in the primary analysis to analyze the completed data using PROC
MIXED on the multiple imputed data
5) Obtaining the overall results using PROC MIANALYZE.
Placebo Based Imputation Methods (Treatment Policy Strategy) 
Similar to “Standard” multiple imputations, except parameters for imputation model obtained 
from only the placebo (control) group. Missing data for both placebo and pimavanserin group are 
imputed based on the imputation model derived from placebo data within each stage. If 
pimavanserin improved outcomes prior to dropout, this benefit is carried into subsequent 
imputed values, but will diminish over time in accordance with the correlation structure.  
13.1.2.1. Remote Assessment  
To assess the impact of the intercurrent events of remote assessments on the primary analysis, an 
indicator variable will be assigned to flag subjects that had assessments done remotely for the 
primary efficacy endpoint at any visit including baseline (Yes/No). The remote visit flag 
indicator variable and the interaction between treatment group and remote visit flag indicator 
variable will be included as factors in the MMRM model.  
13.1.2.2. Additional Summaries Evaluating the Impact of COVID-19 on the Primary 
Endpoint 
The following descriptive summaries will be presented to assess the major potential impact of 
COVID-19 on NSA-16 total score: 
•
Number and percentage of subjects having each of the following COVID-19-related ICEs
and overall
o
Treatment discontinuation due to COVID-19
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Protocol ACP-103-064 
Version 4.0 
Statistical Analysis Plan 
11 JAN 2024 
o
Intermediate missing data due to COVID-19
o
Remote assessments
•
Number and percentage of subjects with missed assessments due to COVID-19 for the
analysis of the primary endpoint by visit
•
Number and percentage of subjects with remote assessments for the analysis of the
primary endpoint by visit
13.1.3. 
Supportive Analysis  
Supportive analysis of the primary endpoint will be analyzed, similarly to the primary analysis as 
described in Section 13.1.1, using the Per-Protocol Analysis set. 
13.2. 
Key Secondary Efficacy Analysis 
The key secondary endpoint, change from baseline to Week 26 in the CGI-SCH-S of negative 
symptoms score, will be analyzed in the same manner as the primary efficacy endpoint as 
described in Section 13.1.1, and the same subgroup and supportive analyses will be performed. 
13.3. 
Other Secondary Efficacy Analyses 
13.3.1. 
Responder Analysis 
Multiple responder criteria will be used to define a NSA-16 responder (Schooler et al., 2015): 
•
≥20%, ≥30%, ≥40%,  ≥50%, ≥75% and 100% reduction in total score from Baseline
Responder will also be evaluated based on CGI-SCH-I: score of 1 (very much improved) or 
2 (much improved) 
Note that since NSA-16 is an interval scale that lacks a natural zero point, the percent change in 
NSA-16 total score will be calculated based on corrected scores after subtracting 16 points from 
the raw scores (Leucht et al., 2007; Leucht et al., 2009). For example, if a subject’s Baseline 
NSA-16 total score is 60 and Week 26 NSA-16 total score is 16 (absent of all symptoms), the 
percent change from Baseline to Week 26 in NSA-16 total score will be calculated as [(16 – 16) 
– (60 – 16)] ÷ (60 – 16) × 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 (pimavanserin group 
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Protocol ACP-103-064 
Version 4.0 
Statistical Analysis Plan 
11 JAN 2024 
 
minus 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 NSA-16 responders at Week 26 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 NSA-16 total score from Baseline, the cumulative distribution function at Week 26 
for the observed cases will be plotted by treatment group. 
The proportion of subjects who were worsened or no change, based on CGI-SCH-I evaluation, 
will be summarized by treatment group for each 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-SCH-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). 
13.3.2. 
Other Secondary Efficacy Analysis for Continuous Variables 
The change from Baseline to each post-Baseline timepoint in the NSA-16 global negative 
symptoms rating, NSA-16 domain scores (communication, emotion/affect, social involvement, 
motivation, and retardation), PSP score, PANSS total score, PANSS subscores (negative scale), 
and PANSS Marder factor (negative symptoms) score will be analyzed using an MMRM model. 
The model will include effects for treatment group, visit, the treatment-by-visit interaction, 
geographic region, the Baseline value of the endpoint being analyzed, and the Baseline-by-visit 
interaction. 
