A 52-Week Open-Label Extension Study of Pimavanserin in Children and Adolescents With Irritability Associated With Autism Spectrum Disorder (ASD)
Phase: PHASE2
Conditions: Irritability Associated With Autism Spectrum Disorder
Sponsor: ACADIA Pharmaceuticals Inc.

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CLINICAL STUDY PROTOCOL
A 52-Week Open-Label Extension Study of Pimavanserin in Children and 
Adolescents with Irritability Associated with Autism Spectrum Disorder 
(ASD)
Protocol Number: ACP-103-070
Amendment 3-Consolidated
 EudraCT Number: 2021-005388-32
EUCT Number: 2024-512202-25-00
ClinicalTrials.gov Number: NCT05555615 
Original Protocol Date: 30 April 2021
Protocol Amendment 1 Date: 07 December 2021
Protocol Amendment 2 Date: 25 March 2022
Protocol Amendment 3 Date: 21 December 2022
Protocol Amendment 3-IT Date: 12 July 2023
Protocol Amendment 3-Consolidated Date: 29 February 2024
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-103-070 
 
Final Version: 2.0 
Clinical Study Protocol Amendment 3-Consolidated 
 
Date: 29 February 2024 
 
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SPONSOR SIGNATURE PAGE 
Title: A 52-Week Open-Label Extension Study of Pimavanserin in Children and Adolescents 
with Irritability Associated with Autism Spectrum Disorder (ASD) 
 
 Clinical 
Development: 
 MD 
 Clinical 
Development 
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 
 
 
 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

Signature Page for ACP-103-070 OLE Protocol Amendment 3 - Consolidated
Signature Page for ACP-103-070 OLE Protocol Amendment 3 - Consolidated
Approve
14-Mar-2024 17:18:01 GMT+0000
Approve
14-Mar-2024 17:21:43 GMT+0000
PPD
PPD

Study: ACP-103-070 
 
Final Version: 2.0 
Clinical Study Protocol Amendment 3-Consolidated 
 
Date: 29 February 2024 
 
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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-103-070 
 
Final Version: 2.0 
Clinical Study Protocol Amendment 3-Consolidated 
 
Date: 29 February 2024 
 
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PROTOCOL SYNOPSIS 
Protocol number 
ACP-103-070 Pediatric OLE 
Protocol title 
A 52-Week Open-Label Extension Study of 
Pimavanserin in Children and Adolescents with 
Irritability Associated with Autism Spectrum 
Disorder (ASD) 
Name of investigational product 
Pimavanserin (capsules) 
Indication 
Irritability associated with ASD 
Phase of development 
2 
Sponsor 
Acadia Pharmaceuticals Inc. 
12830 El Camino Real, Suite 400 
San Diego, CA 92130 USA  
Safety hypothesis 
Pimavanserin, a selective serotonin receptor (5-HT2A) 
inverse agonist/antagonist will be a safe and well 
tolerated treatment for children and adolescents with 
ASD. 
Primary objective 
• To evaluate the long-term 
safety and tolerability of 
pimavanserin after 52 weeks of 
treatment in children and 
adolescents with ASD 
Primary endpoints 
• Treatment-emergent adverse events (TEAEs) 
Safety will also be evaluated by analyses of the 
following: 
• Vital signs 
• Weight and body mass index (BMI) 
• 12-lead electrocardiograms (ECGs) 
• Physical examination results 
• Clinical laboratory tests (including urinalysis) 
and hormonal assessments 
• Columbia–Suicide Severity Rating Scale 
(C-SSRS) 
• Extrapyramidal Symptom Rating Scale-
Abbreviated (ESRS-A) 
Efficacy hypothesis 
Pimavanserin, a selective 5-HT2A inverse 
agonist/antagonist, will be effective in the treatment of 
ASD symptoms. 

Study: ACP-103-070 
 
Final Version: 2.0 
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Date: 29 February 2024 
 
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Secondary objective 
• To evaluate the continued 
response to long-term 
pimavanserin treatment in 
children and adolescents with 
ASD 
Secondary endpoint 
• Proportion of subjects who have at least 25% 
reduction in the Aberrant Behavior 
Checklist-Irritability (ABC-I) subscale score 
AND a Clinical Global 
Impression-Improvement (CGI-I) of irritability 
score of 1 (very much improved) or 2 (much 
improved) compared to the antecedent study 
baseline status at Week 52 
Exploratory objectives 
• To evaluate the continued 
benefit of long-term 
pimavanserin treatment on the 
symptoms of ASD, in children 
and adolescents with ASD in 
the following clinical areas: 
o Aberrant Behavior 
Checklist (ABC) 
symptom domains 
o Maintenance of benefit 
o Response to treatment 
Exploratory endpoints 
• Change from Baseline at Week 52 in the 
caregiver-rated ABC subscale scores: 
o Irritability 
o Stereotypic behavior 
o Lethargy 
o Hyperactivity 
o Inappropriate speech 
• Change from Baseline at Week 52 in the 
Clinical Global Impression–Severity (CGI-S) 
of irritability score  
• CGI-I of irritability score from antecedent 
study Baseline at Week 52 
• Change from Baseline at Week 52 in the 
Caregiver Strain Questionnaire (CGSQ) 
• Proportion of subjects who have at least 25% 
reduction from the antecedent study Baseline 
in the ABC-I subscale score (ABC-I 
responders) at Week 52 
• Proportion of subjects who have CGI-I of 
irritability score of 1 (very much improved) or 
2 (much improved) compared to the antecedent 
study baseline status (CGI-I of irritability 
responders) at Week 52 
Number of study sites 
Approximately 60 global sites and approximately 
eight countries will participate in this study. 

Study: ACP-103-070 
 
Final Version: 2.0 
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Date: 29 February 2024 
 
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Number of subjects planned 
The planned sample size is not based on statistical 
power but will depend on the number of subjects who 
complete the antecedent double-blind study and who 
rollover into this open-label extension (OLE) study. 
Test product, dose, and 
administration 
Pimavanserin “low dose” (see below details), or 
pimavanserin “high dose” (see below details), 
administered orally, once daily. 
Dose 
Subjects will be stratified by age group (5- through 
12-year-olds or 13- through 17-year-olds). Subjects 
will remain in the age group they were stratified into 
during the antecedent double-blind study, throughout 
the OLE study.  
Each age group has its own “low dose” and high 
dose”. For the 5- through 12-year-olds, the “low dose” 
will be 10 mg/day pimavanserin, and the “high dose” 
will be 20 mg/day pimavanserin. For the 
13- through 17-year-olds, the “low dose” will be 
20 mg/day pimavanserin and the “high dose” will be 
34 mg/day pimavanserin. 
All subjects will receive once daily (QD) doses of 
pimavanserin over 52 weeks of treatment. 
Within each age group, eligible subjects will receive 
pimavanserin “low dose” for the first two weeks of the 
study. At the Week 2 visit, the dose may be increased 
to pimavanserin “high dose”, based on the 
Investigator’s assessment of clinical response. 
After the Week 2 visit, and up to and including the 
Week 20 visit, dose adjustments, either increases or 
decreases, may be made at any clinic visit (scheduled 
or unscheduled), based on the Investigator’s 
assessment of clinical response and tolerability. 
No further dose adjustments are allowed after the 
Week 20 visit. 
 
Pimavanserin dosages below: 
Pimavanserin 10 mg (provided as 1×10 mg capsule) 
Pimavanserin 20 mg (provided as 1×20 mg capsule) 
Pimavanserin 34 mg (provided as 1×34 mg capsule) 
Study design 
This study will be conducted as a 52-week, open-label 
extension study of the antecedent double-blind study 

Study: ACP-103-070 
 
Final Version: 2.0 
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Date: 29 February 2024 
 
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to determine the long-term safety and tolerability of 
pimavanserin for the treatment of irritability 
associated with ASD in children and adolescents 
(5 through 17 years old at the time of enrolling into 
the antecedent double-blind study).  
Subjects who have completed the antecedent 
double-blind study and who have shown no significant 
worsening of symptoms at the end of the study as 
evidenced by the CGI-I of irritability will be included 
in this long-term extension study. 
Study ACP-103-070 subjects must be consented prior 
to the procedures being performed at the End of 
Treatment (EOT) visit in the antecedent double-blind 
study. Procedures performed at the EOT visit of the 
antecedent double-blind study will be carried over to 
the ACP-103-070 study to be included as baseline 
information, and this visit will be considered the 
Baseline Visit (Visit 1) of the ACP-103-070 study. 
An independent data and safety monitoring board 
(DSMB) will review interim safety data including data 
on TEAEs and serious TEAEs. 
The study will have two periods: 
• Open-label treatment period (52 weeks) 
• Safety follow-up period (at least 30 days) 
The study design schema is provided in Figure S–1. 
The schedule of assessments is provided in Table S-1. 
Open-Label Treatment Period (52 weeks) 
During the treatment period, clinic visits will be 
conducted at Baseline and Weeks 2, 6, 12, 20, 28, 36, 
44, and 52, or upon early termination (ET) from the 
study. 
Study drug will be dispensed to the subject to take 
home at the Baseline visit and at each subsequent 
clinic visit. The subject and their parent/legally 
acceptable representative (LAR) will be provided 
instructions for the subject’s first dose of study drug 
the day after the Baseline visit. It is recommended that 
the subject take the study drug at approximately the 
same time each day as a single, oral dose. 
All concomitant medications should remain at a stable 
dose throughout the study, if possible, except as 

Study: ACP-103-070 
 
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described in Appendix A to minimize confounding 
interpretation of any correlating pimavanserin dose 
changes, including treatment discontinuations. 
Safety Follow-up Period (30[+3] days) 
A follow-up safety assessment will be conducted by 
telephone call at least 30 days after the last dose of 
study drug. 
Study duration 
The duration of participation for individual study 
subjects will be up to approximately 56 weeks, 
consisting of a 52-week open-label treatment period, 
and a safety follow-up period of at least 30(+3) days 
(Figure S–1). 
The study start date is defined as the date the first 
subject is enrolled, which is the Baseline visit date for 
the first subject for this open-label study. 
The primary completion date is the last date that 
subject data was collected for the primary outcome 
measure. 
The study completion date (End of Study) is defined 
as the last date that subject data was collected, which 
includes the safety follow-up telephone call visit. The 
total duration of exposure to pimavanserin may be 
greater than 52 weeks (e.g., up to 58 weeks) as some 
subjects have been treated with pimavanserin in an 
antecedent double-blind study. 
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 
to enter this open-label extension study. 
Inclusion Criteria: 
Study Population  
1. Has completed the treatment period of the 
antecedent double-blind study 
2. Informed consent prior to the conduct of any 
study procedures is required as follows: 
a. The subject should provide written or 
oral assent if deemed able by the 
Investigator.  

Study: ACP-103-070 
 
Final Version: 2.0 
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b. The subject’s parent/LAR must provide 
written consent. The subject’s 
parent/LAR must be considered 
reliable by the Investigator, able to 
complete assessments regarding the 
subject's development and behavior 
throughout the study, and able to help 
ensure compliance with study 
treatment, study visits, and protocol 
procedures 
c. If a person other than the parent/LAR 
has been designated as a caregiver for 
the purpose of providing input for 
caregiver-reported scales, that person 
must also provide written consent. 
Such a designee should be a family 
member, adult and responsible, living 
with or in very frequent contact with 
the subject participating in the study, 
who is committed to providing 
responses for the caregiver-reported 
scales for the duration of the study 
The process of obtaining informed consent 
will be conducted in accordance with 
institutional review board (IRB) or ethics 
committee (EC) policy and applicable local 
law. 
3. In the Investigator’s opinion, the subject, to the 
best of his/her ability, the parent/LAR, and the 
designated caregiver (if applicable, and in 
accordance with IRB or EC policy and 
applicable local law) are able to understand the 
nature of the study, follow protocol 
requirements and be willing to comply with 
study drug administration requirements 
Psychiatric Diagnosis  
4. Continues to be both clinically stable and not 
at imminent risk of suicide or injury to self, 
others, or property, in the opinion of the 
Investigator 
5. Continues to be medically stable at enrollment, 
in the opinion of the Investigator 

Study: ACP-103-070 
 
Final Version: 2.0 
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Contraceptives 
6. Female subjects who participate in this study 
must either be unable to become pregnant 
(e.g., premenarchal, surgically sterile, 
etc.) -OR- must agree to use two clinically 
acceptable methods of contraception 
(e.g., oral, intrauterine device [IUD], 
diaphragm plus spermicide, injectable, 
transdermal or implantable contraception) 
during the treatment period, and for at least 
45 days after last dose. 
All female subjects of childbearing potential 
must have a negative urine human chorionic 
gonadotropin (hCG) pregnancy test at Baseline 
and all clinic visits. Females of childbearing 
potential are defined as females who have 
begun menstruating. 
Exclusion Criteria: 
Study Population 
 
1. Subject or parent/LAR is judged by the 
Investigator to be inappropriate for the study 
(e.g., significantly noncompliant in the 
antecedent double-blind study) 
CNS, Psychiatric, and Illicit Drug Use Criteria 
2. Requires treatment with a medication 
prohibited by the protocol, including 
concomitant psychotropic drugs targeting 
irritability, including those used off-label 
(clonidine, guanfacine, and propranolol; 
lithium, valproate), medications that prolong 
the QT interval; and strong cytochrome P450 
(CYP) 3A4 enzyme (CYP3A4) inhibitors and 
inducers (see Appendix A and Appendix B) 
3. Is at a significant risk of suicide, or is a danger 
to self or others, in the opinion of the 
Investigator based upon all available sources 
of information including C-SSRS (positive 
answer to suicidal ideation questions 4 or 5 [or 
positive answer to suicidal behavior questions 
at Baseline]) 
4. Is at risk of significant violent behavior to the 
extent that participation would pose an undue 

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risk to other patients, caregivers, or others in 
the opinion of the Investigator 
5. Has a positive urine drug test at Baseline. For 
study eligibility, the urine toxicology (drug) 
screen (UDS) must be negative for any 
substance for which the subject does not have 
a valid prescription. 
Medical Criteria 
6. Has developed a serious and/or unstable 
psychiatric, neurologic, cardiovascular 
(e.g., long QT syndrome, torsade de pointes, 
unstable cardiac syndrome or syncope, 
congestive heart failure, ongoing uncorrected 
hypokalemia or hypomagnesemia, 
non-sustained or sustained ventricular 
tachycardia), 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, or has major surgery planned 
during the study 
7. Has experienced any change in medical or 
treatment status that may increase the risk 
associated with taking pimavanserin, would 
interfere with safety assessments, or would 
confound the interpretation of study results, 
based on the Investigator’s judgment 
8. For age <13 years, a resting position (sitting or 
supine) systolic (SBP) and/or diastolic blood 
pressure (DBP) level ≥90th percentile for 
gender-specific age and height charts from the 
National Heart and Lung Institute (NHLI), at 
Baseline. For age ≥13 years a resting position 
(sitting or supine) SBP ≥120 mmHg and/or a 
DBP ≥80 mmHg, at Baseline. 
9. Has a clinically significant abnormal ECG at 
Baseline or any of the following cardiac 
conduction abnormalities: 
a. Corrected QT interval using Fridericia’s 
correction method (QTcF) ≥450 ms 
b. PR interval on ECG >220 ms 

Study: ACP-103-070 
 
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c. Evidence of second- or third-degree 
atrioventricular block 
d. Evidence of complete left bundle branch 
block 
e. Intraventricular conduction delay with 
QRS interval on ECG (QRS) >110 ms  
f. QRS or T wave morphology that could, in 
the Investigator’s opinion, render 
QT interval assessment unreliable 
g. Sick sinus syndrome 
h. Non-sinus rhythm 
i. Resting heart rate <50 beats per minute 
One repeat set of triplicate ECGs is allowed at 
Baseline. 
10. Weight <15 kg 
11. In Italy only: Has a sensitivity to any 
compound present in pimavanserin or any 
metabolites or compounds listed in the 
Investigator’s brochure as being present in this 
medication 
Sample size calculations 
The planned sample size for this study is not based on 
statistical power but will depend on the number of 
subjects who complete the antecedent double-blind 
study, and who rollover into this open-label extension 
study. 
Statistical methods 
The primary objective of this study is to evaluate the 
long-term safety and tolerability of pimavanserin after 
52 weeks of treatment in children and adolescents 
with ASD. Secondary and exploratory objectives 
include assessment of efficacy outcome measures over 
time. No formal statistical testing will be performed 
for any of the safety or efficacy endpoints. 
All safety and efficacy measures will be summarized 
using descriptive statistics. 
For each continuous measure in safety and efficacy 
analyses, changes from Baseline results will be 
presented in two ways: 
1. using the Baseline of this study to report the 
changes across the timepoints of this 
open-label study 

Study: ACP-103-070 
 
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2. using the Baseline from the antecedent double-
blind study to report the changes across the 
timepoints of this open-label study 
Descriptive Statistics 
For continuous variables, the following summary 
statistics will be provided: number of subjects, mean, 
standard error of the mean, standard deviation, 
minimum, maximum, and median. For categorical 
variables, summaries will include the number and 
percentage of subjects in each category. 
Population Analysis Sets 
The Safety Analysis Set will include all subjects who 
received at least one dose of open-label study drug. 
The Safety Analysis Set will be used for all analyses. 
Subgroup Analysis 
Selected analyses may be performed in subgroups 
defined in the statistical analysis plan (SAP). 
Missing Data 
Handling of missing values will be described in detail 
in the SAP. 
Primary Analyses 
The primary endpoints for this study are TEAEs. All 
adverse events will be classified into standard 
terminology using the Medical Dictionary for 
Regulatory Activities (MedDRA). The number and 
frequency of TEAEs will be summarized by system 
organ class and preferred term. TEAEs leading to 
discontinuation, TEAEs related to study drug, TEAEs 
by maximum severity, fatal TEAEs, serious TEAEs, 
and serious TEAEs related to study drug will also be 
summarized.  
Other Safety Analyses 
Descriptive statistics for ECGs, vital signs, weight, 
BMI, ESRS-A, 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 
corrected QT interval on ECG (QTc) intervals and 
changes in QTc intervals in accordance with 
International Council for Harmonisation (ICH) 
guidelines. 

Study: ACP-103-070 
 
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For the C-SSRS, the number and percentage of 
subjects with suicidal ideation or behavior during the 
study will be tabulated. 
Efficacy Analyses 
Descriptive statistics for all efficacy endpoints will be 
tabulated by timepoint. 
Date 
29 February 2024 
 

Study: ACP-103-070 
 
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Figure S–1 
Schematic of Study Design for ACP-103-070 
 
Abbreviations: EOT=end of treatment; ET=early termination; yrs=years 
a 
A dose increase, based on the Investigator’s assessment of clinical response, may be made at the Week 2 visit. After the Week 2 visit and up to and including 
the Week 20 visit, dose adjustments, either increases or decreases, may be made at any clinic visit (scheduled or unscheduled), based on the Investigator’s 
assessment of clinical response and tolerability. No further dose adjustments are allowed after the Week 20 visit. 

Study: ACP-103-070 
 
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Table S-1 
Schedule of Events and Assessments for ACP-103-070 
Period 
 
Open-label treatment period 
Follow-up 
 Baselinew 
 
 
 
 
 
 
 
EOT/ETn Unscheduleda 
Safety  
follow-upb 
Visit Week 
0 
2 
6 
12 
20 
28 
36 
44 
52 
 
56 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
 
10 
Visit window (days) 
 
3 
3 
3 
3 
3 
3 
3 
3 
 
+3 
Type of visitc  
Clinic 
Clinic 
Clinic 
Clinic 
Clinic  
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Telephone 
Informed consent/assentd 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
Xe 
 
 
 
 
 
 
 
 
 
 
Physical examination and 
self- or caregiver-reported 
Tanner stagingq 
X 
 
 
X 
 
X 
 
X 
X 
 
 
Vital signs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Heights, weight, and BMI 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECGf, g, m 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Clinical laboratory testsg, m, r, v, x 
X 
 
 
X 
 
X 
 
X 
X 
 
 
Pregnancy testg, h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urine toxicology (drug) screen 
(UDS)o  
X 
 
 
 
 
 
 
 
X 
 
 
ABCq 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
CGI-S of irritability 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
CGI-I of irritabilityi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
RBS-Rq 
X 
 
 
X 
 
X 
X 
X 
X 
 
 
VABS-Socializationq 
X 
 
 
X 
 
X 
X 
X 
X 
 
 
Table continues on next page 
 
 

Study: ACP-103-070 
 
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Table S-1 
Schedule of Events and Assessments for ACP-103-070 (Continued) 
Period 
 
Open-label treatment period 
Follow-up 
 Baselinew 
 
 
 
 
 
 
 
EOT/ETn Unscheduleda 
Safety  
follow-upb 
Visit Week 
0 
2 
6 
12 
20 
28 
36 
44 
52 
 
56 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
 
10 
Visit window (days) 
 
3 
3 
3 
3 
3 
3 
3 
3 
 
+3 
Type of visitc  
Clinic 
Clinic 
Clinic  Clinic 
Clinic  
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Telephone 
CGSQq 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
C-SSRSq 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ESRS-Aq  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Assessment of concomitant 
medicationsp 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of syncope 
occurrencet 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of somnolence 
occurrenceu 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug dispensation 
Xj 
X 
X 
X 
X 
X 
X 
X 
 
Xk 
 
Study drug return and 
accountabilityl 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Abbreviations: ABC=Aberrant Behavior Checklist; ASR=accurate symptom reporting; BMI=body mass index; CGI-I=Clinical Global Impression–Improvement; 
CGI-S=Clinical Global Impression–Severity; CGSQ=Caregiver Strain Questionnaire; C-SSRS=Columbia–Suicide Severity Rating Scale; 
ECG=electrocardiogram; eGFR=estimated glomerular filtration rate; EOT=end of treatment; ESRS-A=Extrapyramidal Symptom Rating Scale–Abbreviated; 
ET=early termination; LAR=legally acceptable representative; RBS-R= Repetitive Behavior Scale–Revised; UDS=urine toxicology (drug) screen; 
VABS=Vineland Adaptive Behavior Scales 
a 
At a minimum the safety assessments indicated should be completed at unscheduled visits. Other assessments may be completed at unscheduled visits at the 
discretion of the Investigator. 
b 
This visit is a safety follow-up telephone call visit for subjects who complete the study or discontinue treatment prematurely from the study. This visit will 
occur 30(+3) days after the last dose of study drug. The safety follow-up visit will not be done if the subject withdraws consent to participate in all parts of 
the study. 
c 
Circumstances may arise (e.g., pandemic, natural disaster, political upheaval, or to minimize subject and caregiver burden) when on-site assessments of 
efficacy and/or safety are not possible. In those cases, assessments may be performed offsite by raters either in person, or via video technology or telephone 

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where possible. For all visits that are conducted remotely, the Investigator must contact the Medical Monitor for approval of the plan. Sites must keep a log 
to identify details of all visits that are administered remotely. Provided that the subject is physically in the clinic, and accompanied by a relative, all 
caregiver-rated assessments may be provided remotely. 
d 
Consent from the subject, parent/LAR, and caregiver (if different from the parent/LAR), for the present study must be obtained for entry into the present 
study prior to the final procedures being performed at the end of treatment (EOT) visit in the antecedent double-blind study. Data from the EOT/ET visit 
procedures of the antecedent double-blind study will be carried over as baseline information in the present study, as applicable 
e 
All assessments must be completed and subject must meet required eligibility criteria before being enrolled. 
f 
12-lead ECGs should be performed in sequential triplicate. Electrocardiograms should be performed before blood sampling or at least 30 minutes after blood 
sampling. The subject must rest in a sitting or supine position for 5 minutes before the ECG is obtained. One repeat set of triplicate ECGs is allowed at 
Baseline. 
g 
Mild sedation is allowed exceptionally for ECGs and blood draws during the study (e.g., alprazolam at a pediatric-appropriate dose per age, and the lowest 
dose deemed necessary by the Investigator) just in cases when the subject’s agitation/anxiety does not allow a safe and accurate measurement and the 
Investigator, with agreement from the caregiver, considers it safe and appropriate for the subject. 
h 
For female subjects of childbearing potential, a urine pregnancy dipstick test will be completed at all scheduled and unscheduled visits. If positive, the result 
will be confirmed with a serum pregnancy test. 
i 
Relative to baseline status in the antecedent double-blind study. 
j 
The subject and their parent/LAR will be provided instructions for the subject’s first dose of study drug on the day after the Baseline visit. 
k 
Study drug may be dispensed to the subject at unscheduled visits if needed. 
l 
If visit is remote, accountability will be assessed verbally with the caregiver, and verified at the next clinic visit. 
m 
The involvement of experienced personnel in the conduction of routine procedures such as blood drawing and ECG recording in this population is strongly 
recommended.  
n 
The ET visit will not be done if the subject (and/or parent/LAR) withdraws consent to participate in all parts of the study and withdrawal of consent happens 
before that timepoint.  
o 
A urine toxicology dipstick should be used in addition to the urine toxicology screen at the Baseline visit (to confirm eligibility). 
p 
Including coronavirus disease 2019 (COVID-19) vaccination 
q 
For scales that require caregiver input, the caregiver should be the parent/LAR or designee. A designee should be a family member, adult and responsible, 
living with or in very frequent contact with the subject participating in the study, who is committed to providing responses for the caregiver-reported scales 
for the duration of Studies ACP-103-069 and ACP-103-070. Caregivers providing input for the ABC, RBS-R, and CGSQ scales will be trained in accurate 
symptom reporting (ASR) prior to completing the scales. ASR training should be done at Screening in the antecedent study (Study ACP-103-069) before the 
caregiver completes any scales, and repeated whenever there is a change in caregiver or if the site feels a caregiver requires retraining. 
r 
Prolactin 
 Results will be monitored 
 
 
s 
As measured by stadiometer. 
t 
If the caregiver reports an occurrence of syncope, the investigator should ask the “syncope adverse event questions” in Appendix G. 
u 
If the caregiver reports an occurrence of somnolence, the investigator should ask the “somnolence adverse event questions” in Appendix H. 
CCI
CCI

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v 
Circumstances may arise (e.g., pandemic, natural disaster, political upheaval, or technical issues) 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. 
w 
Procedures performed at the EOT visit for Study ACP-103-069 will be carried over as baseline information, if applicable. 
x 
In Italy only: 
 
 
 
 
CCI

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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ............................................................................................... 2 
DECLARATION OF INVESTIGATOR .................................................................................... 4 
PROTOCOL SYNOPSIS ........................................................................................................... 5 
TABLE OF CONTENTS ......................................................................................................... 21 
LIST OF TABLES ................................................................................................................... 26 
LIST OF FIGURES ................................................................................................................. 26 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................. 27 
1 
INTRODUCTION ................................................................................................... 29 
1.1 
Background Information ......................................................................................... 29 
1.1.1 
Autism Spectrum Disorder ...................................................................................... 29 
1.1.2 
Current Treatments for Irritability Associated With Autism Spectrum Disorder .... 29 
1.1.3 
Scientific Rationale ................................................................................................. 30 
1.2 
Investigational Product ............................................................................................ 32 
1.3 
Previous Clinical Experience .................................................................................. 32 
1.3.1 
Studies in Adults With Schizophrenia ..................................................................... 33 
1.3.2 
Phase 1 Study in Adolescents With Psychiatric Disorders ...................................... 35 
1.4 
Study Rationale ....................................................................................................... 35 
1.4.1 
Rationale for Study Design ..................................................................................... 35 
1.4.2 
Rationale for Dose Selection ................................................................................... 36 
1.5 
Benefit/Risk Assessment ......................................................................................... 37 
1.5.1 
Known Potential Risks ............................................................................................ 37 
1.5.2 
Known Potential Benefits ........................................................................................ 38 
2 
STUDY OBJECTIVES AND ENDPOINTS ........................................................... 38 
2.1 
Primary Objective .................................................................................................... 38 
2.1.1 
Primary Endpoints ................................................................................................... 38 
2.2 
Secondary Objective ................................................................................................ 39 
2.2.1 
Secondary Endpoint ................................................................................................ 39 
2.3 
Exploratory Objectives ............................................................................................ 39 
2.3.1 
Exploratory Endpoints ............................................................................................. 39 
3 
STUDY DESCRIPTION ......................................................................................... 40 
3.1 
Overview of Study Design ...................................................................................... 40 
3.1.1 
Open-label Treatment Period (52 Weeks) ............................................................... 41 
3.1.2 
Safety Follow-up Period (30 Days) ......................................................................... 41 

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4 
SUBJECT ELIGIBILITY AND WITHDRAWAL CRITERIA ............................... 41 
4.1 
Inclusion Criteria ..................................................................................................... 42 
4.2 
Exclusion Criteria .................................................................................................... 43 
4.3 
Screen Failures ........................................................................................................ 45 
4.4 
Subject Withdrawal of Consent ............................................................................... 45 
4.5 
Subject Discontinuation .......................................................................................... 45 
4.5.1 
Handling of Subject Discontinuation During the Treatment Period ....................... 46 
4.6 
Subject Lost to Follow-up ....................................................................................... 46 
4.7 
Study Discontinuation ............................................................................................. 46 
4.8 
Prior and Concomitant Therapy .............................................................................. 47 
4.8.1 
Prior Medication ...................................................................................................... 47 
4.8.2 
Concomitant Medication ......................................................................................... 47 
4.8.2.1 
Permitted, Restricted, and Prohibited Medications ................................................. 47 
4.8.3 
Rescue Medications, Treatments, and Procedures .................................................. 48 
5 
INVESTIGATIONAL PRODUCT .......................................................................... 48 
5.1 
Investigational Product Description ........................................................................ 48 
5.1.1 
Formulation, Appearance, Packaging, and Labeling ............................................... 48 
5.1.2 
Product Storage and Stability .................................................................................. 49 
5.1.3 
Dosing and Administration ...................................................................................... 49 
5.1.3.1 
Dose Modification ................................................................................................... 49 
5.1.4 
Blinding ................................................................................................................... 49 
5.1.5 
Study Drug Compliance .......................................................................................... 49 
5.1.6 
Overdose .................................................................................................................. 50 
5.2 
Investigational Product Accountability Procedures ................................................ 50 
6 
STUDY ASSESSMENTS ....................................................................................... 50 
6.1 
Baseline Assessments .............................................................................................. 51 
6.1.1 
Physical Examination and Self- or Caregiver-reported Tanner Staging .................. 51 
6.1.2 
Vital Signs ............................................................................................................... 51 
6.1.3 
Height, Weight, and Body Mass Index .................................................................... 51 
6.1.4 
12-lead ECG ............................................................................................................ 51 
6.1.5 
Clinical Laboratory Tests ........................................................................................ 51 
6.1.6 
Pregnancy Test ......................................................................................................... 51 
6.1.7 
Urine Toxicology (Drug) Screen ............................................................................. 51 
6.1.8 
Aberrant Behavior Checklist ................................................................................... 51 
6.1.9 
CGI-S ....................................................................................................................... 52 
6.1.10 
CGI-I ....................................................................................................................... 52 

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6.1.11 
RBS-R ..................................................................................................................... 52 
6.1.12 
VABS-Socialization ................................................................................................. 52 
6.1.13 
CGSQ ...................................................................................................................... 52 
6.1.14 
C-SSRS .................................................................................................................... 52 
6.1.15 
ESRS-A ................................................................................................................... 52 
6.1.16 
Concomitant Medications and Adverse Events ....................................................... 52 
6.2 
Efficacy Assessments .............................................................................................. 52 
6.2.1 
Aberrant Behavior Checklist ................................................................................... 52 
6.2.2 
CGI-S ....................................................................................................................... 53 
6.2.3 
CGI-I ....................................................................................................................... 53 
6.2.4 
Repetitive Behavior Scale–Revised ........................................................................ 53 
6.2.5 
Vineland Adaptive Behavior Scales–Socialization ................................................. 54 
6.2.6 
Caregiver Strain Questionnaire ............................................................................... 54 
6.3 
Safety Scales ............................................................................................................ 55 
6.3.1 
Columbia–Suicide Severity Rating Scale ................................................................ 55 
6.3.2 
Extrapyramidal Symptom Rating Scale–Abbreviated ............................................ 55 
6.4 
Safety Assessments .................................................................................................. 56 
6.4.1 
Physical Examination and Self- or Caregiver-reported Tanner Staging .................. 56 
6.4.2 
Vital Signs ............................................................................................................... 57 
6.4.3 
Electrocardiograms .................................................................................................. 57 
6.4.4 
Laboratory Evaluations ........................................................................................... 58 
6.4.5 
Syncope ................................................................................................................... 60 
6.4.6 
Somnolence ............................................................................................................. 60 
6.5 
Blood Sampling ....................................................................................................... 61 
6.6 
Safety Follow-up ..................................................................................................... 62 
6.7 
Unscheduled Visits .................................................................................................. 63 
6.8 
Remote Assessments or Visits ................................................................................. 63 
7 
ADVERSE EVENTS .............................................................................................. 63 
7.1 
Specification of Safety Parameters .......................................................................... 63 
7.1.1 
Definition of Adverse Event .................................................................................... 63 
7.1.2 
Definition of Serious Adverse Event ....................................................................... 64 
7.2 
Classification of an Adverse Event ......................................................................... 65 
7.2.1 
Severity of Event ..................................................................................................... 65 
7.2.2 
Relationship to Study Drug ..................................................................................... 65 
7.2.3 
Duration ................................................................................................................... 66 
7.2.4 
Frequency ................................................................................................................ 66 