The CGI-SCH-I of negative symptoms score at each post-Baseline timepoint will be analyzed 
using an MMRM model. The model will include effects for treatment group, visit, the treatment-
by-visit interaction, geographic region, the Baseline CGI-SCH-S of negative symptoms score, 
and the Baseline-by-visit interaction. 
To assess whether there is a linear correlation between the change in NSA-16 total score from 
Baseline and CGI-SCH-I rating, the change in NSA-16 total score from Baseline will also be 
summarized by CGI-SCH-I rating and treatment group for all post-baseline visits.  The mean 
+ SE change in NSA-16 total score from Baseline by CGI-SCH-I rating will also be plotted for 
Week 26 observed cases. 
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Protocol ACP-103-064 
Version 4.0 
Statistical Analysis Plan 
11 JAN 2024 
13.4. 
Exploratory Efficacy Analyses  
The change from Baseline to each post-Baseline timepoint in the PANSS subscores (positive 
scale and general psychopathology scale), PANSS Marder factor (positive symptoms, 
disorganized thought, uncontrolled hostility/excitement, and anxiety/depression factors) score, 
WoRQ total score, and CDSS score will be analyzed using an MMRM model. The model will 
include effects for treatment group, visit, the treatment-by-visit interaction, geographic region, 
the Baseline value of the endpoint being analyzed, and the Baseline-by-visit interaction. 
The proportion of subjects who are rated as ready for work in the WoRQ readiness to work 
question (item 8) and the shift from the Baseline status of the readiness to work will be 
summarized at each timepoint. In addition, the odds of being ready for work at Week 26 will be 
estimated using logistic regression adjusted for Baseline status. 
The change from Baseline to Week 26 in the normalized BACS composite and domain scores 
will be analyzed using an analysis of covariance (ANCOVA) model with effects for treatment 
group (pimavanserin or placebo), geographic region, and the Baseline BACS score. 
At Week 26, 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. 
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 24.0 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 abnormal 
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Protocol ACP-103-064 
Version 4.0 
Statistical Analysis Plan 
11 JAN 2024 
 
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 and more related 
occurrence for the summarization by severity and by relationship to study drug, respectively. The 
display in these tables will be sorted alphabetically by SOC and then by descending subject 
frequency for the preferred terms 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. 
The relationship of selected AEs to COVID-19 will be assessed as detailed in the GSD. TEAEs 
tabulated by SOC and preferred term will be presented with and without COVID-19 related 
TEAEs. 
The incidence of most frequently reported (preferred terms reported by  5% of subjects in either 
treatment group) TEAEs, treatment emergent SAEs, and TEAEs leading to discontinuation of 
study drug, TEAEs related to study drug will be summarized by SOC, preferred term, and 
treatment group. The tables will be sorted alphabetically by SOC and then by descending 
frequency within each SOC. In addition, the incidence of fatal treatment-emergent AEs 
(i.e., events that cause death) will be summarized separately by SOC, preferred term and 
treatment group. These summary tables except for the most frequently reported TEAEs table will 
also be presented with and without COVID-19 related events.  
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 last dose, 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 treatment-
emergent SAEs, related TEAEs, TEAEs leading to discontinuation, fatal TEAEs (if any), and all 
COVID-19 related events. 
14.2. 
Clinical Laboratory Variables 
Clinical laboratory tests are performed at Screening, Baseline and Week 26/ET visits. Due to 
various circumstances (e.g., pandemic, natural disaster, or political upheaval), it is possible that 
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Confidential and Proprietary Information of Acadia Pharmaceuticals Inc.
Page 44 of 68


Protocol ACP-103-064 
Version 4.0 
Statistical Analysis Plan 
11 JAN 2024 
 
will also be summarized in shift tables by treatment group, to determine the number and 
percentage of subjects with values classified as below (low), within (normal), and above (high) 
normal ranges at Week 26, 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 26 and overall post-baseline will be summarized by treatment group for selected 
parameters. PCI criteria are listed in Table 2 and Table 3. 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. 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc.
Page 45 of 68


Protocol ACP-103-064 
Version 4.0 
Statistical Analysis Plan 
11 JAN 2024 
 
Table 2 
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 
 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc.