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7.2.5 
Action Taken With Study Drug ............................................................................... 66 
7.2.6 
Therapy .................................................................................................................... 67 
7.2.7 
Outcome .................................................................................................................. 67 
7.2.8 
Seriousness .............................................................................................................. 67 
7.2.9 
Definition of Unexpectedness ................................................................................. 67 
7.3 
Time Period and Frequency for Event Assessment and Follow-up ........................ 67 
7.4 
Reporting Procedures .............................................................................................. 67 
7.4.1 
Adverse Event Reporting ........................................................................................ 67 
7.4.2 
Serious Adverse Event Reporting ............................................................................ 68 
7.4.3 
Reporting of Pregnancy ........................................................................................... 69 
7.4.3.1 
Reporting Paternal Drug Exposure .......................................................................... 69 
7.4.4 
Reporting of Overdose ............................................................................................ 69 
8 
MONITORING ....................................................................................................... 69 
9 
STATISTICAL METHODS AND DATA ANALYSIS ........................................... 70 
9.1 
Statistical and Analytical Plans ............................................................................... 70 
9.2 
Statistical Hypotheses .............................................................................................. 70 
9.3 
Sample Size Determination ..................................................................................... 70 
9.4 
Population Analysis Sets ......................................................................................... 70 
9.5 
Statistical Analyses .................................................................................................. 70 
9.5.1 
Primary Analyses ..................................................................................................... 71 
9.5.2 
Other Safety Analyses ............................................................................................. 71 
9.5.3 
Secondary Endpoint and Analysis ........................................................................... 71 
9.5.4 
Exploratory Endpoints and Analyses ...................................................................... 71 
9.5.5 
Subgroup Analyses .................................................................................................. 72 
9.6 
Interim Analyses ...................................................................................................... 72 
9.7 
Data and Safety Monitoring Board ......................................................................... 72 
10 
STUDY MANAGEMENT AND DATA COLLECTION ....................................... 72 
10.1 
Data Collection and Management Responsibilities ................................................. 72 
10.2 
Source Documents ................................................................................................... 73 
10.3 
Case Report Forms .................................................................................................. 73 
10.4 
Confidentiality ......................................................................................................... 73 
10.5 
Study Records Retention ......................................................................................... 73 
10.6 
Protocol Exceptions and Deviations ........................................................................ 74 
10.7 
Protocol Amendments ............................................................................................. 74 
11 
QUALITY MANAGEMENT.................................................................................. 74 

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11.1 
Risk Management .................................................................................................... 74 
11.2 
Quality Control and Quality Assurance ................................................................... 75 
12 
ETHICAL CONSIDERATIONS ............................................................................. 76 
12.1 
Ethical Standard ...................................................................................................... 76 
12.2 
Institutional Review Board/Ethics Committee ........................................................ 76 
12.3 
Informed Consent/Assent Process ........................................................................... 76 
12.3.1 
Subject Assent Form ................................................................................................ 77 
12.3.2 
Parent and Legally Acceptable Representative Informed Consent ......................... 77 
12.3.3 
Consent and Other Informational Documents Provided to Subjects ....................... 77 
12.3.4 
Consent Procedures and Documentation ................................................................. 77 
12.3.4.1 Remote Consent Procedures and Documentation ................................................... 78 
13 
PUBLICATION PLAN ........................................................................................... 78 
14 
CONFLICT OF INTEREST POLICY .................................................................... 78 
14.1 
Finance, Insurance, and Indemnity .......................................................................... 78 
15 
LITERATURE REFERENCES ............................................................................... 79 
16 
APPENDICES ......................................................................................................... 81 
Appendix A Prohibited and Restricted Medicationsa ............................................................ 81 
Appendix B Prohibited and Restricted Concomitant Medications: Inhibitors and Inducers 
of Cytochrome P450 Enzyme 3A4 .......................................................................... 86 
Appendix C Criteria for Identifying Potentially Clinically Important Laboratory Values.... 88 
Appendix D Criteria for Potentially Clinically Important ECG Values ................................ 89 
Appendix E Criteria for Identifying Additional ECG Measurements of Potential Clinical 
Relevance. To be Used for Medical Monitoring Purposes ...................................... 90 
Appendix F Criteria for Potentially Clinically Important Vital Signs................................... 91 
Appendix G Syncope Adverse Event Questions ................................................................... 92 
Appendix H Somnolence Adverse Event Questions ............................................................. 93 
 

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LIST OF TABLES 
Table S-1 
Schedule of Events and Assessments for ACP-103-070 
17 
Table 6–1 
Safety Laboratory Evaluations 
60 
Table 6–2 
Blood Collection Volume Limits in Affected Children 
61 
Table 6–3 
Blood Collection Volumes for Safety Labs (6- through 17-year-olds) 
62 
Table 6–4 
Blood Collection Volumes for Safety Labs (5-year-olds) 
62 
 
LIST OF FIGURES 
Figure S–1 
Schematic of Study Design for ACP-103-070 ...................................................... 16 
 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Term 
Definition 
5-HT 
5-hydroxytryptamine (serotonin) 
5-HT2A receptor 
5-hydroxytryptamine (serotonin) receptor subtype 2A 
5-HT2C receptor 
5-hydroxytryptamine (serotonin) receptor subtype 2C 
ABC 
Aberrant Behavior Checklist 
ABC-I 
Aberrant Behavior Checklist–Irritability 
AC-279 
N-desmethyl-pimavanserin, major metabolite of pimavanserin 
AE 
adverse event 
ASD 
autism spectrum disorder 
ASR 
accurate symptom reporting 
AUC 
area under the plasma concentration-time curve 
AUCτ 
area under the plasma concentration-time curve during any dosing 
interval at steady state 
BMI 
body mass index 
CGI-I 
Clinical Global Impression–Improvement 
CGI-S 
Clinical Global Impression–Severity 
CGSQ 
Caregiver Strain Questionnaire 
CFR 
Code of Federal Regulations 
Cmax 
maximum (peak) observed drug concentration 
Cmax-ss 
Cmax at steady state 
C-SSRS 
Columbia–Suicide Severity Rating Scale 
DSMB 
data and safety monitoring board 
EC 
ethics committee 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
EOT 
end of treatment 
ESRS-A 
Extrapyramidal Symptom Rating Scale–Abbreviated 
ET 
early termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HDL 
high-density lipoprotein 
ICF 
informed consent form 
ICH 
International Council for Harmonisation  
IRB 
institutional review board 

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Term 
Definition 
LAR 
legally acceptable representative 
NSA-16 
Negative Symptom Assessment–16 
PANSS 
Positive and Negative Syndrome Scale 
PDP 
Parkinson’s disease psychosis 
PK 
pharmacokinetic(s) 
QD 
once daily 
QRS 
QRS interval on ECG 
QT 
QT interval on ECG 
QTc 
corrected QT interval on ECG  
QTcF 
corrected QT interval using Fridericia’s correction method 
RBS-R 
Repetitive Behavior Scale–Revised 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
TEAE 
treatment-emergent adverse event 
US 
United States 
VABS 
Vineland Adaptive Behavior Scales 

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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 
1.1.1 
Autism Spectrum Disorder  
Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder characterized 
by impairments in social interactions, communication, and restricted interests and stereotyped 
behaviors. In 2014, the Centers for Disease Control and Prevention (CDC) estimated that an 
average of 1 in 59 children in the United States (US) has an ASD. In the Diagnostic and 
Statistical Manual of Mental Disorders–Fifth Edition (DSM-5) criteria, ASD includes autistic 
disorder, Asperger’s syndrome, pervasive developmental disorder-not otherwise specified 
(PDD-NOS), and childhood disintegrative disorder (Grzadzinski et al. 2013). The etiology of 
ASD is highly genetic although environmental factors also contribute. Heritability estimates 
from family and twin studies suggest that about 90% of variance can be attributed to genetic 
factors, making ASD the neuropsychiatric disorder most affected by genetic factors 
(Levy et al. 2009). Core symptoms of ASD are usually observed by 3 years of age, although 
typical language development might delay the diagnosis of ASD. 
Beyond the variability in the presentation of core symptoms of ASD, affected individuals also 
vary with respect to associated non-ASD symptoms. Both cognitive and intellectual disabilities 
often coexist with language deficits, motor abnormalities, attentional difficulties, hyperactivity, 
and sleep disruptions. Seventy-five percent of ASD patients suffer from comorbid psychiatric 
conditions, but also a number of medical comorbidities. While the association between 
comorbidities and the severity of autism-related symptoms remains unclear (Aldinger et al. 
2015), the clinical picture of severe irritability and behavioral problems, aggravated by the 
child’s inability to verbally express discomfort or anxiety, causes families and peers greater 
distress and requires treatment. 
1.1.2 
Current Treatments for Irritability Associated With Autism Spectrum Disorder  
At present, no pharmacological treatment has been Food and Drug Administration (FDA) 
approved for treatment of core deficits in ASD. Both pharmacological and nonpharmacological 
interventions that provide partial symptomatic relief of core and associated symptoms are seen in 
clinical practice. Pharmacological treatments include psychostimulants, atypical antipsychotics, 
antidepressants, and alpha-2 adrenergic receptor agonists (Sharma et al. 2018). In the absence of 
methods to identify specific behavioral phenotypes with shared underlying pathophysiology to 
develop targeted treatment, management of irritability and maladaptive, self-injurious behaviors 

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regardless of their underlying cause becomes a priority. Consequently, the only two FDA 
approved drugs, indicated for treatment of irritability associated with autistic disorder in children 
and adolescents 5 to 17 years of age (6 to 17 years for aripiprazole, 5 to 16 years for risperidone), 
are Risperdal® (risperidone) and Abilify® (aripiprazole). However, both are associated with a 
number of serious side effects of which significant weight gain and metabolic side-effects are 
particularly prominent (McPheeters et al. 2011). Accordingly, there is a high unmet medical need 
for pharmacological treatments of both core and associated symptoms of the disorder that would 
have better efficacy and safety and tolerability profile. 
1.1.3 
Scientific Rationale 
Pimavanserin exerts its antipsychotic activity as an inverse agonist/antagonist (Vanover et al. 
2006) at 5-hydroxytryptamine (serotonin) receptor subtype 2A (5-HT2A) receptors, and to a lesser 
extent at 5-hydroxytryptamine (serotonin) receptor subtype 2C (5-HT2C) receptors. Both 
risperidone and aripiprazole are dopamine type-2 (D2) receptor antagonists but also have 
5-HT2A receptor antagonist activity (risperidone is also an inverse 5-HT2A agonist) and are 
approved for the treatment of irritability and behavioral symptoms in children with autism. 
Irritability associated with ASD is often caused by multiple underlying comorbid conditions 
(anxiety, sleep disorders, mood instability due to epilepsy, etc.) many of which are linked to 
serotonergic system dysfunction). 
The serotonin system has long been implicated in autism spectrum disorder by both peripheral 
and brain findings (Muller et al. 2016). In people with autism, brain activation differences of 
inhibitory control regions are differentially modulated by serotonin, and may partially underpin 
some of the core and associated symptoms of ASD (Daly et al. 2014). Consequently, while the 
underlying mechanism of irritability is not well established, it is possible that such modulation of 
the serotonergic system, a property shared by pimavanserin and two approved antipsychotics, is 
associated with the treatment effect on irritability associated with ASD. The involvement of 
neurotransmitters such as 5-hydroxytryptamine (serotonin) (5-HT) has been suggested 
previously in autistic disorder as increased platelet 5-HT levels were found in 40% of the autistic 
population, suggesting that hyperserotonemia may be a pathologic factor in infantile autism. 
Alterations in platelet serotonin 5-HT2A binding were also detected (Aaron et al. 2019). Perhaps 
one of the earliest neurochemical investigations of autism suggested that the mean level of 
5-HT in the whole blood of autistic children was elevated compared to levels in non-autistic 
children (Ritvo et al. 1970; Rolf et al. 1993). The many repeated observations of this difference 
have led to the “hyperserotonin hypothesis of autism” hypothesizing that ASD behavior is a 
consequence of some defect in tryptophan or 5-HT biochemistry in specific brain regions. Both 
ritanserin and cyproheptadine, two known 5-HT2 receptor antagonists, have been tried as 
monotherapy and adjunct therapy in children with irritability associated with ASD. A positive 

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effect of ritanserin, a selective 5-HT2 receptor antagonist, in children with ASD and mental 
retardation was reported mostly in reduction of psychomotor instability and impaired 
concentration and attention (Paclt and Hellerová 1993). Likewise, improvement in disruptive 
behavior was seen in an adjunctive treatment study with cyproheptadine (Akhondzadeh et al. 
2004). 
Studies in rodent models also demonstrate that the serotonin system is involved in both social 
function and repetitive behavior, the two core symptom domains of ASD. Importantly, 
risperidone and aripiprazole, both of which have significant action on the serotonin 5-HT2A 
receptor as inverse agonists/antagonists, have shown improvement in repetitive behaviors as a 
side benefit when used to treat irritability/agitation (Fung et al. 2016). 
Hence, considering that pimavanserin is a more selective 5-HT2A inverse agonist/antagonist 
without measurable activity at dopaminergic, histaminergic, adrenergic, or muscarinic receptors, 
it is plausible that pimavanserin would show efficacy (and potentially better tolerability due to 
reduced off-target effects) in the treatment of irritability associated with ASD. This is particularly 
important as children with autism usually have medical comorbidities and may be more sensitive 
to the side effects of medications especially in the context of polypharmacy. Beneficial effects on 
some of the core symptoms of ASD may also be anticipated given its 5-HT2A activity. 
Supportive Pimavanserin Data 
Although the data from recently completed adult adjunctive studies in schizophrenia provide 
limited evidence of efficacy on symptoms of interest in ASD, directly selective 5-HT2A inverse 
agonists like pimavanserin improve slow wave sleep, restore circadian rhythms, and may thereby 
alleviate irritability. It is proposed that pimavanserin’s downregulation of 5-HT2A-induced 
anxiety, supported by data from Study ACP-103-042 in patients with major depressive disorder 
and an inadequate response to antidepressant therapy, may improve depression and anxiety often 
present with a clinical picture of irritability in the pediatric population with ASD. The potential 
efficacy in social deficits has been demonstrated in greater efficacy in the social involvement 
domain of the Negative Symptom Assessment–16 (NSA-16) in the recently completed study 
adjunctive treatment of negative symptoms of schizophrenia. Finally, pimavanserin does not 
exert troublesome and persistent sedative effects that would impact overall functioning or 
already challenging school performance in this population. 
Pimavanserin’s lack of off-target activity that supports its use in this vulnerable pediatric 
population. Both short- and long-term data from completed adult studies with pimavanserin as 
monotherapy and in an adjunctive setting confirm its benign safety profile and consistent side 
effect profile. In comparison to the other approved antipsychotics, there has been no or negligible 
impact on weight, metabolic parameters, or extrapyramidal changes, and the impact on corrected 

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QT interval on ECG (QTc) prolongation even with the maximum pimavanserin dose has been 
minimal. 
1.2 
Investigational Product 
Pimavanserin is an atypical antipsychotic that is present in the investigational product (IP) 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 US for the 
treatment of hallucinations and delusions associated with Parkinson’s disease psychosis (PDP). 
Pimavanserin is a novel small molecule designed to specifically block serotoninergic 
neurotransmission mediated by the 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 in vitro. 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 non-clinical 
data, drug metabolism, pharmacokinetics (PK), efficacy, and safety. 
The clinical PK, pharmacodynamics, efficacy, and safety of pimavanserin have been evaluated in 
a total of 34 completed studies, four studies in reporting, nine otherwise ongoing studies, and one 
completed expanded-access program (EAP). As of 28 April 2020, approximately 3594 subjects 
had been exposed to pimavanserin, including 552 healthy subjects, 12 renally impaired subjects, 
25 hepatically impaired subjects, 34 adolescents with psychiatric disorders, 711 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, 433 subjects in additional studies in frail subjects 
with neurodegenerative disease and neuropsychiatric symptoms, 909 subjects diagnosed with 
schizophrenia, and 340 subjects with major depressive disorder. 
According to the most recent estimate (28 April 2020), at least 32,291 patients have received 
NUPLAZID® (pimavanserin) commercially, representing 21,001 person-years of exposure. 
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, 
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1.3.1 
Studies in Adults With Schizophrenia 
The use of pimavanserin in schizophrenia has been evaluated in three Phase 2 studies 
(ACP-103-007, ACP-103-008, and ACP-103-038) and one Phase 3 study (ACP-103-034). 
Patients completing ACP-103-034 and ACP-103-038 also had the opportunity to enroll in an 
ongoing open-label extension study (ACP-103-035). 
Studies ACP-103-007 and ACP-103-008 evaluated the efficacy of pimavanserin as concomitant 
therapy (with risperidone or haloperidol) in subjects with schizophrenia. Results of Study 
ACP-103-007 suggested a rapid onset of anti-akathisia effects with pimavanserin treatment 
(difference from placebo not statistically significant), without affecting haloperidol 
concentrations. Study ACP-103-008 demonstrated that pimavanserin 17 mg plus 
2 mg risperidone was significantly more efficacious than 2 mg risperidone plus placebo and 
similar in efficacy to standard (6 mg) risperidone. Pimavanserin 17 mg plus 2 mg risperidone 
appeared to demonstrate greater efficacy at Day 15 than either 2 mg risperidone plus placebo or 
6 mg risperidone plus placebo (or 2 mg haloperidol plus placebo). 
Study ACP-103-034 was a Phase 3, 6-week, randomized, double-blind, placebo-controlled study 
in outpatients with schizophrenia with an inadequate response to current antipsychotic treatment. 
A total of 396 subjects (198 per treatment group) were randomized across 88 sites in Europe and 
North America. Subjects were randomized to receive up to 6 weeks of adjunctive placebo or 
pimavanserin, at 20 mg once daily (QD) for Week 1, remaining at 20 mg or adjusted to 
10 or 34  mg QD over the next 2 weeks, and remaining at the same dose for the last 3 weeks. Of 
the 396 randomized subjects, 364 (91.9%) completed the study, including 190 (96.0%) in the 
placebo group and 174 (87.9%) in the pimavanserin group. 
Adding pimavanserin to existing antipsychotic treatment resulted in improvement of psychotic 
symptoms. The change from Baseline to Week 6 on the primary efficacy endpoint (Positive and 
Negative Syndrome Scale [PANSS] total score) was numerically greater in the pimavanserin 
group (-15.3) than in the placebo group (-13.4), although the difference was not statistically 
significant (mixed-effect model repeated measures [MMRM] least squares mean [LSM] 
difference: -2.1, 95% CI -4.5, 0.4, p=0.0940; Cohen’s d=0.173). A positive trend was observed 
on the key secondary endpoint, the change from Baseline to Week 6 in Clinical Global 
Impression–Severity (CGI-S) score. 
In the prespecified subgroup analysis by region, consistent positive results were observed for 
subjects enrolled in Europe on both the primary endpoint, PANSS total score (unadjusted 
p=0.0234), and the key secondary endpoint, CGI-S score (unadjusted p=0.0214). 
Notable improvements in favor of pimavanserin were seen on prespecified measures of negative 
symptoms: the secondary endpoint PANSS negative subscale score (unadjusted p=0.0474) and 