Page 46 of 68


Protocol ACP-103-064 
Version 4.0 
Statistical Analysis Plan 
11 JAN 2024 
Table 3 
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 and the urine drug screen results 
will be presented in a listing. 
14.3. 
Vital Signs 
Vital signs are assessed at Screening, Baseline, Weeks 2, 4, 8, 14, 20, and Week 26/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 4. 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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Confidential and Proprietary Information of Acadia Pharmaceuticals Inc.
Page 48 of 68


Protocol ACP-103-064 
Version 4.0 
Statistical Analysis Plan 
11 JAN 2024 
 
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 5. 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 5 
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, Weeks 2, 14 and Week 26/ET visits. 
Physical examination results (normal, abnormal, and not done) at Baseline and all post-Baseline 
visits will be summarized in a frequency table by treatment group, body system and visit.  
A listing of physical examination data will be listed. 
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Confidential and Proprietary Information of Acadia Pharmaceuticals Inc.
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Protocol ACP-103-064 
Version 4.0 
Statistical Analysis Plan 
11 JAN 2024 
 
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 2, 8, 14, and Week 26/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. 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 modeling will be 
presented in a separate report. Pimavanserin and AC-279 plasma concentration data will remain 
blinded to the Investigators and the Sponsor until the unblinding of the clinical database at the 
end of the study. 
16. 
UNBLINDED INTERIM ANALYSIS 
No interim analysis for efficacy is planned for this 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, 
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Statistical Analysis Plan 
11 JAN 2024 
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 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. 
19.
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL
No changes are made to the analyses specified in the protocol. 
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Protocol ACP-103-064 
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Statistical Analysis Plan 
11 JAN 2024 
20.
REFERENCES
Leucht S, et al. Defining ‘response’ in antipsychotic drug trials: recommendations for the use of 
scale-derived cutoffs. Neuropsychopharmacology. 2007; 32: 1903-1910. 
Leucht S, et al. Definitions of response and remission in schizophrenia: recommendations for 
their use and their presentation. Acta Psychiatr Scand. 2009; 119 (Suppl. 438): 7-14. 
Schooler N, et al. Defining therapeutic benefit for people with schizophrenia: focus on negative 
symptoms. Schizophr Res. 2015; 162(1-3): 169-174. 
EMA (2009). Guideline on Missing Data in Confirmatory Clinical Trials, European Medicines 
Agency, London, UK. 
FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic | 
Guidance for Industry, Investigators, and Institutional Review Boards (March 2020). 
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Protocol ACP-103-064 
Version 4.0 
Statistical Analysis Plan 
11 JAN 2024 
21.
APPENDICES
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Protocol ACP-103-064 
Version 4.0 
Statistical Analysis Plan 
11 JAN 2024 
21.1. 
Appendix A Schedule of Events and Assessments 
Period 
Screening Period 
Treatment Period 
Follow-Upa 
Visitb 
1 
2 (Baseline) 
3 
4 
5 
6 
7 
8 (EOT/ET) 
Safety 
Follow-up 
Day or Week 
(Up to 42 days) 
Day 1/Week 0 Week 2 Week 4 Week 8 Week 14 Week 20 
Week 26 
Week 30 
Allowable visit window (# days) 
3 
3 
±3 
7 
7 
7 
+4
Informed consentc 
X 
Inclusion/exclusion criteria 
X 
X 
Demography 
X 
Medical and psychiatric historyd 
X 
Schizophrenia disease history 
X 
SCID-5-CT customized module 
X 
Interview by an independent cliniciane 
X 
Physical examinationf 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
Height and weightg 
X 
X 
X 
12-lead ECGh
X 
X 
X 
X 
Clinical laboratory testsi 
X 
X 
X 
Confirmation of main antipsychoticj 
X 
Pregnancy testk 
X 
X 
X 
X 
X 
X 
X 
X 
Urine toxicity (drug) screen 
X 
X 
X 
PK blood drawsl 
X 
X 
X 
X 
X 
NSA-16 
X 
X 
X 
X 
X 
X 
X 
PANSS and IQ-PANSS 
X 
X 
X 
X 
CGI-SCH-S of negative symptoms 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-SCH-I of negative symptoms 
X 
X 
X 
X 
X 
X 
PSP 
X 
X 
X 
X 
X 
BACS 
X 
X 
CDSS 
X 
X 