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the exploratory endpoint PANSS Marder Negative Symptoms Factor score (unadjusted 
p=0.0362). Numerical difference in favor of pimavanserin was also seen in the change from 
Baseline to Week 6 in Karolinska Sleepiness Scale score (unadjusted p=0.0265). 
Study ACP-103-038 was a Phase 2, 26-week, randomized, double-blind, placebo-controlled, 
outpatient study in subjects with schizophrenia who had predominant negative symptoms while 
on adequate treatment with an antipsychotic. A total of 403 subjects were randomized to receive 
double-blind placebo (202 subjects) or pimavanserin (201 subjects) at 83 sites in North America 
and Europe, and 346 (85.9%) subjects completed the study (pimavanserin, 172 subjects [85.6%]; 
placebo, 174 subjects [86.1%]). Treatment began at 20 mg QD pimavanserin or matching 
placebo, could be adjusted to 10-34 mg QD between Weeks 2 and 8, and then remained stable. 
Adding pimavanserin to existing antipsychotic treatment resulted in statistically significant 
improvement of negative symptoms of schizophrenia. A statistically significant improvement 
was observed in the pimavanserin group compared to the placebo group for the primary efficacy 
endpoint, the change from Baseline to Week 26 in the NSA-16 total score (p=0.0434). 
Improvement was observed in the pimavanserin group versus placebo at each postbaseline visit, 
achieving statistical significance at Week 4 (p=0.0334) and Week 20 (p=0.0067) as well as 
Week 26. In the post hoc analysis, significant superiority in the NSA-16 total score versus 
placebo was seen in pimavanserin subjects (56.9%) whose last dose level was 34 mg (p=0.0065), 
but not in subjects whose last dose level was 20 mg. 
Statistically significant improvement, at the nominal alpha level of 0.05, in NSA-16 total score 
was observed in the pimavanserin group compared to the placebo group for subjects who were 
enrolled in Europe (p=0.0266), male (p=0.0016), White (p=0.0405), had a baseline body mass 
index (BMI) <25 kg/m2 (p=0.0356), had schizophrenia duration >5 years (p=0.0009), had a 
duration of negative symptoms of schizophrenia >5 years (p=0.0005), or were markedly or 
severely ill, as defined by Clinical Global Impression Schizophrenia Scale–Severity 
(CGI-SCH-S) of negative symptoms score ≥5 (p=0.0199). Related clinical subgroups showed a 
similar magnitude of treatment effects for pimavanserin, but differences between treatment arms 
were smaller. However, the lack of separation was largely driven by higher responses in the 
placebo treatment group. 
At Week 26, more subjects in the pimavanserin group compared to placebo were responders, 
based on percentage improvement on NSA-16 total score (46.7% vs. 41.8% of subjects with 
≥20% improvement and 28.1% vs. 25.4% of subjects with ≥30% improvement). The change in 
NSA-16 domain scores from Baseline to Week 26 was numerically greater in the pimavanserin 
group for each domain score, with statistically significant improvement in the social involvement 
domain (p=0.0111). 

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Overall, safety results demonstrated that pimavanserin was generally safe and well-tolerated in 
subjects with schizophrenia.  
1.3.2 
Phase 1 Study in Adolescents With Psychiatric Disorders 
The PK profile of pimavanserin was evaluated in a Phase 1, open-label, multiple ascending dose 
(10, 20, or 34 mg) study in adolescents (male or female adolescents between 13 and <18 years) 
with psychiatric disorders (ACP-103-050). When adjusted for weight at Baseline, pimavanserin 
steady state systemic exposure was approximately dose proportional over the studied dose range 
(10 to 34 mg). There were no consistent differences in pimavanserin or N-desmethyl-
pimavanserin, major metabolite of pimavanserin (AC-279) Cmax-ss and AUCτ between the age 
subsets; however, small differences observed were likely due to weight and not age. 
Accumulation of pimavanserin (approximately 3- to 5-fold overall) and AC-279 (approximately 
13- to 18-fold) is consistent with adults and was expected based on the known respective 
half-lives (57 hours and 200 hours) relative to dosing interval. The parent (pimavanserin) to 
metabolite (AC-279) steady state ratio for Cmax-ss and AUCτ was comparable across dose cohorts 
and ranged from 120% to 151%. These values are comparable to those in adults confirming the 
lack of difference in metabolism between adults and adolescents. 
Additional information on previous pimavanserin clinical studies is provided in the pimavanserin 
Investigator’s Brochure and in the US package insert for NUPLAZID® (pimavanserin) for oral 
use. 
1.4 
Study Rationale 
Irritability associated with ASD is often caused by multiple underlying comorbid conditions, 
many of which are linked to serotonergic system dysfunction. Based on the efficacy of two 
approved antipsychotics with 5-HT2A antagonism (and inverse 5-HT2A agonism in case of 
risperidone) it is hypothesized that pimavanserin, a more selective 5-HT2A inverse 
agonist/antagonist, may be effective in the treatment of irritability and other ASD symptoms. 
1.4.1 
Rationale for Study Design 
This protocol describes an open-label extension study to determine the long-term safety and 
tolerability of pimavanserin for the treatment of irritability associated with ASD. The study 
follows a 6-week, Phase 2, dose ranging, randomized, double-blind, placebo-controlled study in 
pediatric patients (5 through 17 years of age) with a diagnosis of ASD will evaluate the efficacy, 
safety, and tolerability of pimavanserin by dose level (high pimavanserin dose and low 
pimavanserin dose). 
While the focus of the double-blind study is to assess the efficacy of selected doses of 
pimavanserin versus placebo, evaluate the overall clinical benefit in various symptom domains 

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and functioning, and obtain short-term safety and tolerability data, the purpose of this open-label 
extension is to obtain long-term information on the safety and tolerability of pimavanserin in 
children and adolescents. Exploratory information about the sustained efficacy of pimavanserin 
will also be collected in the efficacy assessments throughout the study. The primary endpoint is 
treatment-emergent adverse events (TEAEs). 
Examining pimavanserin long-term safety, tolerability, and efficacy is of critical importance to 
eventually help clinicians make an informed decision on pharmacotherapy for patients. 
1.4.2 
Rationale for Dose Selection 
Selection of the pimavanserin high dose (34 mg for children and adolescents 13 through 
17 years, and 20 mg for children 5 through 12 years) is based on achieving the same systemic 
exposure (maximum (peak) observed drug concentration [Cmax] and area under the plasma 
concentration-time curve [AUC]) in adults with pimavanserin 34 mg once daily that consistently 
demonstrated efficacy and safety in the adult population in several psychiatric conditions. 
Specifically, data from studies in Parkinson’s disease psychosis, dementia-related psychosis, 
major depressive disorder, and schizophrenia, show that pimavanserin 34 mg QD is the more 
effective dose for adults. Similarly, exposure-response analyses consistently demonstrated that 
higher pimavanserin exposure is associated with greater response across all studied indications. 
Exposure associated with the 34 mg dose in adults was thus considered the “target exposure”. 
Stochastic simulations using actual and virtual adolescent (13 through 17 years) and adult 
populations (18 through 49 years) were undertaken to help guide pimavanserin dose selection in 
pediatric subjects within the age range of 5 through 17 years (ACP-103-MS-010) that are likely 
to achieve the target exposure. The results showed that compared to the adult population 
(18 through 49 years), steady-state AUC for the 34 mg dose was largely consistent across all age 
groups (5 through 49 years) and body weight groups (16 through >75 kg) with comparable 
median values and considerable overlap in the distribution of AUC values across the different 
groups. 
Steady state Cmax, following 34 mg dosing, was progressively higher with decreasing age, as well 
as with decreasing body weight. A 20 mg dose produced Cmax exposures in children 5 through 
9 years of age that were comparable to the 34 mg dose in the adolescents and adults. Because 
body-weight adjusted PK for children 12 years and younger are usually different from 
adolescents and adults for similar doses, a conservative approach was adopted and the older 
children (10 through 12 years) were grouped with the younger children (5 through 9) to receive 
the lower doses. As such, the selected high dose that achieves the target exposure (equivalent to a 
34 mg dose in adults) for children 5 through 12 years is 20 mg. For children and adolescents 
13 through 17 years the selected dose is 34 mg to achieve the target exposure 

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The pimavanserin low dose (20 mg for children and adolescents 13 through 17 years of age, and 
10 mg for children 5 through 12 years of age) was selected to reduce the extent of exposure 
overlap between the low and high dose, while offering the potential to explore efficacy in ASD 
patients with lower pimavanserin doses/exposures that were well tolerated in the adult population 
in various psychiatric indications. 
Rationale for dosing periods 
To ensure safe rollover of those subjects previously on placebo and minimize the risks of 
potential unblinding all eligible subjects will receive pimavanserin “low dose” for the first two 
weeks of the study. Subjects who were on “
 dose” during the antecedent double-blind study 
will likely experience 
 efficacy during this period, due to the long half-life 
of pimavanserin, and having achieved steady state by the end of the antecedent double-blind 
study. At the Week 2 visit, the dose may be increased to pimavanserin “high dose”, based on the 
Investigator’s assessment of clinical response. 
After the Week 2 visit, and up to and including the Week 20 visit, dose adjustments, either 
increases or decreases, may be made at any clinic visit (scheduled or unscheduled), based on the 
Investigator’s assessment of clinical response and tolerability. 
No further dose adjustments are allowed after the Week 20 visit. 
1.5 
Benefit/Risk Assessment 
1.5.1 
Known Potential Risks 
The Prescribing Information for NUPLAZID® (pimavanserin) tablets and capsules 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.  
The Warnings and Precautions section of the Prescribing Information for pimavanserin also 
includes information about QT interval on ECG (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 
CCI
CCI

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symptomatic bradycardia, hypokalemia or hypomagnesemia, and the presence of congenital 
prolongation of the QT interval. 
NUPLAZID is contraindicated in patients with a history of a hypersensitivity reaction to 
pimavanserin or any of its components. Rash, urticaria, reactions consistent with angioedema 
(e.g., tongue swelling, circumoral edema, throat tightness, and dyspnea) have been reported. In 
addition, adverse reactions of somnolence, falls, agitation, and aggression have been reported 
during postapproval use of NUPLAZID. 
Pimavanserin has not yet been studied as monotherapy in children and adolescents therefore no 
data are available on specific risks in this population. In adolescents treated with pimavanserin in 
combination with other psychotropics, pimavanserin dose-related QTc prolongation, and a trend 
for higher exposure with decreasing age and decreasing body weight, have been observed. 
1.5.2 
Known Potential Benefits 
Pimavanserin has not been studied in children and adolescents with ASD, thus there are no 
known benefits. It has shown antipsychotic properties in the indications of PDP, and is currently 
being evaluated as adjunctive treatment in adults with negative symptoms of schizophrenia. 
Based on the mechanism of action of pimavanserin, potential benefits may include its clinical 
utility in the treatment of irritability and other symptoms of ASD. This is particularly the case 
with subjects previously randomized to placebo. Subjects may benefit from the increased 
medical care and attention for the study duration. 
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 long-term safety and tolerability of pimavanserin after 52 weeks of 
treatment in children and adolescents with ASD 
2.1.1 
Primary Endpoints 
• Treatment-emergent adverse events (TEAEs) 
Safety will also be evaluated by analyses of the following: 
• Vital signs 
• Weight and body mass index (BMI) 
• 12-lead electrocardiograms (ECGs) 
• Physical examination results 

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• Clinical laboratory tests (including urinalysis) and hormonal assessments 
• Columbia–Suicide Severity Rating Scale (C-SSRS) 
• Extrapyramidal Symptom Rating Scale-Abbreviated (ESRS-A) 
2.2 
Secondary Objective 
• To evaluate the continued response to long-term pimavanserin treatment in children and 
adolescents with ASD 
2.2.1 
Secondary Endpoint 
• Proportion of subjects who have at least 25% reduction from the antecedent study 
Baseline in the Aberrant Behavior Checklist–Irritability (ABC-I) subscale score AND a 
Clinical Global Impression–Improvement (CGI-I) of irritability score of 1 (very much 
improved) or 2 (much improved) compared to the antecedent study baseline status at 
Week 52. 
2.3 
Exploratory Objectives 
• To evaluate the continued benefit of long-term pimavanserin treatment on the symptoms 
of ASD, in children and adolescents with ASD in the following clinical areas: 
o Aberrant Behavior Checklist (ABC) symptom domains 
o Maintenance of benefit 
o Response to treatment 
2.3.1 
Exploratory Endpoints 
• Change from Baseline at Week 52 in the caregiver-rated ABC subscale scores: 
o Irritability 
o Stereotypic behavior 
o Lethargy 
o Hyperactivity 
o Inappropriate speech 
• Change from Baseline at Week 52 in the Clinical Global Impression–Severity (CGI-S) of 
irritability score 
• CGI-I of irritability score from the antecedent study Baseline at Week 52 
• Change from Baseline at Week 52 in the Caregiver Strain Questionnaire (CGSQ) 
• Proportion of subjects who have at least 25% reduction from the antecedent study 
Baseline in the ABC-I subscale score (ABC-I responders) at Week 52 

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• Proportion of subjects who have CGI-I of irritability score of 1 (very much improved) or 
2 (much improved) compared to the antecedent study baseline status (CGI-I of irritability 
responders) at Week 52 
3 STUDY DESCRIPTION 
3.1 
Overview of Study Design 
This study will be conducted as a 52-week, open-label extension study of the antecedent 
double-blind study to determine the long-term safety and tolerability of pimavanserin for the 
treatment of irritability associated with ASD in children and adolescents (5 through 17 years old 
at the time of enrolling into the antecedent double-blind study). Approximately 60 global sites 
and approximately eight countries will participate in this study. 
The duration of participation for individual study subjects will be up to approximately 56 weeks. 
The total duration of exposure to pimavanserin may be greater than 52 weeks (e.g., up to 
58 weeks) as some subjects have been treated with pimavanserin in an antecedent double-blind 
study. 
The study will have two periods: 
• Open-label treatment period (52 weeks) 
• Safety follow-up period (at least 30 days) 
Subjects who have completed the antecedent double-blind study and who have shown 
no significant worsening of symptoms at the end of the study as evidenced by the CGI-I of 
irritability will be included in this long-term extension study. 
Study ACP-103-070 subjects must be consented prior to the procedures being performed at the 
End of Treatment (EOT) visit in the antecedent double-blind study. Procedures performed at the 
EOT visit of the antecedent double-blind study will be carried over to the ACP-103-070 study to 
be included as baseline information, and this visit will be considered the Baseline Visit (Visit 1) 
of the ACP-103-070 study. 
The study start date is defined as the date the first subject is enrolled, which is the baseline visit 
date for the first subject for this open-label study. 
The primary completion date is the last date that subject data was collected for the primary 
outcome measure. 
The study completion date (End of Study) 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 4.6. 

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3.1.1 
Open-label Treatment Period (52 Weeks) 
Subjects will be stratified by age group (5- through 12-year-olds or 13- through 17-year-olds). 
Subjects will remain in the age group they were stratified into during the antecedent double-blind 
study, throughout the OLE study. 
All subjects will receive QD doses of pimavanserin over 52 weeks of treatment. Subjects will 
start at the “low dose” for their age group (10 mg for 5- through 12-year-olds; 20 mg for 
13- through 17-year-olds) for the first two weeks. At the Week 2 visit, the daily dose may be 
adjusted to the “high dose” for their age group (20 mg for 5- through 12-year-olds; 34 mg for 
13- through 17-year-olds), based on the Investigator’s assessment of clinical response. After the 
Week 2 visit and up to and including the Week 20 visit, dose adjustments, either increases or 
decreases, may be made at any clinic visit (scheduled or unscheduled), based on the 
Investigator’s assessment of clinical response and tolerability. No further dose adjustments are 
allowed after the Week 20 visit. 
During the treatment period, clinic visits will be conducted at Baseline and Weeks 2, 6, 12, 20, 
28, 36, 44, and 52, or upon early termination (ET) from the study. 
Study drug will be dispensed to the subject to take home at the Baseline visit and at each 
subsequent clinic visit. The subject and their parent/legally acceptable representative (LAR) will 
be provided instructions for the subject’s first dose of study drug the day after the Baseline visit. 
It is recommended that the subject take the study drug at approximately the same time each day 
as a single, oral dose. 
All concomitant medications should remain at a stable dose throughout the study, if possible, 
except as described in Appendix A to minimize confounding interpretation of any correlating 
pimavanserin dose changes, including treatment discontinuations. 
3.1.2 
Safety Follow-up Period (30 Days) 
A follow-up safety assessment will be conducted by telephone call at least 30 days after the last 
dose of study drug. The safety follow-up assessment will not be done if the subject (and/or 
parent/LAR) withdraws consent to participate in all parts of the study. 
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 to enter this open-label extension study. 

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4.1 
Inclusion Criteria 
A subject must meet all of the following inclusion criteria to be eligible for participation in the 
study: 
Study Population  
1. Has completed the treatment period of the antecedent double-blind study 
2. Informed consent prior to the conduct of any study procedures is required as follows: 
a. The subject should provide written or oral assent if deemed able by the 
Investigator. 
b. The subject’s parent/LAR must provide written consent. The subject’s 
parent/LAR must be considered reliable by the Investigator, able to complete 
assessments regarding the subject’s development and behavior throughout the 
study, and able to help ensure compliance with study treatment, study visits, and 
protocol procedures.  
c. If a person other than the parent/LAR has been designated as a caregiver for the 
purpose of providing input for caregiver-reported scales, that person must also 
provide written consent. Such a designee should be a family member, adult and 
responsible, living with or in very frequent contact with the subject participating 
in the study, who is committed to providing responses for the caregiver-reported 
scales for the duration of the study. 
The process of obtaining informed consent will be conducted in accordance with 
institutional review board (IRB) or ethics committee (EC) policy and applicable local law 
3. In the Investigator’s opinion, the subject, to the best of his/her ability, the parent/LAR, 
and the designated caregiver (if applicable, and in accordance with IRB or EC policy and 
applicable local law) are able to understand the nature of the study, follow protocol 
requirements and be willing to comply with study drug administration requirements 
Psychiatric Diagnosis  
4. Continues to be both clinically stable and not at imminent risk of suicide or injury to self, 
others, or property, in the opinion of the Investigator 
5. Continues to be medically stable at enrollment, in the opinion of the Investigator 

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Contraceptives 
6. Female subjects who participate in this study must either be unable to become pregnant 
(e.g., premenarchal, surgically sterile, etc.) -OR- must agree to use two clinically 
acceptable methods of contraception (e.g., oral, intrauterine device [IUD], diaphragm 
plus spermicide, injectable, transdermal or implantable contraception) during the 
treatment period, and for at least 45 days after last dose. 
All female subjects of childbearing potential must have a negative urine human chorionic 
gonadotropin (hCG) pregnancy test at Baseline and all clinic visits. Females of 
childbearing potential are defined as females who have begun menstruating. 
 
4.2 
Exclusion Criteria 
A subject must meet none of the following exclusion criteria to be eligible for the study: 
Study Population 
1. Subject or parent/LAR is judged by the Investigator to be inappropriate for the study 
(e.g., significantly noncompliant in the antecedent double-blind study) 
CNS, Psychiatric, and Illicit Drug Use Criteria 
2. Requires treatment with a medication prohibited by the protocol, including concomitant 
psychotropic drugs targeting irritability, including those used off-label (clonidine, 
guanfacine, and propranolol; lithium, valproate), medications that prolong the QT interval; 
and strong cytochrome P450 (CYP) 3A4 enzyme (CYP3A4) inhibitors and inducers 
(see Appendix A and Appendix B) 
3. Is at a significant risk of suicide, or is a danger to self or others, in the opinion of the 
Investigator based upon all available sources of information including C-SSRS (positive 
answer to suicidal ideation questions 4 or 5 [or positive answer to suicidal behavior 
questions at Baseline]) 
4. Is at risk of significant violent behavior to the extent that participation would pose an 
undue risk to other patients, caregivers, or others in the opinion of the Investigator 
5. Has a positive urine drug test at Baseline. For study eligibility, the urine toxicology (drug) 
screen (UDS) must be negative for any substance for which the subject does not have a 
valid prescription. 

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Medical Criteria 
6. Has developed a serious and/or unstable psychiatric, neurologic, cardiovascular (e.g., long 
QT syndrome, torsade de pointes, unstable cardiac syndrome or syncope, congestive heart 
failure, ongoing uncorrected hypokalemia or hypomagnesemia, non-sustained or sustained 
ventricular tachycardia), 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, or has 
major surgery planned during the study 
7. Has experienced any change in medical or treatment status that may increase the risk 
associated with taking pimavanserin, would interfere with safety assessments, or would 
confound the interpretation of study results, based on the Investigator’s judgment 
8. For age <13 years, a resting position (sitting or supine) systolic (SBP) and/or diastolic 
blood pressure (DBP) level ≥90th percentile for gender-specific age and height charts 
from the National Heart and Lung Institute (NHLI), at Baseline. For age ≥13 years a 
resting position (sitting or supine) SBP ≥120 mmHg and/or a DBP ≥80 mmHg, at 
Baseline.  
9. Has a clinically significant abnormal ECG at Baseline or any of the following cardiac 
conduction abnormalities: 
a. Corrected QT interval using Fridericia’s correction method (QTcF) ≥450 ms 
b. PR interval on ECG >220 ms 
c. Evidence of second- or third-degree atrioventricular block 
d. Evidence of complete left bundle branch block 
e. Intraventricular conduction delay with QRS interval on ECG (QRS) >110 ms  
f. QRS or T wave morphology that could, in the Investigator’s opinion, render 
QT interval assessment unreliable 
g. Sick sinus syndrome 
h. Non-sinus rhythm 
i. Resting heart rate <50 beats per minute 
One repeat set of triplicate ECGs is allowed at Baseline. 
10. Weight <15 kg 
11. In Italy only: Has a sensitivity to any compound present in pimavanserin or any 
metabolites or compounds listed in the Investigator’s brochure as being present in this 
medication 

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4.3 
Screen Failures 
The Investigator will maintain a screening log to record details of all participants screened and to 
confirm eligibility or record reasons for screening failure, as applicable. 
4.4 
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 parent/LAR) 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 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 parent/LAR) 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. 
Every reasonable effort should be made to keep the same parent/LAR or designee who 
completed the observer’s study scales in study ACP-103-069 to complete them throughout study 
ACP-103-070 in order to maintain the validity of the scoring.  
4.5 
Subject Discontinuation 
Subjects may be discontinued from the study treatment for a number of reasons, including, but 
not limited to, those listed below: 
• Adverse event 
• Death 
• Lack of efficacy 
• Lost to follow-up (Section 4.6) 
• Non-compliance with study drug 
• Physician decision 
• Pregnancy 
• Protocol deviation 

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• Study terminated by sponsor 
• Use of prohibited medication 
• Withdrawal of consent by subject (or by parent/LAR) 
• Other 
4.5.1 
Handling of Subject Discontinuation During the Treatment Period 
Unless the subject (or parent/LAR) has withdrawn consent from all components of the study, 
every reasonable effort should be made to complete Visit 6/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 electronic case report form 
(eCRF). 
If a subject is discontinued from the study treatment 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 continue 
to be followed for safety, serious adverse events (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. 
4.6 
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 parent/LAR is unable to be contacted by the 
study site after repeated attempts.  
Every reasonable effort should be made to contact the subject and parent/LAR and will include a 
minimum of three documented phone calls 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. 
4.7 
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. 

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4.8 
Prior and Concomitant Therapy 
All medications used from study baseline until completion of the safety follow-up visit are to be 
recorded. 
4.8.1 
Prior Medication 
Prior medication is defined as any medication with a stop date prior to the date of the first dose 
of study drug. 
4.8.2 
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. 
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). Non-pharmacological 
treatment should remain the same throughout the study duration. 
The Investigator may prescribe appropriate medication to treat AEs (see Appendix A and 
Appendix B). 
4.8.2.1 
Permitted, Restricted, and Prohibited Medications 
Prohibitions and restrictions for concomitant medications should be followed between the 
Baseline visit and Visit 6/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. The Investigator may 
prescribe appropriate medication to treat AEs. 
Medications that can prolong QT interval are prohibited (or restricted) as specified in 
Appendix A. 
Permitted concomitant medications should remain at a stable dose throughout the treatment 
period.  
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. 

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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. 
4.8.3 
Rescue Medications, Treatments, and Procedures 
Rescue medication, as determined by the Investigator, is permitted for a maximum of 
7 consecutive days, provided it is consistent with the prohibitions and restrictions in Appendix A 
and Appendix B. 
5 INVESTIGATIONAL PRODUCT 
5.1 
Investigational Product Description 
The investigational product will be pimavanserin 10 mg (provided as 1×10 mg capsule), 
pimavanserin 20 mg (provided as 1×20 mg capsule), or pimavanserin 34 mg (provided as 
1×34 mg capsule). Capsules will be administered orally as a single dose once daily. 
Pimavanserin dosages below: 
Pimavanserin 10 mg (provided as 1×10 mg capsule) 
Pimavanserin 20 mg (provided as 1×20 mg capsule) 
Pimavanserin 34 mg (provided as 1×34 mg capsule) 
5.1.1 
Formulation, Appearance, Packaging, and Labeling 
The Sponsor will supply pimavanserin 10 mg, 20 mg and 34 mg capsules. 
Pimavanserin 10 mg, 20 mg, and 34 mg capsules, are white to off-white capsules.  
Each 34 mg pimavanserin capsule contains 40 mg of pimavanserin tartrate, which is equivalent 
to 34 mg of pimavanserin free base.  
Each 20 mg pimavanserin capsule contains 23.5 mg of pimavanserin tartrate, which is equivalent 
to 20 mg of pimavanserin free base.  
Each 10 mg pimavanserin capsule contains 11.8 mg of pimavanserin tartrate, which is equivalent 
to 10 mg of pimavanserin free base.  

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Inactive ingredients include magnesium stearate, microcrystalline cellulose, and the components 
of the capsule shell (hypromellose and titanium dioxide). 
Pimavanserin capsules are manufactured under current Good Manufacturing Practice. 
Pimavanserin capsules will be provided in kits containing two blister cards, with each card 
containing 10 capsules in a blister strip (total 20 capsules per kit). Each kit will be labeled as 
required per country requirement. 
During the treatment period, study drug will be distributed in a quantity sufficient to ensure the 
subject has an adequate supply of study drug between study visits.  
5.1.2 
Product Storage and Stability 
Investigational product must be stored in a secure area with restricted access, not above 
25°C (77°F), and according to local and national regulations. To prevent potential capsule color 
fading, protect from light. 
5.1.3 
Dosing and Administration 
At the Baseline visit of Study ACP-103-070, study drug will be dispensed to the subject to take 
home. The subject and their parent/LAR will be provided instructions for the subject’s first dose 
of study drug on the day after the Baseline visit.  
Each daily dose consists of one capsule. Subjects should be instructed to take one capsule, orally, 
once daily, in the morning, at the same time every day. Subjects should be instructed to not to 
open the capsules. The capsules may be taken with or without food. 
5.1.3.1 
Dose Modification  
All subjects will receive the “low dose” for their age group for the first two weeks of the study. 
After the Week 2 visit the dose may be increased to the “high dose” based on the Investigator’s 
assessment of clinical response. After the Week 2 visit, and up to and including the 
Week 20 visit, dose adjustments, either increases or decreases, may be made at any clinic visit 
(scheduled or unscheduled), based on the Investigator’s assessment of clinical response and 
tolerability. 
No further dose adjustments are allowed after the Week 20 visit. 
5.1.4 
Blinding 
This is an open-label study. 
5.1.5 
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 

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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. 
5.1.6 
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 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. 
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, as allowed by country specific regulations. 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. 
For scales that require caregiver input, the caregiver should be the parent/LAR or designee. A 
designee should be a family member, adult and responsible, living with or in very frequent 

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contact with the subject participating in the study, who is committed to providing responses for 
the caregiver-reported scales for the duration of Studies ACP-103-069 and ACP-103-070. 
Caregivers providing input for the ABC, RBS-R, and CGSQ scales will be trained in accurate 
symptom reporting (ASR) prior to completing the scales. ASR training should be done at 
Screening in the antecedent study (Study ACP-103-069) before the caregiver completes any 
scales, and repeated whenever there is a change in caregiver or if the site feels a caregiver 
requires retraining. 
6.1 
Baseline Assessments 
Subject consent for the present study must be obtained prior to the final procedures being 
performed at the EOT visit of the antecedent double-blind study and before any new procedures 
are performed for Study ACP-103-070. Data from the EOT procedures of antecedent 
double-blind study will be carried over to the ACP-103-070 study to be included as baseline 
information for the present study and this visit will be considered Baseline (Visit 1). Subject 
eligibility will be assessed by the site and the Sponsor through an eligibility review process. 
6.1.1 
Physical Examination and Self- or Caregiver-reported Tanner Staging 
See Section 6.4.1 
6.1.2 
Vital Signs 
See Section 6.4.2. 
6.1.3 
Height, Weight, and Body Mass Index 
See Section 6.4.1. 
6.1.4 
12-lead ECG 
See Section 6.4.3. 
6.1.5 
Clinical Laboratory Tests 
See Section 6.4.4. 
6.1.6 
Pregnancy Test 
See Section 6.4.4. 
6.1.7 
Urine Toxicology (Drug) Screen 
See Section 6.4.4 
6.1.8 
Aberrant Behavior Checklist 
See Section 6.2.1. 

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6.1.9 
CGI-S 
See Section 6.2.2. 
6.1.10 
CGI-I 
See Section 6.2.3 
6.1.11 
RBS-R 
See Section 6.2.4. 
6.1.12 
VABS-Socialization 
See Section 6.2.5. 
6.1.13 
CGSQ 
See Section 6.2.6. 
6.1.14 
C-SSRS 
See Section 6.3.1 
6.1.15 
ESRS-A 
See Section 6.3.2 
6.1.16 
Concomitant Medications and Adverse Events 
All medications used from Baseline until completion of the safety follow up visit are to be 
recorded (Section 4.8).  
All adverse events (Section 7) from Baseline until completion of the safety follow up visit are to 
be recorded. 
6.2 
Efficacy Assessments 
6.2.1 
Aberrant Behavior Checklist 
The Aberrant Behavior Checklist (ABC) is a caregiver-rated scale comprised of five empirically-
derived subscales encompassing 58 items that describe various behavior problems (Aman et al. 
1985; Kaat et al. 2014). The subscales have been labeled: 
I. Irritability (irritability, agitation, and crying) (15 items) 
II. Lethargy (lethargy and social withdrawal) (16 items) 
III. Stereotypic Behavior (7 items) 
IV. Hyperactivity (hyperactivity and noncompliance) (16 items) 
V. Inappropriate Speech (4 items) 

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The ABC will be administered at Baseline, and at all visits from Week 2 through Week 52. 
A score for each item ranges from 0 indicating “not at all a problem” to 3 indicating “the 
problem is severe in degree”. Subscale scores are calculated by summing the items within that 
subscale. Higher scores indicate greater impairment.  
The reliable caregiver identified upon subject’s ACP-103-070 Baseline visit will complete the 
rating scale. A clinician will be available to assist the caregiver during completion of the 
questionnaire. 
This assessment will take approximately 10 to 20 minutes to complete. 
The same rater or clinician should perform the ABC throughout the study together with the same 
caregiver as established at the Baseline visit. 
6.2.2 
CGI-S 
The CGI-S is a clinician-rated, 7-point scale that is designed to rate the severity of the subject's 
illness, in this case irritability associated with ASD, at the time of assessment, making use of the 
clinician’s judgment and past experience with subjects who have the same disorder (Guy 1976). 
The CGI-S of irritability will be administered at Baseline, and at all visits from Week 2 through 
Week 52. The same clinician should administer the CGI-S of irritability throughout the study as 
established at the Baseline visit. 
6.2.3 
CGI-I 
The CGI-I is a clinician-rated, 7-point scale that is designed to assess how much the subject’s 
illness, in this case irritability associated with ASD, has improved or worsened relative to a 
baseline state at the beginning of the intervention (Guy 1976). In this study, improvement or 
worsening is assessed relative to the baseline status in the antecedent double-blind study. 
The CGI-I of irritability will be administered at Baseline, and at all visits from Week 2 through 
Week 52. 
The same clinician should administer the CGI-I of irritability throughout the study as established 
at the Baseline visit. 
6.2.4 
Repetitive Behavior Scale–Revised 
The Repetitive Behavior Scale–Revised (RBS-R) (Lam and Aman 2007) is a 43-item 
parent/caregiver-facing questionnaire. Items are conceptually grouped into six subscales: 
• stereotyped behavior (movements with no obvious purpose that are repeated in a similar 
manner) 
• self-injurious behavior (actions that cause or have the potential to cause redness, 
bruising, or other injury to the body) 