X 
X 
WoRQ 
X 
X 
X 
X 
C-SSRSm
X 
X 
X 
X 
X 
X 
X 
X 
AIMS, BARS, and SAS 
X 
X 
X 
X 
X 
Assessment of prior and concomitant 
medicationsn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense study drug 
X 
Xo 
Xo 
Xo 
Xo 
Xo 
Study drug accountability 
X 
X 
X 
X 
X 
X 
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Protocol ACP-103-064 
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Statistical Analysis Plan 
11 JAN 2024 
Abbreviations: AIMS=Abnormal Involuntary Movement Scale; BACS=Brief Assessment of Cognition for Schizophrenia; BARS=Barnes Akathisia Rating Scale; 
CDSS=Calgary Depression Scale for Schizophrenia; CGI-SCH-I=Clinical Global Impression of Schizophrenia–Improvement; CGI-SCH-S=Clinical Global 
Impression of Schizophrenia–Severity; C-SSRS=Columbia–Suicide Severity Rating Scale; ECG=electrocardiogram; EOT=end of treatment; ET=early 
termination; HCV=hepatitis C virus; HIV=human immunodeficiency virus; IQ-PANSS=Informant Questionnaire for the Positive and Negative Syndrome 
Scale; NSA-16=Negative Symptom Assessment–16 scale; PANSS=Positive and Negative Syndrome Scale; PK=pharmacokinetic(s); PSP=Personal and 
Social Performance; SAS=Simpson-Angus Extrapyramidal Side Effects Scale; SCID-5-CT=Structured Clinical Interview for DSM-5, Clinical Trials 
Version; WoRQ=Work Readiness Questionnaire 
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 visit will occur 30 (+4) days after the last dose of study drug. 
b
Study visits are designated by weeks and have a window, calculated from the Baseline visit, of ±3 days for Visits 3, 4, and 5 and of ±7 days for Visits 6, 7, 
and 8. The Screening Period is up to 42 days long (Day -42 to Day -1) and all Screening procedures should be completed as early in the Screening Period as 
possible. The window for the 30-day follow-up telephone call visit is +4 days. Circumstances may arise (e.g., pandemic, natural disaster, or political 
upheaval) when on-site assessments of efficacy and/or safety are not possible. In those cases, assessments may be performed at the subject’s place of 
residence by raters either in person, or via video technology or telephone where possible. The Investigator must contact the Medical Monitor for approval 
with the plan. Sites must keep a log to identify details of all visits that are administered remotely. For some remote efficacy assessments (i.e., NSA-16, 
PANSS, CGI), the vendor will provide additional training  to ensure calibration to reduce discrepancy between on-site and remote assessments. 
c
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 will be performed during the Screening Period. The interview will be 
conducted by video and will not be recorded. 
f
A complete physical examination should be performed at Screening, Baseline, and Week 26; symptom-directed examinations will be performed at Weeks 2 
and 14. Pelvic and/or urogenital examination may be deferred, unless the Investigator deems this to be clinically indicated. 
g
Height will only be measured at the Screening visit. 
h
A 12-lead ECG will be performed in triplicate at Screening. Single 12-lead ECG recordings will be performed at Baseline, Week 14, and at the Week 26 
(EOT/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. 
Circumstances may arise (e.g., pandemic, natural disaster, or political upheaval) when on-site ECG assessment is not possible. In those cases, ECG 
assessments may be performed at the subject’s place of residence by study staff. The Investigator must contact the Medical Monitor for approval with the 
plan. Sites must keep a log to identify details of all visits that are administered remotely. 
i
To include hematology, serum chemistry, prolactin levels, and urinalysis (note: additional laboratory studies [in addition to scheduled timepoints shown in 
the table] for a given subject may be repeated at any time throughout the Treatment Period, at the discretion of the Investigator). It is preferable but not 
required that subjects be in a fasted state (e.g., fasting for approximately 10 hours) before the blood sample for clinical chemistry is obtained. Circumstances 
may arise (e.g., pandemic, natural disaster, or political upheaval) when on-site clinical laboratory tests are not possible. In those cases, clinical laboratory 
tests may be performed at the subject’s place of residence by study staff or at a local laboratory. The Investigator must contact the Medical Monitor for 
approval with the plan. Sites must keep a log to identify details of all visits that are administered remotely. 