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• compulsive behavior (behavior that is repeated and performed according to a rule or 
involves things being done “just so”) 
• ritualistic behavior (performing activities of daily living in a similar manner) 
• sameness behavior (resistance to change, insisting that things stay the same) 
• restricted behavior (limited range of focus, interest, or activity) 
Items are rated on a 4-point Likert scale ranging from (0) “behavior does not occur” to 
(3) “behavior occurs and is a severe problem”, and raters are asked to refer to the previous month 
when completing the scale. 
The RBS-R will be administered at Baseline, and at the Week 12, Week 28, Week 36, Week 44, 
and Week 52 visits. This scale will take approximately 20 to 30 minutes to complete. 
The same rater or clinician should perform the RBS-R throughout the study together with the 
same caregiver as established at the Baseline visit.  
6.2.5 
Vineland Adaptive Behavior Scales–Socialization 
The Vineland Adaptive Behavior Scales (VABS) is a parent/caregiver-facing measure of adaptive 
behavior, organized into three domains: communication, daily living skills, and socialization 
(Sparrow et al. 2016). Only the socialization domain will be used in this study. 
The VABS-Socialization will be administered at Baseline, and at the Week 12, Week 28, 
Week 36, Week 44, and Week 52 visits.  
The same rater or clinician should perform the VABS-Socialization together with the same 
caregiver throughout the study as established at baseline visit.  
6.2.6 
Caregiver Strain Questionnaire  
The CGSQ (Brannan et al. 1997) is a 21-item parent/caregiver-facing questionnaire of 
self-reported strain experienced since last visit by parents/caregivers and families of youth with 
emotional problems. Responses are on a 5-point Likert scale ranging from (1) “not at all a 
problem” to (5) “very much a problem”. 
The following areas of strain are included: 
• disruption of family life and relationships 
• demands on time 
• negative mental and physical health effects for any member 
• financial strain 
• sacrifice 

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• disruption of social/community life 
• worry and guilt 
• fatigue and strain 
• embarrassment 
• child-caregiver relationship 
The CGSQ will be administered at Baseline, and at the Week 6, Week 20, Week 28, Week 36, 
Week 44, and Week 52 visits. 
The same rater or clinician should perform the CGSQ together with the same caregiver 
throughout the study as established at Baseline visit.  
6.3 
Safety Scales 
6.3.1 
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 Since Last Visit version 
will be administered at Baseline, and at all subsequent visits. The C-SSRS results for each 
subject should be reviewed by the Investigator at each visit. If at any time the C-SSRS results for 
a given subject reveal potential suicidality, then the Investigator should assess the clinical 
significance of such results. If a clinically significant risk of suicidality is identified for a subject, 
then the Investigator should discontinue the subject and implement appropriate treatment 
(Sections 4.4 and 3.1.2). 
The C-SSRS will be administered at Baseline, at all visits from Week 2 through Week 52, and at 
unscheduled visits. 
The same rater or clinician should perform the C-SSRS together with the same caregiver 
throughout the study as established at Baseline visit.  
6.3.2 
Extrapyramidal Symptom Rating Scale–Abbreviated 
The ESRS (Chouinard and Margolese 2005) was developed to assess drug induced movement 
disorders such as parkinsonism, akathisia, dystonia and tardive dyskinesia with established 
reliability, validity, and sensitivity. It consists of a questionnaire of parkinsonian symptoms, 
physician examination of parkinsonism, dyskinetic movements, and global impression of tardive 
dyskinesia. The ESRS-A, an accepted modified form of the original ESRS, will be used during 

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the study to monitor for any worsening in extrapyramidal symptoms or signs at scheduled and 
unscheduled visits. 
The ESRS-A will be administered at Baseline, at all visits from Week 2 through Week 52, and at 
unscheduled visits. 
The same rater or clinician should perform the ESRS-A together with the same caregiver 
throughout the study as established at Baseline visit. 
6.4 
Safety Assessments  
As known potential class side effects of antipsychotics, the following adverse events will be 
actively monitored, including hyperglycemia, leucopenia/neutropenia/agranulocytosis, 
orthostatic hypotension/bradycardia/syncope, QTc prolongation, akathisia and other 
extrapyramidal symptoms, weight gain, and somnolence. Criteria for identifying potentially 
clinically important laboratory values, ECG values, and vital signs are presented in Appendix C, 
Appendix D, and Appendix F, respectively; and criteria for identifying additional ECG 
measurements of potential clinical relevance for Medical Monitoring purposes are presented in 
Appendix E. 
Circumstances may arise (e.g., pandemic, natural disaster, political upheaval, or technical issues) 
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. 
6.4.1 
Physical Examination and Self- or Caregiver-reported Tanner Staging 
A general physical examination will be conducted. 
Height will be measured and reported. 
Weight will be measured and reported. 
Body mass index will be calculated using the following formula: 
Weight (kg) / [height (m)]2. 
Tanner staging is a scale of physical development in children, adolescents, and adults. The scale 
defines physical measurements of development based on external primary and secondary sex 
characteristics, such as the size of the breasts, genitals, testicular volume and development of 
pubic hair (Marshall and Tanner 1969; Marshall and Tanner 1970). 

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A physical examination will be administered, and Tanner staging will be reported (either by the 
subject or the subject’s caregiver), at Baseline, and at the Week 12, Week 28, Week 44, and 
Week 52 visits. 
Height (as measured by a stadiometer), weight, and BMI will be measured at Baseline, at all 
visits from Week 2 through Week 52, and at unscheduled visits.  
6.4.2 
Vital Signs 
Vital signs will include body temperature, resting respiration rate, sitting (or supine) systolic and 
diastolic blood pressure, and pulse rate. The sitting (or supine) blood pressure should be 
measured after the subject has been sitting (or supine) for ≥3 minutes. If the initial blood 
pressure measurement is: 
• ≥90th percentile systolic and/or diastolic for gender-specific age and height charts from 
the National Heart and Lung Institute (NHLI) for subjects under 13 years or 
• ≥120 mmHg systolic or ≥80 mmHg diastolic for subjects 13 through 17 years, 
at least 5 minutes rest should be allowed after the first measurement; then two additional blood 
pressure measurements are to be performed consecutively. The average of the three blood 
pressure measurements, systolic and diastolic, is the final blood pressure measurement and this 
average is the one to be entered into the EDC. All of the three blood pressure measurements with 
documentation of the time starting the resting and the time at which the two additional blood 
pressures are measured should be source documented. 
If the subject is reporting symptoms of orthostatic hypotension when standing up after the blood 
pressure measurement, then the subject will be asked to lie down for 5 minutes, blood pressure 
and pulse rate will be measured, then the subject will be asked to stand and blood pressure and 
pulse rate measurements will be repeated after standing 1 to 3 minutes in order to measure the 
severity of the orthostatic hypotension. Vital signs will be collected at Baseline, at all visits from 
Week 2 through Week 52, and at unscheduled visits. 
6.4.3 
Electrocardiograms 
All 12-lead ECGs will be complete, standardized recordings, performed in triplicate whenever 
possible at Baseline, and at all visits from Week 2 through Week 52 visits. The involvement of 
experienced personnel in the conduction of ECG recording in this population is strongly 
recommended. 
Electrocardiograms should be performed before blood sampling or at least 30 minutes after 
blood sampling. The subject must rest in a sitting or supine position for 5 minutes before the 
ECG is obtained. Mild sedation is allowed exceptionally for ECGs (e.g., alprazolam at a 
pediatric-appropriate dose per age, and the lowest dose deemed necessary by the Investigator) 

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just in cases when the subject’s agitation/anxiety does not allow a safe and accurate measurement 
and the Investigator, with agreement from the caregiver, considers it safe and appropriate for the 
subject. ECG tracings (paper or electronic) will be reviewed and interpreted by a qualified 
clinician. ECG tracings and results (ventricular rate, PR, QRS, QT, QTcF, and corrected 
QT interval using Bazett’s correction method [QTcB] intervals) will be included in the subject's 
study records. 
Eligibility at Baseline should be based on ECG tracings collected on the study-provided 
ECG device during the visit and on the ECG central read. All ECGs will be centrally read; the 
cardiology central overread is considered final. The QTcF/QRS as well as other exclusionary 
values and abnormalities of all the tracings of adequate quality will be reviewed to determine 
eligibility. 
A maximum of one repeat ECG procedure is allowed at Baseline. 
6.4.4 
Laboratory Evaluations 
Clinical laboratory sample collection (including HbA1c) 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), carbon dioxide (CO2), chloride (Cl), phosphorus (P), 
calcium (Ca), blood urea nitrogen (BUN), creatinine (CR), glucose, albumin (ALB), 
total protein 
 In Italy only: 
 
 
 
 
 
 
 
  
o Alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl 
transpeptidase (GGT), alkaline phosphatase (ALP), total bilirubin (TBIL), lactate 
dehydrogenase (LDH) 
o Lipid panel 
CCI

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 Total cholesterol, high-density lipoprotein (HDL)-cholesterol, triglycerides, 
low-density lipoprotein (LDL)-cholesterol, cholesterol/HDL ratio, 
non-HDL cholesterol 
o HbA1c  
o Prolactin 
 Prolactin 
 
 Results will be monitored 
 
 
o Creatine kinase (CK)/creatine phosphokinase (CPK) 
• Pregnancy test 
o A urine pregnancy test should be performed at all designated visits (Table 6–1) for 
women of child-bearing potential. If positive, the result will be confirmed with a 
serum pregnancy test. 
 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, RBCs, WBCs, protein, glucose, ketones, specific gravity, pH 
o Reasonable efforts should be made to collect a urine sample from all subjects. When 
collection of a urine sample proves impractical or impossible (e.g., because the 
subject is incontinent or unable to cooperate), failure to collect a urine sample should 
be recorded in the subject’s eCRF, and will not be considered a protocol deviation. 
• Urine toxicology screen 
o Urine toxicology screen will test for controlled substances. The following controlled 
substances may be tested with a urine toxicology screen according to the schedule 
presented in Table 6–1: amphetamine, barbiturates, benzodiazepines, cocaine, 
methadone, morphine/opiates, methamphetamine, marijuana (tetrahydrocannabinol 
[THC]), phencyclidine (PCP), ecstasy (3,4-methylenedioxymethamphetamine 
[MDMA]). A negative drug screen is required for study eligibility. 
CCI
CCI

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o Subjects who test positive and have a valid prescription for a controlled substance 
may be retested if they agree to abstain from the medication for the length of their 
participation in the study. The repeat test, and any other tests, must be negative for 
them to participate in the study. 
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 (Baseline) 
CHEM, CBC, UA, urine toxicology screen and dipstick, urine 
pregnancy test  
Visit 2 (Week 2) 
Urine pregnancy test 
Visit 3 (Week 6) 
Urine pregnancy test 
Visit 4 (Week 12) 
CHEM, CBC, UA, urine pregnancy test 
Visit 5 (Week 20) 
Urine pregnancy test 
Visit 6 (Week 28) 
CHEM, CBC, UA, urine pregnancy test 
Visit 7 (Week 36) 
Urine pregnancy test 
Visit 8 (Week 44) 
CHEM, CBC, UA, urine pregnancy test 
Visit 9 (ET/EOT)  
CHEM, CBC, UA, urine toxicology screen, urine pregnancy test 
Abbreviations: CBC=complete blood count; CHEM=clinical chemistry serum tests; EOT=end of treatment; 
ET=early termination; UA=urinalysis 
6.4.5 
Syncope 
At each study visit, the investigator should query the caregiver for occurrences of syncope since 
the last visit. An occurrence of syncope should be reported as an adverse event. If the caregiver 
reports an occurrence of syncope, the investigator should ask the “syncope adverse event 
questions” in Appendix G.  
6.4.6 
Somnolence 
At each study visit, the investigator should query the caregiver for occurrences of somnolence 
since the last visit. An occurrence of somnolence should be reported as an adverse event. If the 
caregiver reports an occurrence of somnolence, the investigator should ask the “somnolence 
adverse event” questions in Appendix H. 

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6.5 
Blood Sampling 
The involvement of experienced personnel in the conduction of blood drawing in this population 
is strongly recommended. 
During blood sampling, measures to reduce pain are encouraged and can include application of 
numbing medication (e.g., lidocaine/prilocaine cream) to the draw site and/or use of a winged 
infusion set (i.e., a “butterfly” needle). Mild sedation is allowed exceptionally for blood draws 
(e.g., alprazolam at a pediatric-appropriate dose per age, and the lowest dose deemed necessary 
by the Investigator) just in cases when the subject’s agitation/anxiety does not allow a safe and 
accurate measurement and the Investigator, with agreement from the caregiver, considers it safe 
and appropriate for the subject. 
The total amount of blood to be obtained from each subject for safety laboratory blood samples 
during the course of this study will not exceed approximately 40 mL (6- through 17-year-olds) 
and 31.1 mL (5-year-olds). Note: this total amount does not account for additional blood samples 
that may be collected (e.g., to verify elevated laboratory results, etc.). 
Table 6–2 tabulates the maximum allowable blood collection volumes by weight for affected 
children and Table 6–3 and Table 6–4 summarize the blood volumes to be drawn from 
6-through 17-year-olds and 5-year-olds, respectively, in both a 24-hour and a 30-day period. The 
total amount of blood to be obtained from each subject should not exceed the allowable limits for 
affected children. 
Table 6–2 
Blood Collection Volume Limits in Affected Children 
Weight 
14 kg 
15 kg 
16 kg 
17 kg 
Maximum allowable blood volume in a 24-hour 
period 
28 mL 
30 mL 
32 mL 
34 mL 
Maximum allowable blood volume in a 30-day 
period 
56 mL 
60 mL 
64 mL 
68 mL 
Sources: North Shore LIJ Human Subject Protection Program Guidance Document, Maximum Blood Draw Limits, 
Version 11/24/14; National Center for Health Statistics (CDC) 2-20 years: Stature-for-age and weight-for-age 
percentiles 
Notes: 5th percentile body weight for 5 year old girls≈14.6 kg; 5th percentile body weight for 5 year old 
boys≈15.1 kg. 

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Table 6–3 
Blood Collection Volumes for Safety Labs (6- through 17-year-olds) 
 
Baseline 
Visit 
Visit 4 
(Week 12) 
Visit 6 
(Week 28) 
Visit 8 
(Week 44) 
Visit 9 
(Week 52) 
Total safety labs each study visit 
8 mL 
8 mL 
8 mL 
8 mL 
8 mL 
Total volume in any 24-hour period  
8 mL 
8 mL 
8 mL 
8 mL 
8 mL 
Total volume in any 30-day period 
 
 
 
 
 
Baseline 
8 mL 
- - 
- - 
- - 
- - 
Week 12 
- - 
8 mL 
- - 
- - 
- - 
Week 28 
- - 
- - 
8 mL 
- - 
- - 
Week 44 
- - 
- - 
- - 
8 mL 
- - 
Week 52 
- - 
- - 
- - 
- - 
8 mL 
 
Table 6–4 
Blood Collection Volumes for Safety Labs (5-year-olds) 
 
Baseline 
Visit 
Visit 4 
(Week 12) 
Visit 6 
(Week 28) 
Visit 8 
(Week 44) 
Visit 9 
(Week 52) 
Total safety labs each study visit 
5.9 mL 
6.3 mL 
6.3 mL 
6.3 mL 
6.3 mL 
Total volume in any 24-hour period  
5.9 mL 
6.3 mL 
6.3 mL 
6.3 mL 
6.3 mL 
Total volume in any 30-day period 
 
 
 
 
 
Baseline 
5.9 mL 
- - 
- - 
- - 
- - 
Week 12 
- - 
6.3 mL 
- - 
- - 
- - 
Week 28 
- - 
- - 
6.3 mL 
- - 
- - 
Week 44 
- - 
- - 
- - 
6.3 mL 
- - 
Week 52 
- - 
- - 
- - 
- - 
6.3 mL 
 
6.6 
Safety Follow-up 
A 30-day safety follow-up telephone contact is to be completed for subjects who complete the 
treatment period of the study, as well as those who discontinue prematurely from the study. 
Subjects should have the following completed at 30(+3) days after last dose of study drug: 
• Assessment of concomitant medications/treatments 
• Assessment of AEs 
• Assessment of syncope 

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• Assessment of somnolence 
6.7 
Unscheduled Visits 
Unscheduled visits may occur as determined by the Investigator. The following safety 
assessments generally should be recorded at each unscheduled visit: assessment of AEs, 
assessment of syncope, assessment of somnolence, assessment of concomitant 
medications/treatments, measurement of vital signs and weight, the ESRS-A, and completion of 
the C-SSRS. The Investigator may perform any additional safety evaluations deemed by the 
Investigator to be clinically indicated. 
6.8 
Remote Assessments or Visits 
Circumstances may arise (e.g., pandemic, natural disaster, political upheaval, or to minimize 
subject and caregiver burden) when on-site assessments of efficacy and/or safety are not 
possible. In those cases, assessments may be performed offsite by raters either in person, or via 
video technology or telephone where possible. For all visits that are conducted remotely, the 
Investigator must contact the Medical Monitor for approval of the plan. Sites must keep a log to 
identify details of all visits that are administered remotely. For some remote efficacy assessments 
the vendor will provide additional training to ensure calibration to reduce discrepancy between 
on-site and remote assessments (ABC, CGI-S, RBS-R, VABS-Socialization).  
Provided that the subject is physically in the clinic, and accompanied by a relative, all 
caregiver-rated assessments may be provided remotely. 
7 ADVERSE EVENTS 
7.1 
Specification of Safety Parameters 
7.1.1 
Definition of Adverse Event 
An AE is defined as “any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study drug, whether or not considered related to study 
drug”. 
An AE can therefore be any unfavorable and unintended sign (e.g., an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a drug, without any 
judgment about causality or seriousness. An AE can arise from any use of the drug (e.g., off-label 
use, use in combination with another drug) and from any route of administration, formulation, or 
dose, including an overdose. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the drug 
caused the AE. 

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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) 
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.  

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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. 
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 

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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: 
• 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 
• Dose increased: Study drug dose increased (can only be done up to and including 
Week 20 visit) 
• Dose reduced: Study drug dose reduced (can only be done up to and including Week 20 
visit) 
• Drug interrupted: Study drug temporarily stopped 
• Drug withdrawn: Study drug discontinued permanently 
• Not applicable 
• Unknown 

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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 first dose of open-label study drug through the study 
safety follow-up period. All ongoing AEs from the antecedent double-blind study will be carried 
over and recorded from Baseline for the ACP-103-070 study until resolution or the follow-up 
safety assessment. If an AE is ongoing at the end of the study safety follow-up period, every 
reasonable attempt should be made to follow and appropriately treat the subject until the 
AE resolves or until the Investigator deems the AE to be chronic or stable. 
In the event that a subject discontinues from the study and has an ongoing AE at the time of 
discontinuation (Section 4.5.1), 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 
from the study because of an AE, no additional assessments may be performed (Section 4.4). 
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 

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different since your last visit?”) to assess whether any AEs have been experienced since the last 
report or visit. 
Note that any use of medication (and specifically any newly prescribed medication) during the 
course of a study may indicate the occurrence of an AE that may need to be recorded on both the 
AE and the concomitant medication page. 
All AEs, serious and not serious, will be recorded on the AE eCRF page using appropriate 
medical terminology. Severity and relationship to study drug will be assessed by the Investigator. 
When possible, clinical AEs should be described by diagnosis and not by symptoms (e.g., “cold” 
or “seasonal allergies” instead of “runny nose”). 
All AEs, whether or not related to the study drug, must be fully and completely documented on 
the AE eCRF and in the subject’s notes. 
7.4.2 
Serious Adverse Event Reporting 
The reporting of SAEs by the Sponsor or designee to the regulatory authorities is a regulatory 
requirement. Each regulatory authority has established a timetable for reporting SAEs based 
upon established criteria. 
Serious AEs must be reported within 24 hours of discovery to the Sponsor or its designee; both 
using the appropriate 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 
IRB/EC, as per applicable regulations. These will be provided by the Sponsor after their 
assessment. For European Union member states, the Sponsor or its designee will provide reports 
of suspected unexpected serious adverse reactions (SUSARs) directly to the ECs, as required by 
local legislation. In all other countries, it is the Investigator’s responsibility to provide these 
expedited reports to the responsible IRB/EC. It is also the Investigator’s responsibility to notify 
the responsible IRB/EC regarding any new and significant safety information. 
When an SAE occurs, Investigators will review all documentation related to the event and will 
complete the paper SAE form, 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 will be followed through the safety follow-up period (i.e., 30[+3] 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. 

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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 informed consent form 
(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[+3] days after last dose of study 
drug) should be reported if in the judgment of the Investigator there is “a reasonable possibility” 
that the event may have been caused by the product. 
SAEs should also be reported to the IRB/EC according to local regulations. 
7.4.3 
Reporting of Pregnancy 
Any female subject who becomes pregnant during the study (with or without AEs) must be 
discontinued from the study and the pregnancy must be reported on the Pregnancy form within 
24 hours of discovery to the Sponsor or its designee. Any female subject who becomes pregnant 
during the study will be followed through the pregnancy outcome. 
Any AEs that are the consequence of pregnancy and which meet the criteria for serious should 
also be reported via the SAE form. 
7.4.3.1 
Reporting Paternal Drug Exposure  
Paternal drug exposure is defined as a father’s exposure to a medicinal product before or during 
his partner’s pregnancy. Any paternal drug exposure cases must be reported to the Sponsor 
within 24 hours of discovery via the Pregnancy form. Any AEs that are the consequence of 
paternal drug exposure and which meet the criteria for serious must also be reported to the 
Sponsor within 24 hours of discovery via the SAE form. 
7.4.4 
Reporting of Overdose 
An overdose is a deliberate or inadvertent administration of a treatment at a dose higher than the 
maximum recommended dose per protocol. It must be reported to the Sponsor or designee on the 
Sponsor Overdose Reporting form within 24 hours of discovery. In addition, all events of 
overdose are to be captured as protocol deviations (see Section 5.1.6). 
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. 

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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, if any, will 
be described and justified in the final clinical study report. 
9.2 
Statistical Hypotheses 
The primary objective of this study is to evaluate the long-term safety and tolerability of 
pimavanserin after 52 weeks of treatment in children and adolescents with ASD. Secondary and 
exploratory objectives include assessment of efficacy outcome measures over time. No formal 
statistical testing will be performed for any of the safety or efficacy endpoints. 
All safety and efficacy measures will be summarized descriptively. 
9.3 
Sample Size Determination 
The planned sample size for this study is not based on statistical power but will depend on the 
number of subjects who complete the antecedent double-blind study, and who rollover into this 
open-label extension study. 
Assuming a drop-out rate of 15% in the antecedent study, it is estimated that approximately 
193 subjects will be eligible to enroll in this OLE. Assuming all 193 subjects do enroll, then 
according to the Rule of Three, the 95% confidence interval for the occurrence rate of an 
unobserved adverse event is estimated as (0, 1.6%). 
9.4 
Population Analysis Sets 
The Safety Analysis Set will include all subjects who received at least one dose of open-label 
study drug. The Safety Analysis Set will be used for all analyses. 
9.5 
Statistical Analyses 
For continuous variables, the following summary statistics will be provided: number of subjects, 
mean, standard error of the mean, standard deviation, minimum, maximum, and median. For 
categorical variables, summaries will include the number and percentage of subjects in each 
category. 
For each continuous measure in safety and efficacy analyses, changes from Baseline results will 
be presented in two ways: 
1. using the Baseline of this study to report the changes across the timepoints of this 
open-label study  

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2. using the Baseline from the antecedent double-blind study to report the changes across 
the timepoints of this open-label study  
9.5.1 
Primary Analyses 
The primary endpoints for this study are TEAEs. All adverse events will be classified into 
standard terminology using the Medical Dictionary for Regulatory Activities (MedDRA). 
A TEAE is defined as an AE that started after first study dose administration and no later than 
last study dose date +30 days. The number and frequency of TEAEs will be summarized by 
system organ class and preferred term. TEAEs leading to discontinuation, TEAEs related to 
study drug, TEAEs by maximum severity, fatal TEAEs, serious TEAEs, and serious TEAEs 
related to study drug will also be summarized.  
9.5.2 
Other Safety Analyses 
Descriptive summary statistics for ECGs, vital signs, weight, BMI, ESRS-A, 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 ICH guidelines. 
For the C-SSRS, the number and percentage of subjects with suicidal ideation or behavior during 
the study will be tabulated. 
9.5.3 
Secondary Endpoint and Analysis 
The secondary endpoint in this study is the proportion of subjects who have at least 
25% reduction from the antecedent study Baseline in the ABC-Irritability (ABC-I) subscale score 
AND a CGI-I of irritability score of 1 (very much improved) or 2 (much improved) compared to 
the antecedent study baseline status at Week 52. 
The number and percentage of subjects who have at least 25% reduction from antecedent-study 
Baseline in the ABC Irritability (ABC-I) subscale score AND a CGI-I of irritability score of 
1 (very much improved) or 2 (much improved) compared to the antecedent study baseline status 
will be tabulated by timepoint. 
9.5.4 
Exploratory Endpoints and Analyses 
Exploratory endpoints are the following: 
• Change from Baseline at Week 52 in the caregiver-rated ABC subscale scores 
o Irritability 
o Stereotypic behavior 
o Lethargy 
o Hyperactivity 

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o Inappropriate speech 
• Change from Baseline at Week 52 in the CGI-S of irritability score 
• CGI-I of irritability score compared to the antecedent study baseline status at Week 52 
• Change from Baseline at Week 52 in the CGSQ scores 
• Proportion of subjects who have at least 25% reduction from the antecedent study 
Baseline in the ABC-I subscale score (ABC-I responders) at Week 52 
• Proportion of subjects who have CGI-I of irritability score of 1 (very much improved) or 
2 (much improved) compared to the antecedent study baseline status (CGI-I of irritability 
responders) at Week 52 
Descriptive summary statistics for each of the ABC subscale score, CGI-S of irritability score, 
CGI-I of irritability score and CGSQ score, and associated change from Baseline values (except 
for CGI-I of irritability), will be tabulated by timepoint. 
The number and percentage of subjects who have at least 25% reduction from Baseline in the 
ABC-I subscale score, and the number and percentage of subjects with CGI-I of irritability score 
of 1 (very much improved) or 2 (much improved) compared to the antecedent-study baseline 
status will also be tabulated by timepoint. 
9.5.5 
Subgroup Analyses 
Selected analyses may 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 Data and Safety Monitoring Board (DSMB) will review interim safety data, 
including data on AEs, SAEs and safety laboratory data. 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 membership, activities, responsibilities, and frequency of meetings will be 
described separately in the DSMB charter. 
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. 

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The Investigator and institution must permit authorized representatives of the Sponsor or 
designees (including monitors and auditors), regulatory authorities (including inspectors), and 
the IRB/EC direct access to source documents (such as original medical records) as allowed by 
local regulations. Direct 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 
remote video/electronic medium (such as email) if applicable. 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 
personnel. The source documentation may consist of source notes captured by site personnel in 
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 
captured electronically by data vendors. 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. 
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 

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eCRFs, documentation of eCRF corrections, signed ICFs, audio recordings, subject-related 
source documentation, and adequate records for the receipt and disposition of all study drug. 
Investigators should maintain all essential study documentation, for a period of at least 2 years 
following the last approval of marketing application in an ICH region (US, Europe, and Japan), 
or until at least 2 years after the drug investigational program is discontinued, unless a longer 
period is required by applicable law or regulation. Only the Sponsor can notify an Investigator or 
vendor when any records may be discarded. Investigators should contact the Sponsor before 
destroying any files.
10.6 Protocol Exceptions and Deviations 
No prospective entry criteria protocol deviations are allowed; all subjects must meet all 
eligibility criteria in order to participate in the study.
Protocol waivers for eligibility will not be granted by the Sponsor under any circumstances. If, 
during the course of a subject’s post-enrollment participation in the trial it is discovered that the 
subject did not meet all eligibility criteria, this will be reported as a major protocol deviation and 
not a waiver. In this situation, the subject will be discontinued, unless the discontinuation 
presents an unacceptable medical risk. The justification to allow the subject to continue in the 
trial will be made by the Sponsor, with medical input from the Investigator, and will be 
documented. All follow-up safety assessments must be completed and documented as outlined in 
the protocol (Section 6.6). The Investigator must report any protocol deviation to the Sponsor 
and, if required, to the IRB/EC in accordance with local regulations, within reasonable time.
10.7 Protocol Amendments 
Changes to the protocol may be made only by the Sponsor (with or without consultation with the 
Investigator). All protocol modifications must be submitted to the site IRB/EC in accordance 
with local requirements and, if required, to regulatory authorities, as either an amendment or a 
notification. Approval for amendments must be awaited before any changes can be implemented, 
except for changes necessary to eliminate an immediate hazard to trial subjects, or when the 
changes involve only logistical or administrative aspects of the trial. No approval is required for 
notifications.
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 

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operationally feasible and that any unnecessary complexity, procedures, and data 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., pharmacy, 

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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 European Union General Data Protection Regulation [EU GDPR]). 
The study will be performed in accordance with current US Health Insurance Portability and 
Accountability Act (HIPAA) regulations, US FDA GCP Regulations (US CFR 21 parts 50, 54, 
56, and 312), and ICH guidance on GCP (E6) and clinical safety data management (E2A). 
In accordance with Directive 75/318/EEC, as amended by Directive 91/507/EEC, the final 
clinical study report will be signed by an Investigator and/or Coordinating Investigator who will 
be designated prior to the writing of the clinical study report. 
12.2 Institutional Review Board/Ethics Committee 
The Investigator or designee will provide the IRB/EC with all requisite material, including a 
copy of the protocol, informed consent, 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/Assent Process 
Properly executed, written informed assent/consent must be obtained from each subject and/or 
subject's parent/LAR prior to any Baseline procedures. 
The informed consent must, at a minimum, include the elements of consent described in the 
ICH guidance on GCP and the US CFR 21 part 50.25. A copy of the ICF planned for use will be 

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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 and their parent/ LAR. 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 
Subject Assent Form 
To participate in the study, the subject will assent to an understanding of, and sign the assent 
form. The subject will be made aware of the ability to withdraw from the study at any time, 
without prejudice. The subject’s assent for participation must be documented. Assent is the 
affirmative agreement to participate in the research of a minor. If the subject cannot sign the 
form, a witness will be allowed to provide written verification of oral assent 
12.3.2 
Parent and Legally Acceptable Representative Informed Consent 
Written informed consent will be obtained from the subject’s parent/LAR before the subject 
participates in any study-related procedure. To provide consent for the subject’s participation in 
the study, the subject’s parent/LAR will read, assent to an understanding of, and sign an ICF or 
other locally applicable regulations and authorization form after having had an opportunity to 
discuss the forms with the Investigator. The parent/LAR will be made aware that the subject may 
withdraw from the study at any time and will receive a copy of the signed ICF. Subjects who 
reach the age of majority (i.e., 18 years in most jurisdictions) during the course of the study are 
required to be re-consented. 
12.3.3 
Consent and Other Informational Documents Provided to Subjects 
The subject and/or parent/LAR must be given a copy of the signed informed consent and the 
original maintained in the designated location at the site. 
12.3.4 
Consent Procedures and Documentation 
It is the Investigator or designee’s responsibility to obtain written informed consent from the 
subject and/or parent/LAR after adequate explanation of the aims, methods, anticipated benefits, 
and potential hazards of the study. The subject and/or parent/LAR 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 or parent/LAR 
with subject assent and by the person who conducted the informed-consent discussion. The 

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Investigator or appropriate site personnel must document the details of obtaining informed consent 
in the subject’s study documents. 
Records related to a study subject’s participation will be maintained and processed according to 
local laws, and where applicable, the European Union General Data Protection Regulation 
(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. 
12.3.4.1 
Remote Consent Procedures and Documentation 
In exceptional circumstances, and with the approval of the Medical Monitor, Investigators may 
obtain informed consent from the subject or parent/LAR when these individuals are unable to 
travel to the site where the Investigator is located due to extenuating circumstances 
(e.g., pandemic, natural disaster, or political upheaval). This is only permitted when a new 
consent is approved by the IRB/EC and the subject and/or parent/LAR need to be re-consented. 
The consent form may be sent to the subject or the subject’s parent/LAR by facsimile or e-mail, 
and the consent interview may then be conducted by telephone when the subject or subject’s 
parent/LAR 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 conducting any assessments at the visit the re-consent was 
conducted. The Investigator should have the subject and/or parent/LAR confirm verbally during 
the consent interview that the subject and/or parent/LAR has signed and dated the form. In 
addition, the person signing the consent form must receive a copy of the consent form. 
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 
Aaron E, Montgomery A, Ren X, et al. Whole blood serotonin and platelet 5-HT2A binding in 
autism spectrum disorder. J Autism Dev Disord. 2019;49(6):2417-2425.  
Acadia Pharmaceuticals Inc. NUPLAZID® [package insert]. San Diego, CA, November 2020. 
Akhondzadeh S, Erfani S, Mohammadi MR, et al. Cyproheptadine in the treatment of autistic 
disorder: a double‐blind placebo‐controlled trial. J Clin Pharm Ther. 2004;29(2):145-150. 
Aldinger KA, Lane CJ, Veenstra-VanderWeele J, Levitt P. Patterns of risk for multiple co‐
occurring medical conditions replicate across distinct cohorts of children with autism spectrum 
disorder. Autism Res. 2015;8(6):771-781. 
Aman MG, Singh NN, Stewart AW, Field CJ. Psychometric characteristics of the Aberrant 
Behavior Checklist. Am J Ment Defic. 1985;89(5):492-502. 
Brannan AM, Heflinger CA, Bickman L. The Caregiver Strain Questionnaire: measuring the 
impact on the family of living with a child with serious emotional disturbance. J Emot Behav 
Disord. 1997;5(4):212-222.  
Chouinard G, Margolese HC. Manual for the Extrapyramidal Symptom Rating Scale (ESRS). 
Schizophr Res. 2005;76(2-3):247-265. 
Daly E, Ecker C, Hallahan B, et al. Response inhibition and serotonin in autism: a functional 
MRI study using acute tryptophan depletion. Brain. 2014;137(Pt 9):2600-2610. 
Fung LK, Mahajan R, Nozzolillo A, Bernal P, Krasner A, Jo B, et al. Pharmacologic treatment of 
severe irritability and problem behaviors in autism: A systematic review and meta-analysis. 
Pediatrics. 2016;137(Suppl 2):S124-S135. 
Grzadzinski R, Huerta M, Lord C. DSM-5 and autism spectrum disorders (ASDs): an 
opportunity for identifying ASD subtypes. Mol Autism. 2013;4:12. 
Guy W. Clinical Global Impressions. In: ECDEU Assessment Manual for Psychopharmacology 
—Revised (DHEW publication number ADM 76–338). Rockville, MD, U.S. Department of 
Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health 
Administration, NIMH Psychopharmacology Research Branch, Division of Extramural Research 
Programs, 1976, 218-222. 
Kaat AJ, Lecavalier L, Aman MG. Validity of the Aberrant Behavior Checklist in children with 
autism spectrum disorder. J Autism Dev Disord. 2014;44(5):1103-1116. 
Lam KSL, Aman MG. The Repetitive Behavior Scale-Revised: independent validation in 
individuals with autism spectrum disorders. J Autism Dev Disord. 2007:37(5):855-866.  