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Statistical Analysis Plan 
11 JAN 2024 
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 of childbearing potential; urine pregnancy tests will be completed at 
all other scheduled time-points for all female subjects of childbearing potential. 
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. Circumstances may arise (e.g., pandemic, natural disaster, or political
upheaval) when on-site assessment of PK is not possible. In those cases, PK assessments may be performed at the subject’s place of residence by study staff.
The Investigator must contact the Medical Monitor for approval with the plan. Sites must keep a log to identify details of all visits that are administered
remotely.
m
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.
n
Prior medication history will only be collected at the Screening visit.
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. In addition to the
study drug dispensed at the site, investigational product may be delivered directly to the subject’s place of residence; related procedures will be described in
the study-specific pharmacy manual.
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Protocol ACP-103-064 
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Statistical Analysis Plan 
11 JAN 2024 
21.2. 
Appendix B Composite z score and T-score Transformation for Brief 
Assessment of Cognition in Schizophrenia (BACS) 
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PSYCHOMETRIC AND ANALYSIS METHODOLOGY 
ACP-103-064 
Brief Assessment of Cognition in Schizophrenia (BACS) 
Project Lead: 
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 Acadia BACS Norms
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Table of Contents
Table of Contents ...................................................................................................................................... 2 
Description of the Brief Assessment of Cognition in Schizophrenia (BACS) ......................................... 3 
STATISTICAL ANALYSES ................................................................................................................................. 4 
BACS z score and T Score computation ................................................................................................ 4 
BACS Composite Score .......................................................................................................................... 4 
Data Ranges for each BACS Subtest...................................................................................................... 4 
Handling Missing Scores on the BACS Composite ................................................................................ 4 
References .................................................................................................................................................... 5
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Description of the Brief Assessment of Cognition in Schizophrenia (BACS)
The Brief Assessment of Cognition in Schizophrenia (BACS) was used to assess cognition. The validity and 
reliability properties of the BACS have been established in patients with schizophrenia and healthy 
controls, and the BACS composite score has proven high test-retest reliability, increasing the likelihood 
of detecting a treatment-related effect (Keefe et al., 2004, 2006, 2008). 
BACS Component Test Scores 
The BACS consists of 6 subscales: 
The Brief Assessment of Cognition in Schizophrenia (BACS) battery was administered to subjects. The 
BACS includes the following tests with the primary domain(s) of cognition they measure in parentheses: 
1. Verbal memory task (verbal memory) – a subject was given 5 attempts to remember 15 words and
recall as many words as possible;
2. Digit sequencing task (working memory) – a subject was presented with clusters of numbers of
increasing length and then asked to repeat in order from the lowest to highest length;
3. Token motor task (motor speed) – a subject was given 100 plastic tokens and asked to place 2 tokens
at a time within a container as quickly as possible within 60 seconds;
4. Verbal fluency (language, speed of processing) – divided into semantic and letter fluency, whereby a
subject was asked to name as many words as possible within a specific category (e.g., supermarket
items), and to name words that begin with a specific letter (e.g., F and S) within 60 seconds,
respectively;
5. Symbol coding task (attention, speed of processing) – a subject was asked to write matching numbers
from 1 to 9 to symbols within 90 seconds;
6. Tower of London (executive functions) –a subject was shown two pictures of three balls of different
colors arranged on three different pegs, whereby the balls were arranged differently on each picture
and the subjects were asked to give the total number of times the balls in one picture needed to be
moved in order to end with the arrangement in the other picture.
Scaled Test Component Scores and the BACS Composite 
For each subscale, higher scores reflect better cognition. For each subscale, a Standard Deviation Score 
was calculated based on normative data (Keefe et al. 2008). The BACS composite score is calculated as 
the average Standard Deviation Score of the 6 subscale scores, standardized so that the mean of the 
composite score in the healthy normative sample is 50 and the standard deviation is 10. The change in
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 Acadia BACS Norms
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BACS  composite  score  was  calculated  as  the  BACS  composite  score  at  Week  26  minus  the  BACS 
composite score at baseline. BACS assessments were completed in the following languages: Bulgarian, 
Croatian, Czech, Hungarian, Italian, Lithuanian, Polish, Russian, Serbian, Spanish, Ukrainian and 
Romanian. Individual test scores were converted into standardized (T) scores and composite scores that 
were corrected for age and gender (Keefe et al., 2008). 
STATISTICAL ANALYSES
BACS z score and T Score computation
i= each of the 6 subscales of the BACS 
z{i}=(raw score for subscale{i}-mean score from the norms{i})/standard deviation of the norms {i} 
z{i}=round(z{i},.01) 
t{i}=round((z{i} x 10)+50) 
Composite z score = (Verbal Memory z + Digit Sequencing z + Token Motor z + Verbal Fluency z + Symbol 
Coding z + Tower of London z)/denominator 
Composite T Score = round ((composite z x 10)+50) 
BACS Composite Score
The BACS composite score was calculated by averaging all z scores from the BACS subscales, including 
Verbal Memory, Digit Sequencing, Token Motor, Symbol Coding, Verbal Fluency (Semantic Fluency and 
Letter Fluency) and Tower of London. The z scores were produced by available age and gender corrected 
norms. The composite score is a measure of overall cognitive functioning. Raw score means (Standard 
Deviation) and z scores (corrected for gender and age) across visits were presented.   The BACS 
composite scores are calculated by averaging all z-scores of the six subtests from the BACS. 
Data Ranges for each BACS Subtest
Subtest Ranges
Minimum Value
Maximum Value
Verbal Memory 
0
75
Digit Sequencing
0
28
Token Motor
0
100
Verbal Fluency
0
300
Symbol Coding
0
110
Tower of London
0
22
Handling Missing Scores on the BACS Composite
The Composite score for subjects with missing subtests are imputed using the average z or T score of the 
remaining subtests. For ≤ 2 missing BACS subtests, the average of the other non-missing subtests z- 
scores are imputed for the composite score.  If there are more than 2 missing BACS subtests, the
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 Acadia BACS Norms
Confidential
composite score should be set to missing. If a subtest score is missing, the above is only used to impute 
the composite score, but the subtest score should be set to missing.
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References
Keefe RS, Goldberg TE, Harvey PD, Gold JM, Poe MP, Coughenour L. The brief assessment of cognition in 
schizophrenia: reliability, sensitivity, and comparison with a standard neurocognitive battery.Schizophr 
Res. 2004;68:283–97. 
Keefe RS, Harvey PD, Goldberg TE, Gold JM, Walker TM, Kennel C, et al. Norms and standardization of 
the Brief Assessment of Cognition in Schizophrenia (BACS) Schizophr Res. 2008;102:108–15. 
Keefe RS, Poe M, Walker TM, Kang JW, Harvey PD. The schizophrenia cognition rating scale: an 
interview-based assessment and its relationship to cognition, real-world functioning, and functional 
capacity.Am J Psychiatry. 2006;163:426–32. doi: 10.1176/appi.ajp.163.3.426. 
Keefe, R.S.E., Poe, M., Walker, T.M., Harvey, P.D., The relationship of the Brief Assessment of Cognition 
in Schizophrenia (BACS) to functional capacity and real-world functional outcome. J. Clin. Exp. 
Neuropsychol. 2006b. 28, 260-269. 
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Pr ot oc ol A C P -1 0 3 -0 6 4  
Versi o n 4 . 0 
Statistical A nal ysis Pla n  
1 1  J A N 2 0 2 4  
2 1. 4.  
S u m m ar y of Versi o n C h a n ges  
Versi o n N o:  
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A ut h or(s)  
Versi o n  Date  
1. 0  
Ori gi nal versi o n  
0 3  D E C  2 0 2 0  
2. 0  
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relate d t o C O VI D -1 9  
1 2  A P R 2 0 2 1  
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2 4  A U G  2 0 2 1  
4. 0 
U p date d f or c ha n g es i n pr ot oc ol 
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0 3 8 met h o d ; C orrecte d t he Wo R Q 
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