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Levy SE, Mandell DS, Schultz RT: Autism. Lancet. 2009;374(9701):1627-1638. 
Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in girls. Arch Dis Child. 
1969;44(235):291-303. 
Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Arch Dis Child. 
1970;45(239):13-23. 
McPheeters ML, Warren Z, Sathe N, et al. A systematic review of medical treatments for 
children with autism spectrum disorders. Pediatrics. 2011;127(5):e1312-e1321. 
Muller CL, Anacker AM, Veenstra-VanderWeele J. The serotonin system in autism spectrum 
disorder: from biomarker to animal models. Neuroscience. 2016;321:24-41. 
Paclt I, Hellerová P. [Ritanserin in autistic children]. Cesk Psychiatr. 1993;89(2):85-86. 
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. 
Ritvo E, Yuwiler A, Geller E, Ornitz EM, Saeger K, Plotkin S. Increased blood serotonin and 
platelets in early infantile autism. Arch Gen Psychiatry. 1970;23(6):566-572. 
Rolf L, Haarmann F, Grotemeyer K, Kehrer H. Serotonin and amino acid content in platelets of 
autistic children. Acta Psychiatr Scand. 1993;87:312-316. 
Schwartz GJ, Muñoz A, Schneider MF, et al. New equations to estimate GFR in children with 
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Sharma SR, Gonda X, Tarazi FI. Autism spectrum disorder: classification, diagnosis and therapy. 
Pharmacol Ther. 2018;190:91-104. 
Sparrow SS, Cicchetti DV, Saulnier CA. Vineland Adaptive Behavior Scales, Third Edition: 
Vineland-3. Pearson; 2016. 
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) 
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receptor inverse agonist. J Pharmacol Exp Ther. 2006;317(2):910-918. 
 

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16 APPENDICES 
Appendix A Prohibited and Restricted Medicationsa 
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 
Medicationa 
Prohibition/restrictions 
Antiarrhythmic 
drugs 
PROHIBITED 
• ajmaline 
• amakalant, semantilide 
• amiodarone 
• bretylium 
• disopyramide 
• dofetilide 
• dronedarone 
• flecainide 
• ibutilide 
• procainamide 
• propafenone 
• quinidine 
• sotalol, d-sotalol 
Prohibited at antecedent study entry and throughout the 
treatment period 

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Medication Class 
Medicationa 
Prohibition/restrictions 
Anticholinergics 
PROHIBITED 
• Centrally acting 
anticholinergics 
o biperiden 
o trihexiphenidyl 
Centrally acting anticholinergic medications are 
prohibited throughout the treatment period.  
RESTRICTED 
o benztropine 
o oral 
diphenhydramine 
o Benztropine (≤6 mg/day) is allowed for movement 
disorders 
o Oral diphenhydramine is allowed at 
≤50 mg per day for acute extrapyramidal symptoms 
UNRESTRICTED 
• peripherally acting 
anticholinergics 
• topical 
diphenhydramine 
Peripherally acting anticholinergic medications and 
topical diphenhydramine are allowed without restriction 
Anticonvulsant and 
mood stabilizers 
PROHIBITED 
• carbamazepine 
• lamotrigine 
• lithium 
• oxcarbazepine 
• phenytoin 
• valproate 
Prohibited throughout the treatment period 
Antidepressants 
PROHIBITED 
• amitriptyline 
• citalopram 
• clomipramine 
• desipramine 
• desvenlafaxine 
• doxepin 
• duloxetine 
• escitalopram 
• esketamine 
• fluvoxamine 
• fluoxetine 
• imipramine 
• ketamine 
• mianserin 
• mirtazapine 
Prohibited throughout the treatment period 

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Medication Class 
Medicationa 
Prohibition/restrictions 
• nefazadone 
• nortriptyline 
• sertraline 
• trazodone 
• trimipramine 
• venlafaxine 
Antimanic agents 
PROHIBITED 
• lithium 
• valproate 
Prohibited throughout the treatment period 
Antimicrobials, 
antifungals, and 
antimalarials 
PROHIBITED 
• clarithromycin 
• erythromycin 
• levofloxacin 
• moxifloxacin 
• pentamidine 
• roxithromycin 
Prohibited throughout the treatment period 
RESTRICTED 
• artenimol/piperaquine 
• azithromycin 
• bedaquiline 
• ciprofloxacin 
• fluconazole 
• gemifloxacin 
• norfloxacin 
• ofloxacin 
• telavancin 
• telithromycin 
• Prohibited 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 
• These restricted medications are only allowed under 
the following conditions: 
o The subject has a Baseline ECG with a 
QTcF <425 ms IF QRS duration is <120 ms OR 
o The subject has a QTcF <450 ms at Baseline IF 
QRS duration ≥120 ms 
Antipsychotics other 
than pimavanserin 
PROHIBITED 
All in class 
Prohibited throughout the treatment period 
Anxiolytics 
PROHIBITED 
• chlordiazepoxide 
• diazepam 
• flurazepam 
Prohibited throughout the treatment period 
RESTRICTED 
• alprazolam 
• lorazepam 
• midazolam 
• Mild sedation is allowed exceptionally for ECGs and 
blood draws during the study (e.g., alprazolam at a 
pediatric-appropriate dose per age, and the lowest 
dose deemed necessary by the Investigator) just in 

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Medication Class 
Medicationa 
Prohibition/restrictions 
• oxazepam 
• temazepam 
• triazolam 
cases when the subject’s agitation/anxiety does not 
allow a safe and accurate measurement and the 
Investigator, with agreement from the caregiver, 
considers it safe and appropriate for the subject. 
• Short- or medium-acting benzodiazepine may be used 
for acute anxiety 
• May not be used within 12 hours prior to an 
assessment visit 
• Lorazepam, in doses according to age, may be used as 
a rescue medication for a maximum of 7 consecutive 
days. Reassessment and discussion with Medical 
Monitor is required if needed beyond 7 days. 
o If lorazepam is not available, another 
benzodiazepine from the restricted list may be used 
Beta blockers 
PROHIBITED 
• propranolol 
Prohibited throughout the treatment period 
Centrally-acting 
alpha-agonist 
hypotensive agents 
PROHIBITED 
• clonidine 
Prohibited throughout the treatment period 
Centrally-acting 
alpha2A adrenergic 
receptor agonists  
PROHIBITED 
• guanfacine 
Prohibited throughout the treatment period 
Hypnotics and 
sleeping agents 
PROHIBITED 
• eszopiclone 
• zolpidem 
• zopiclone 
Prohibited throughout the treatment period 
RESTRICTED 
• melatonin 
• ramelteon 
• zaleplon 
May not be used within 12 hours of a cognitive 
assessment, and efforts should be made to limit agents to 
lowest dose for the shortest time needed. 
o 
Melatonin is allowed (≤5 mg/day) for insomnia 
Non-stimulant 
ADHD medications 
RESTRICTED 
• atomoxetine 
Allowed if stable throughout the antecedent study and the 
dose is expected to remain the same throughout the 
duration of the study. 
Opioids 
PROHIBITED 
• methadone 
Prohibited throughout the treatment period 
Serotonin 
antagonists  
PROHIBITED 
• cyproheptadine 
Prohibited throughout the treatment period 

Study: ACP-103-070 
 
Final Version: 2.0 
Clinical Study Protocol Amendment 3-Consolidated 
 
Date: 29 February 2024 
 
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Medication Class 
Medicationa 
Prohibition/restrictions 
Stimulants and 
wake-promoting 
agents 
RESTRICTED 
• amphetamine salts 
• armodafinil 
• lisdexamfetamine 
• methylphenidate 
• modafinil 
Allowed if stable throughout the antecedent study and 
the dose is expected to remain the same throughout the 
duration of the study. 
Abbreviations: ADHD=attention-deficit hyperactivity disorder; ECG=electrocardiogram; QTcF=corrected QT 
interval using Fridericia’s correction method; QRS=QRS interval on ECG; QT interval=QT interval on ECG 
a 
Medications within each class include but are not limited to the examples listed in this table. 

Study: ACP-103-070 
 
Final Version: 2.0 
Clinical Study Protocol Amendment 3-Consolidated 
 
Date: 29 February 2024 
 
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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 Cmax and AUC of approximately 3-fold. 
Strong inhibitors of CYP3A4 are to be stopped at least 2 weeks 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®) 
ritonavir (Norvir®, part of Viekira 
Pak™) 
MODERATE 
INHIBITORS 
grapefruit juicea 
amprenavir (Agenerase®) 
aprepitant (Emend®) 
atazanavir (Reyataz®) 
ciprofloxacin (Cipro®) 
conivaptan (Vaprisol®) 
crizotinib 
cyclosporine 
darunavir/ritonavir 
(Prezista®/Ritonavir) 
diltiazem 
dronedarone 
erythromycin (Erythrocin® 
Lactobionate) 
fluconazole (Diflucan®) 

Study: ACP-103-070
Final Version: 2.0
Clinical Study Protocol Amendment 3-Consolidated
Date: 29 February 2024
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− 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®) 
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/DrugInteractionsLabeling/uc 
m093664.htm#classInhibit).

Study: ACP-103-070 
 
Final Version: 2.0 
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Date: 29 February 2024 
 
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Appendix C Criteria for Identifying Potentially Clinically Important Laboratory Values 
Analyte 
Conventional Unit 
Low PCI Criteria 
High PCI Criteria 
Hematology (whole blood) 
 
 
 
Hemoglobin (Male) 
g/dL 
<11 
>17 
Hemoglobin (Female) 
g/dL 
<10 
>17 
Hematocrit (Both) 
% 
<30 
>50  
Leukocyte (White Blood Cell 
Count) 
× 103/uL 
≤2.8 
≥15 
Neutrophils 
× 103/uL 
≤1.5 
No upper limit 
Eosinophils 
% 
≥10% 
No lower limit 
Platelet Count 
× 103/uL 
≤75 
≥700 
Chemistry (serum or plasma) 
 
 
 
ALT (SGPT) 
U/L 
No lower limit  
≥3 × ULN 
AST (SGOT) 
U/L 
No lower limit  
≥3 × ULN 
Gamma-Glutamyl Transferase 
(GGT) 
U/L 
No lower limit 
≥3 ULN 
Lactate Dehydrogenase (LDH) 
U/L 
No lower limit 
≥3 × ULN 
Alkaline Phosphatase 
U/L 
No lower limit 
≥3 × ULN 
Total Bilirubin 
mg/dL 
No lower limit 
≥1.5 ULN 
CPK 
mg/dL 
No lower limit 
≥3 ULN 
BUN 
mg/dL 
No lower limit 
≥30.0 
Serum Creatinine 
mg/dL 
Not Applicable 
>1.5 ULN 
Sodium 
mEq/L 
≤125 
≥155 
Potassium 
mEq/L 
≤3.0 
≥5.5 
Calcium, total 
mg/dL 
<8.0 
>11.0 
Chloride 
mEq/L 
≤85 
≥120 
Phosphorous, inorganic 
mg/dL 
≤1.0 mg/dL 
≥4.5 mg/dL 
Magnesium 
mEq/L 
≤0.7 mEq/L 
≥5.0 mEq/L 
Uric acid  
mg/dL 
No lower limit 
≥8.5 
Albumin 
g/dL 
≤2.6 
≥6.0 
Total Protein 
g/dL 
≤5.0 
≥10.0 
Glucose (random) 
mg/dL 
≤45.1 
≥115.0 
Hb1Ac 
% 
No lower limit 
≥7% 
Total Cholesterol, Fasting 
mg/dL 
No lower limit 
≥240 mg/dL 
Urinalysis 
 
 
 
Blood (occult blood) 
 
Not Applicable 
≥ Moderate 
Protein 
mg/dL 
Not Applicable 
≥100 mg/dL 
Glucose 
mg/dL 
Not Applicable 
≥500 mg/dL 
Abbreviations: ALT (SGPT)=alanine aminotransferase (serum glutamic-pyruvic transaminase); 
AST (SGOT)=aspartate aminotransferase (serum glutamic-oxaloacetic transaminase); BUN=blood urea 
nitrogen; CPK=creatine phosphokinase; HbA1c=glycosylated hemoglobin; PCI=potentially clinically important; 
ULN=upper limit of normal. 
 

Study: ACP-103-070 
 
Final Version: 2.0 
Clinical Study Protocol Amendment 3-Consolidated 
 
Date: 29 February 2024 
 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc. 
Page 89 of 93 
Appendix D Criteria for Potentially Clinically Important ECG Values 
ECG Parameter 
High PCI Criteria 
QRS Interval 
120 ms 
PR Interval 
220 ms 
QTcB 
>500 ms 
QTcF 
>500 ms 
QTcB: change from baseline  
>60 ms  
QTcF: change from baseline  
>60 ms  
Abbreviations: ECG=electrocardiogram; PCI=potentially clinically important; PR interval=PR interval on ECG; 
QRS interval=QRS interval on ECG; QTcB=corrected QT interval using Bazett’s correction method; 
QTcF=corrected QT interval using Fridericia’s correction method; QRS interval=QRS interval on ECG. 

Study: ACP-103-070 
 
Final Version: 2.0 
Clinical Study Protocol Amendment 3-Consolidated 
 
Date: 29 February 2024 
 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc. 
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Appendix E Criteria for Identifying Additional ECG Measurements of Potential Clinical 
Relevance. To be Used for Medical Monitoring Purposes 
Variable 
Criterion Valuea 
Change Relative to 
Baseline 
Rate 
Tachycardia 
>120 bpm 
increase of >15 bpm 
Bradycardia 
≤50 bpm 
decrease of >15 bpm 
Rhythm 
Sinus tachycardiab 
>120 bpm 
increase of >15 bpm 
Sinus bradycardiac 
≤50 bpm 
decrease of >15 bpm 
Supraventricular 
premature beat 
all 
not present - present 
Ventricular premature 
beat 
all 
not present - present 
Supraventricular 
tachycardia 
all 
not present - present 
Ventricular tachycardia 
all 
not present - present 
Atrial fibrillation 
all 
not present - present 
Atrial flutter 
all 
not present - present 
Conduction 
1st atrioventricular block 
PR >0.20 second 
increase of >0.05 second 
2nd atrioventricular block 
all 
not present - present 
3rd atrioventricular block 
all 
not present - present 
 
Left bundle-branch block 
all 
not present - present 
Right bundle-branch 
block 
all 
not present - present 
Pre-excitation syndrome 
all 
not present - present 
Other intraventricular 
conduction block 
QRS >0.12 second 
increase of 0.02 second 
Infarction 
Acute or subacute 
all 
not present - present 
Old 
all 
not present - present 
ST/T Morphological 
>12 weeks post trial entry 
Myocardial Ischemia 
all 
not present - present 
Symmetrical T-wave 
inversion 
all 
not present - present 
Increase in QTc 
QTc 
>450 ms (males) 
>10% increase 
>470 ms (females) 
a 
In order to be identified as potentially clinically relevant, an on-treatment value must meet the “Criterion Value” 
and also represent a change from the subject’s baseline value of at least the magnitude shown in the “Change 
Relative to Baseline” column. 
b 
No current diagnosis of supraventricular tachycardia, ventricular tachycardia, atrial fibrillation, atrial 
flutter, or other rhythm abnormality. 
c 
No current diagnosis of atrial fibrillation, atrial flutter, or other rhythm abnormality. 

Study: ACP-103-070 
 
Final Version: 2.0 
Clinical Study Protocol Amendment 3-Consolidated 
 
Date: 29 February 2024 
 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc. 
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Appendix F Criteria for Potentially Clinically Important Vital Signs 
Vital Sign Parameter 
 
Unit 
Criteria 
Observed Value 
And/Or 
Change Relative to 
Baseline 
Systolic blood pressure 
(supine or sitting) 
mmHg 
140 
And 
Increase of ≥20 
70 
And 
Decrease of ≥20 
Diastolic blood pressure 
(supine or sitting) 
mmHg 
90 
And 
Increase of ≥15 
50 
And 
Decrease of ≥15 
Pulse (supine or sitting) 
bpm 
120 
And 
Increase of ≥15 
50 
And 
Decrease of ≥15 
Weight  
kg 
Not Applicable 
Increase of ≥7% 
Decrease of ≥7% 
 

Study: ACP-103-070 
 
Final Version: 2.0 
Clinical Study Protocol Amendment 3-Consolidated 
 
Date: 29 February 2024 
 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc. 
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Appendix G Syncope Adverse Event Questions 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI

St u d y: A C P -1 0 3 -0 7 0  
 
Fi nal  Versi o n: 2 .0  
Cli nical  St u d y Pr ot oc ol A me n d me nt 3 -C o ns oli date d  
 
Date: 2 9  Fe br uar y  2 0 2 4  
 
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 9 3  of 9 3  
A p pe n di x H  S o m n ole nce A d verse E ve nt Q uesti o ns  
•  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI