Clinical trial NCT05523895
Conditions: Irritability Associated With Autism Spectrum Disorder
Keywords: Randomized Placebo-controlled
Sponsor: ACADIA Pharmaceuticals Inc.
Start date: 2022-08-09; Completion date: 2024-09-27
Enrollment: 237 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
6-week, randomized, double-blind, fixed-dose, placebo-controlled, parallel group study in children and adolescents (aged 5 to17 years) with autism spectrum disorder (ASD) with irritability, agitation, or self-injurious behaviors to study the efficacy and safety of pimavanserin

Detailed description:
This study will be conducted as a 6-week, randomized, double-blind, fixed-dose, placebo-controlled, parallel group study in children and adolescents (5 through 17 years of age) with ASD with irritability, agitation, or self-injurious behaviors.

Arms: arm 1: Placebo given once daily, as one capsule matching in size and color the respective pimavanserin treatment arm 2: Patients aged 5 to 12 years: 10 mg/day pimavanserin Patients aged 13 to 17 years: 20 mg/day pimavanserin

Pimavanserin given once daily, as capsule of 10 or 20 mg dose strength, respectively, according to the patient's age arm 3: Patients aged 5 to 12 years: 20 mg/day pimavanserin Patients aged 13 to 17 years: 34 mg/day pimavanserin

Pimavanserin given once daily, as capsule of 20 or 34 mg dose strength, respectively, according to the patient's age
Interventions: intervention 1: Pimavanserin intervention 2: Placebo
Intervention descriptions: intervention 1: Pimavanserin intervention 2: Pimavanserin matching placebo

Protocol documents:
Prot_000.pdf: 
 
 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc. 
Page 1 of 117 
 
 
CLINICAL STUDY PROTOCOL 
 
A Phase 2, Randomized, Double-blind, Placebo-controlled Study to 
Evaluate the Efficacy and Safety of Pimavanserin for the Treatment of 
Irritability Associated With Autism Spectrum Disorder 
 
 
Protocol Number: ACP-103-069 
Amendment 4 
EudraCT Number: 2021-005387-22 
ClinicalTrials.gov Number: NCT05523895  
 
Original Protocol Date: 30 April 2021 
Protocol Amendment 1 Date: 23 September 2021 
Protocol Amendment 2 Date: 03 December 2021 
Protocol Amendment 3 Date: 25 March 2022 
Protocol Amendment 4 Date: 21 December 2022 
 
 
Protocol Template Version: 0.2  
Confidentiality Statement 
This protocol is the confidential information of Acadia Pharmaceuticals Inc. and is intended solely for the 
guidance of the clinical investigation. This protocol may not be disclosed to parties not associated with the 
clinical investigation or used for any purpose without the prior written consent of Acadia Pharmaceuticals Inc. 


Study: ACP-103-069 
 
Final Version: 1.0 
Clinical Study Protocol Amendment 4 
 
Date: 21 December 2022 
 
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SPONSOR SIGNATURE PAGE 
 
Title: A Phase 2, Randomized, Double-blind, Placebo-controlled Study to Evaluate the 
Efficacy and Safety of Pimavanserin for the Treatment of Irritability Associated With 
Autism Spectrum Disorder 
 
, 
 Clinical 
Development: 
, MD 
(delegate of 
,  
 of Acadia) 
Acadia Pharmaceuticals Inc. 
 
 
  
Phone: 
 
See appended electronic signature page 
 
Signature 
Date 
 
 
 
Acadia Study Lead: 
 MD 
 Clinical Development 
Acadia Pharmaceuticals GmbH 
 
  
 
Phone: 
  
See appended electronic signature page 
 
Signature 
Date 
 
 
 
 
 
 
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Study: ACP-103-069 
 
Final Version: 1.0 
Clinical Study Protocol Amendment 4 
 
Date: 21 December 2022 
 
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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-103-069 
 
Final Version: 1.0 
Clinical Study Protocol Amendment 4 
 
Date: 21 December 2022 
 
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PROTOCOL SYNOPSIS 
Protocol number 
ACP-103-069 
Protocol title 
A Phase 2, Randomized, Double-blind, Placebo-
controlled Study to Evaluate the Efficacy and Safety 
of Pimavanserin for the Treatment of Irritability 
Associated With Autism Spectrum Disorder 
Name of investigational product 
Pimavanserin (capsules) 
 
Indication 
Irritability associated with autism spectrum disorder 
(ASD)  
Phase of development 
2 
Sponsor 
Acadia Pharmaceuticals Inc. 
12830 El Camino Real, Suite 400 
San Diego, CA 92130 USA  
Efficacy hypothesis 
Pimavanserin, a selective serotonin receptor (5-HT2A) 
inverse agonist/antagonist, will be effective in the 
treatment of irritability and other symptoms of ASD. 
Primary efficacy objective 
• To evaluate the efficacy of 
pimavanserin compared with 
placebo in the treatment of 
irritability associated with 
ASD in children and 
adolescents  
Primary endpoint 
• Change from Baseline at Week 6 in the 
caregiver-rated Aberrant Behavior Checklist 
(ABC) Irritability subscale score 
Secondary objectives 
• To evaluate the efficacy of 
pimavanserin compared with 
placebo, in the treatment of 
non-irritability symptoms, the 
magnitude of improvement in 
irritability, and the response 
rate, in children and 
adolescents with ASD 
Secondary endpoints 
• Change from Baseline at Week 6 in the 
caregiver-rated ABC subscale scores 
o Stereotypic behavior 
o Lethargy 
o Hyperactivity 
o Inappropriate speech 
• Change from Baseline at Week 6 in the 
Clinical Global Impression–Severity (CGI-S) 
of irritability score 
• Clinical Global Impression–Improvement 
(CGI-I) of irritability score at Week 6 


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• Change from Baseline at Week 6 in the 
Repetitive Behavior Scale–Revised (RBS-R) 
scores 
• Change from Baseline at Week 6 in the 
Vineland Adaptive Behavior Scales (VABS)–
Socialization subscale score 
• Change from Baseline at Week 6 in the 
Caregiver Strain Questionnaire (CGSQ) scores 
• Proportion of subjects who have at least 25% 
reduction from Baseline in the ABC–Irritability 
subscale score at Week 6 
• Proportion of subjects who have CGI-I of 
irritability score of 1 (very much improved) or 
2 (much improved) at Week 6 
• Proportion of subjects who have at least 25% 
reduction from Baseline in the ABC–Irritability 
subscale score AND a CGI-I of irritability 
score of 1 (very much improved) or 2 (much 
improved) at Week 6 
Safety hypothesis 
Pimavanserin, a selective 5-HT2A inverse agonist 
/antagonist, will be safe and well tolerated in children 
and adolescents with ASD. 
Safety objective 
• To evaluate the safety and 
tolerability of pimavanserin 
compared with placebo in the 
treatment of irritability 
associated with ASD in 
children and adolescents  
Safety endpoints 
Safety will be evaluated by analyses of the following: 
• Treatment-emergent adverse events 
• 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) 


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Pharmacokinetic objective 
• To characterize the 
pharmacokinetics (PK) of 
pimavanserin in children and 
adolescents with ASD 
Pharmacokinetic endpoints 
• Plasma concentrations of pimavanserin, and 
AC-279 
• Pimavanserin PK parameters such as, but not 
limited to, Cmax and AUC, using a population 
PK approach 
Pharmacokinetic/pharmacodynamic 
objective 
• To characterize the 
pharmacokinetic/ 
pharmacodynamic (PK/PD) 
relationship of pimavanserin 
for the treatment of irritability 
associated with ASD in 
children and adolescents  
Pharmacokinetic/pharmacodynamic endpoint 
• PK/PD using appropriate PK/PD analysis 
methods (e.g., evaluate the relationship 
between exposure and efficacy/safety 
endpoints) 
Number of study sites 
Approximately 60 global sites and approximately 
eight countries will participate in this study. 
Number of subjects planned 
Approximately 456 subjects will be screened to 
randomize 228 (76 in each treatment arm), assuming a 
screen failure rate of 50%. 
Test product, dose, and 
administration 
Pimavanserin low dose (see below details), 
pimavanserin high dose (see below details), or 
matching placebo (1×placebo capsule [size- and 
color-matched to pimavanserin capsule]), administered 
orally, once daily. 
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 (Cmax and 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 once daily is the more effective 
dose. Similarly, exposure-response analyses 
consistently demonstrated that higher pimavanserin 
exposure is associated with greater response across all 
studied indications. Exposure associated with the 


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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. 
The selection of 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. 
Dose 
Subjects will be stratified by age group (5- through 
12-year-olds or 13- through 17-year-olds) and region 


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(US or rest of world). Within each stratum, eligible 
subjects will be randomized in a 1:1:1 ratio to 
pimavanserin low dose, pimavanserin high dose, or 
placebo. For the 5- through 12-year-olds, the subjects 
who are randomized to the low dose group will receive 
10 mg/day pimavanserin and the subjects who are 
randomized to the high dose group will receive 
20 mg/day pimavanserin. For the 13- through 17-year-
olds, the subjects who are randomized to the low dose 
group will receive 20 mg/day pimavanserin and the 
subjects who are randomized to the high dose group 
will receive 34 mg/day pimavanserin.  
 
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) 
Placebo (provided as 1×placebo capsule) 
Study design 
This study will be conducted as a 6-week, randomized, 
double-blind, fixed-dose, placebo-controlled, parallel 
group study in children and adolescents (5 through 
17 years of age) with ASD with irritability, agitation, 
or self-injurious behaviors. 
The study will have three periods: 
• Screening period: 3-28 days 
• Double-blind treatment period: 6 weeks 
• Safety follow-up period: 30(+3) days for those 
subjects who discontinue prematurely from the 
study or who do not enroll in the 52-week, 
open-label extension study (Study ACP-103-070) 
The study design schematic is provided in Figure S–1.  
Screening Period (3-28 days) 
During the screening period, subjects will be assessed 
for study eligibility, the ability to swallow a test 
capsule (i.e., placebo), and prohibited medications will 
be discontinued. If the subject is unable to swallow a 
test capsule at the Screening visit, they may take some 
capsules home to practice, and will be re-assessed at 
the Baseline visit. 


Study: ACP-103-069 
 
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Date: 21 December 2022 
 
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Discussion between the Investigator and Medical 
Monitor about subject eligibility is encouraged, to 
ensure that scientifically informed eligibility decisions 
are being made with all the necessary information, and 
in an objective and homogenous manner consistent 
with the protocol. Following the discussion, the 
Principal Investigator will document and sign off on 
the final eligibility decision.  
Medications should be discontinued only if it is 
deemed clinically appropriate to do so and in 
consultation with the treating physician 
(e.g., symptoms are not well controlled or the subject 
cannot tolerate the current medication). 
Investigators should not withdraw a subject’s 
prohibited medication solely for the purpose of 
making the subject eligible to enroll into the study. 
The screening period may be extended up to 7 days to 
confirm subject eligibility when discussed with the 
Medical Monitor in advance. 
Double-blind Treatment Period (6 weeks) 
The Baseline visit (Visit 2) may occur as soon as 
screening procedures are completed and subject 
eligibility has been confirmed by the Investigator. At 
Visit 2, subjects within each stratum will be 
randomized in a 1:1:1 ratio to pimavanserin low dose, 
pimavanserin high dose, or placebo. For the 5- through 
12-year-olds, the subjects who are randomized to the 
low dose group will receive 10 mg/day pimavanserin 
and the subjects who are randomized to the high dose 
group will receive 20 mg/day pimavanserin. For the 
13- through 17-year-olds, the subjects who are 
randomized to the low dose group will receive 
20 mg/day pimavanserin and the subjects who are 
randomized to the high dose group will receive 
34 mg/day pimavanserin. Every attempt will be made 
to recruit equal numbers of subjects from both age 
groups. The total study sample size will be comprised 
of at least 35% subjects in the younger age group. 
Assessments will be conducted at Weeks 0 (Baseline), 
1, 2, 3, 4, 5, and 6/early termination (ET). 
Safety Follow-up Period (30[+3] days) 
For all subjects, including those who complete and 
those who discontinue treatment prematurely from the 
study, a safety follow-up telephone call will be 


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conducted at least 30 days after the last dose of study 
drug. Those who roll over into the 52-week open-label 
extension study, or have withdrawn consent to 
participate in all parts of the study, or who have well 
documented “lost to follow-up” status, will be exempt. 
The schedule of assessments is provided in Table S–1. 
Study duration 
The duration of participation for individual study 
subjects will be up to approximately 14 weeks, 
consisting of a screening period of 3-28 days, a 
6-week double-blind treatment period, and a 
30(+3)-day safety follow-up period. The screening 
period can be extended by 1 week with the approval of 
the Medical Monitor, for a study duration of up to 
15 weeks and a screening period of up to 35 days. 
The study start date is defined as the date the first 
subject is randomized. 
Subjects who successfully complete the double-blind 
6-week Treatment Period may enroll in a 52-week, 
open-label extension study (Study ACP-103-070) if 
they qualify. 
Subjects who discontinue prematurely and have not 
withdrawn consent from the study, or who complete 
the study and do not roll over into the 52-week 
open-label extension study, will have a safety 
follow-up period of at least 30 days (Figure S–1). 
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.  
If the study is terminated for any reason, subjects 
remaining in the study will return to standard of care. 
Main criteria for inclusion and 
exclusion 
To be eligible for this study, subjects must meet all of 
the inclusion criteria and none of the exclusion 
criteria. 
Inclusion Criteria: 
Study Population 
1. Is a male or female 5 through 17 years of age 
at Screening and Baseline visits 


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2. Is within the 5th to 95th percentile for gender 
specific weight for-age and height-for-age 
growth charts from the National Center for 
Health Statistics 
3. 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/legally acceptable 
representative (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.  
4. 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 


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5. Is able to swallow the test placebo capsule 
without difficulty during the Screening or 
Baseline visits 
6. Has a mental age of ≥2 years as determined 
by Investigator based upon school evaluation 
social history or medical records documented 
at any time before or at Screening 
Psychiatric Diagnosis and Concomitant Medications 
7. Meets Diagnostic and Statistical Manual of 
Mental Disorders, Fifth Edition (DSM-5) 
criteria for a primary diagnosis of ASD 
(APA 2013) and the diagnosis is confirmed 
by the Autism Diagnostic Interview–Revised 
(ADI-R)  
8. Has a score ≥18 on the Irritability subscale of 
the Aberrant Behavior Checklist (ABC) at 
Screening and Baseline. If the 
ABC-Irritability score at Baseline exceeds 
≥20% improvement from Screening, the 
patient will not be randomized and will be 
screen failed. 
9. Has a score ≥4 (moderate or greater severity) 
on the Clinical Global Impression–Severity 
(CGI-S) of irritability score at Screening and 
Baseline 
10. Has no current comorbid psychiatric disorder 
other than attention-deficit hyperactivity 
disorder (ADHD), or anxiety disorder 
11. Is drug-naïve to antipsychotic treatment (OR 
had less than 2 weeks antipsychotic 
treatment for any reason), OR had prior lack 
of tolerability to adequate dose of any 
duration of antipsychotic confirmed by 
caregiver and medical records review when 
available 
12. Has been discontinued from previous 
treatments for irritability associated with 
ASD and washed out for at least 5 drug 
half-lives or 2 weeks (whichever is longer) 
prior to Baseline  


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13. Is able to discontinue all prohibited 
concomitant medications to meet protocol 
requirements prior to and during the study 
period (for further information see 
Appendix A and Appendix B). Investigators 
should not withdraw a subject’s medication 
solely for the purpose of enrolling them into 
the study unless discontinuation of the 
medication is deemed to be clinically 
appropriate (e.g., symptoms are not well 
controlled or the subject cannot tolerate the 
current medication). 
14. If subject is undergoing concurrent 
behavioral therapy for autism related 
symptoms or behaviors, this non-
pharmacological treatment regimen has been 
stable for at least 4 weeks prior to Screening, 
and will be consistent throughout the study 
15. Is judged by the Investigator to be clinically 
stable (i.e., no psychiatric hospitalization, 
unless it took place exclusively for social 
reasons, within 12 weeks prior to Screening) 
and not at imminent risk of suicide or injury 
to self, others, or property 
Contraceptives 
16. Female subjects who participate in this study 
must either be unable to become pregnant 
(e.g., premenarchal, surgically sterile, 
etc.) - OR- agree to use a highly effective 
non-hormonal method of contraception 
(e.g., intrauterine device, condom or 
diaphragm with spermicides, or 
contraceptive sponge) from 28 days before 
Baseline to 45 days after last dose (if subject 
does not roll over into the open-label 
extension study). 
Females of childbearing potential must have 
a negative serum human chorionic 
gonadotropin (hCG) pregnancy test at 
Screening and a negative urine hCG 
pregnancy test at Baseline. Females of 
childbearing potential are defined as females 
who have begun menstruating. 
 


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Exclusion Criteria: 
Central Nervous System, Psychiatric, and Illicit Drug 
Use Criteria 
1. 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) 
2. Subjects who have had changes in 
medications or medication doses (for medical 
and allowed comorbid psychiatric 
conditions) within 4 weeks of Baseline 
3. Any history as reported by the caregiver or 
documented by medical records, when 
available, of angioedema, serotonin or 
neuroleptic malignant syndromes, dystonic 
reaction, or tardive dyskinesia, due to an 
antipsychotic or psychotropic medication. 
4. 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 
[current or over last 6 months]) at Screening 
or Baseline and including more than one 
life-threatening suicide attempt (positive 
answer to suicidal behavior questions [over 
last 6 months])  
5. 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 
6. Has a positive urine drug test at Screening or 
Baseline or positive urine drug dipstick test 
result at Baseline (Day 1). For study 
eligibility, the urine toxicology (drug) screen 
(UDS) must be negative for any substance of 
which the subject does not have a valid 
prescription. 


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7. Has met DSM-5 criteria for substance use 
disorders within the last 6 months prior to 
Baseline  
8. Has been treated once or several times for 
≥2 weeks for irritability with an adequate 
dose of any antipsychotic treatment including 
off-label medication and has discontinued 
due to lack of efficacy as confirmed by 
caregiver reports and medical records when 
available. Discontinuation due to lack of 
tolerability for antipsychotic treatments of 
any duration is not exclusionary. 
9. Has a current comorbid diagnosis of bipolar 
disorder, schizophrenia, major depressive 
disorder, substance use disorder, Rett 
syndrome, or fragile-X syndrome, as 
confirmed by the Mini International 
Neuropsychiatric Interview for Children and 
Adolescents (MINI-KID) at Screening. 
ADHD and anxiety disorders are 
exclusionary if they are the primary disorder, 
or are not stable or adequately treated. 
Medical Criteria 
10.  Has any of the following: 
a. a confirmed genetic disorder associated 
with ASD 
b. a cognitive and/or behavioral 
disturbance or profound intellectual 
disability (IQ≤50) documented at any 
time before or at Screening (measured 
and documented standardized, 
individualized, test of intelligence) 
11. Has a history of seizures, unless seizure-free 
and off epileptic drugs for at least 6 months 
prior to Screening 
12. Has any condition that, in the opinion of the 
Investigator, would interfere with the ability 
to comply with study instructions, or that 
might confound the interpretation of the 
study results or put the subject at undue risk 


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13. Has current evidence, or history within the 
previous 12 weeks prior to Screening, of a 
serious and/or unstable psychiatric, 
neurologic, cardiovascular, respiratory, 
gastrointestinal, renal, hepatic, hematologic, 
or other medical disorder, including cancer or 
malignancies that in the judgment of the 
Investigator would jeopardize the safe 
participation of the subject in the study  
14. Clinically significant finding(s) on physical 
examination determined by the Investigator 
to pose a health concern to the subject while 
on study 
15. Weight <15 kg 
16. 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 Screening or Baseline. For age 
≥13 years a resting position (sitting or 
supine) SBP ≥120 mmHg and/or a DBP 
≥80 mmHg, at Screening or Baseline.  
17. Has a clinically significant abnormal ECG at 
Screening or at Baseline 
18. Has a history or presence on at least one 
ECG at Screening or at Baseline, of any of 
the following cardiac conduction 
abnormalities: 
a. QTcF ≥450 ms 
b. PR interval >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 >110 ms  
f. QRS or T wave morphology that 
could, in the Investigator’s 
opinion, render QT interval 
assessment unreliable 
g. Sick sinus syndrome 


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h. Non-sinus rhythm 
i. Resting heart rate <50 beats per 
minute 
For the Baseline visit, the decision to allow 
study entry should be based on the 
Investigator’s interpretation of the ECG 
tracing collected on the study-provided ECG 
device during the visit and that the QTcF 
interval is not exclusionary. 
One repeat set of triplicate ECGs is allowed 
that can occur either at Screening or Baseline.  
19. Has a known family or personal history or 
symptoms of long QT syndrome or has a 
history of cardiac arrhythmias or risk factors 
for torsade de pointes and/or sudden death, 
including symptomatic bradycardia, 
hypokalemia or hypomagnesemia, and the 
presence of congenital prolongation of the 
QT interval 
20. Has a known history of hepatitis B virus 
(HBV), hepatitis C virus (HCV), or human 
immunodeficiency virus (HIV). Subjects 
with a history of hepatitis B are eligible if 
there is documentation of a negative test for 
hepatitis B surface antigen and a positive test 
for antibodies to the HBV surface antigen. 
Subjects with a history of hepatitis C are 
eligible if there is documentation of a 
negative HCV RNA test. 
21. The subject, or any member of the 
household, has suffered from coronavirus 
disease 2019 (COVID-19) or had a 
COVID-19 (PCR or immunoglobulin) 
positive test in the last 4 weeks before 
Screening  
22. Has had greater than 10% blood loss within 
60 days prior to study drug administration 
23. Has one or more clinical laboratory test 
value(s) at Screening outside the limits 
specified below, or any other clinically 
significant laboratory abnormality as 
determined by the Investigator: 


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a.  Hemoglobin value of less than the 
lower limit of normal per central 
lab normal ranges  
b. Aspartate aminotransferase (AST) 
or alanine aminotransferase (ALT) 
value more than 2 × the upper limit 
of normal (ULN) 
c. Total bilirubin value of more than 
25.7 µmol/L (1.5 mg/dL) except in 
subjects with documented 
diagnosis of Gilbert’s syndrome. 
d. Serum creatinine more than 2 × 
ULN 
e. Creatine kinase more than 
1000 U/L  
24. Has unstable diabetes mellitus (DM) as 
measured by a glycosylated hemoglobin 
(HbA1c) ≥7% at Screening 
25. Has a clinically significant thyroid function 
test result at Screening (as measured by 
thyroid stimulating hormone [TSH] and 
reflex free thyroxine [T4]). If TSH is 
abnormal and the reflex free T4 is normal, 
the subject may be randomized. 
26. Has a prolactin concentration greater than or 
equal to 100 ng/mL at Screening 
27. Is breastfeeding or lactating, or has a positive 
pregnancy test result (for subjects who are of 
childbearing potential) 
28. Has a sensitivity to any compound present in 
pimavanserin or any metabolites or 
compounds listed as being present in this 
medication 
29. Has received any other investigational (either 
approved or unapproved) drug within 
30 days or five half-lives (whichever is 
longer) prior to Screening 
30. Is participating in another clinical study of 
any investigational drug, device, or 
intervention 


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31. Has participated in greater than two 
interventional pharmaceutical clinical 
research studies within 6 months of 
Screening 
32. Has a family member who is an employee of 
Acadia 
Pharmacokinetic assessments 
At each predefined timepoint, PK samples will be 
obtained for measurement of concentrations of 
pimavanserin and its metabolite AC-279. When 
possible, an additional PK sample will be collected 
from subjects who experience a serious adverse event 
(SAE) or an adverse event (AE) leading to 
discontinuation, as soon as possible after the 
occurrence of that event. 
For all PK samples (scheduled and unscheduled), the 
dates and times of administration of the last three 
doses of the study drug should be recorded. For 
samples collected from subjects who experience an 
SAE or an AE leading to discontinuation, the date and 
time of the last dose prior to the SAE or AE should 
also be recorded. 
Pimavanserin and AC-279 plasma concentration data 
will remain blinded until the unblinding of the clinical 
database at the end of the study. 
Sample size calculations 
 
The planned sample size is a total of 228 subjects for 
both age groups combined (76 subjects randomized to 
each of the three treatment groups of equal sample 
sizes: pimavanserin high dose group, pimavanserin 
low dose group, and the placebo group). The total 
study sample size will be comprised of at least 35% 
(80) subjects in the younger age group (5 through 
12 years old). 
Assuming the true difference in the mean change in 
the ABC-I subscale score from Baseline to Week 6 is 
5 points between each pimavanserin dose group and 
the placebo group, and assuming the common standard 
deviation is 10 points, 64 evaluable subjects per 
treatment group will provide 80% power to detect the 
difference between either pimavanserin dose group 
and the placebo group at a significance level of 0.05, 
using a 2-sided t-test. Adjusting for a potential 
discontinuation rate of up to 15%, approximately 


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76 subjects per treatment group or 228 total subjects 
will be randomized. 
Statistical methods 
Population Analysis Sets 
The Safety Analysis Set will include all randomized 
subjects who received at least one dose of study drug 
(pimavanserin or placebo). Subjects will be analyzed 
based on the treatment that they actually received. The 
Safety Analysis Set will be used for all safety 
analyses. 
The Full Analysis Set will include all randomized 
subjects who received at least one dose of study drug 
and who have both a baseline value and at least one 
post-Baseline value for the ABC-I subscale score. 
Subjects will be analyzed based on their randomized 
treatment. The Full Analysis Set will be used for the 
analysis of all efficacy endpoints. 
The Pharmacokinetics Analysis Set will include 
subjects in the Safety Analysis Set with at least one 
measurable plasma concentration. The 
Pharmacokinetics Analysis Set will be used for 
pimavanserin and AC-279 plasma concentration 
summaries. 
Subgroup Analysis 
Selected analyses may be performed in subgroups 
defined in the statistical analysis plan (SAP). 
Descriptive Statistics 
Continuous measurement results will be reported 
using the number of subjects with data values, mean, 
standard error of the mean, standard deviation, 
minimum, maximum, and median. For each 
categorical outcome, the number and percentage of 
subjects in each category will be reported. 
Missing Data 
Handling of missing values will be described in detail 
in the SAP.  
Efficacy Analyses  
The estimand used for the primary endpoint analysis is 
described in detail in Section 9.5.1.1. 
The primary efficacy endpoint, change from Baseline 
at Week 6 in the ABC-I score, will be analyzed using 


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mixed-effect model repeated measures (MMRM) 
model. The model will include effects for the age 
group (5 through 12 years old or 13 through 17 years 
old), region (US or rest of world), treatment group 
(pimavanserin high dose, pimavanserin low dose, or 
placebo), visit (Week 1, Week 2, Week 3, Week 4, 
Week 5, or Week 6), the treatment-by-visit interaction, 
and the Baseline ABC-I score. An unstructured 
covariance matrix and Kenward-Roger approximation 
for the denominator degrees of freedom will be used. 
The primary treatment comparisons will be based on 
the difference in least squares means at Week 6 
between each pimavanserin dose group and the 
placebo group using the Full Analysis Set. 
A hierarchical testing procedure will be used to control 
the Type 1 error rate across the two treatment 
comparisons (pimavanserin high dose vs. placebo and 
pimavanserin low dose vs. placebo) for the primary 
endpoint. The hypotheses testing will be conducted in 
sequential order: 1. pimavanserin high dose vs. 
placebo, 2. pimavanserin low dose vs. placebo. If the 
first comparison fails to reach statistical significance at 
the 2-sided 0.05 level, the subsequent comparison will 
be declared as not statistically significant regardless of 
the associated nominal p-value. The study-wise Type 1 
error rate will be maintained at the significance level 
of 0.05. 
Each of the continuous secondary efficacy endpoints 
will be analyzed using the MMRM model similar to 
the analysis of the primary efficacy endpoint. For 
CGI-I of irritability, the baseline CGI-S of irritability 
score will be used as the covariate in the analysis 
model. The proportion of subjects with ≥25% 
reduction in the ABC-I subscale score, the proportion 
of subjects with a CGI-I of irritability score of 1 or 2, 
and the proportion of subjects with ≥25% reduction in 
the ABC-I subscale score AND a CGI-I of irritability 
score of 1 or 2 will be summarized at each 
post-Baseline timepoint. The proportions will be 
compared between each pimavanserin dose group and 
the placebo group using Cochran-Mantel-Haenszel test 
stratified by age group and region. 


Study: ACP-103-069 
 
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Safety Analyses 
Safety results will be summarized by treatment group 
using descriptive statistics in the Safety Analysis Set. 
No formal statistical testing will be performed for any 
of the safety endpoints. Adverse events will be 
classified into standard terminology using the Medical 
Dictionary for Regulatory Activities (MedDRA). 
Treatment-emergent adverse events (TEAEs), TEAEs 
leading to discontinuation, TEAEs related to study 
drug, TEAEs by maximum severity, fatal TEAEs, 
serious TEAEs, and serious TEAEs related to study 
drug will also be summarized. 
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 
QTc intervals and changes in QTc intervals in 
accordance with International Council for 
Harmonisation (ICH) guidelines. 
For the C-SSRS, the number and percentage of 
subjects with suicidal ideation or behavior during the 
study will be tabulated. 
An independent data and safety monitoring board 
(DSMB) will review interim safety data including data 
on TEAEs and serious TEAEs and safety laboratory 
data. 
Pharmacokinetic Analyses 
Plasma concentration data for pimavanserin, and its 
major metabolite (AC-279), will be listed and 
summarized using descriptive statistics. 
Population Pharmacokinetic Analyses 
Pimavanserin exposure parameters such as, but not 
limited to, Cmax and AUC, will be estimated using a 
population PK approach. 
Pharmacokinetic /Pharmacodynamic Analyses 
Using appropriate PK/PD analyses, exposure-response 
relationships for efficacy and safety endpoints will be 
evaluated. 
Date 
21 December 2022 


Study: ACP-103-069 
 
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Figure S–1 
Schematic of Study Design for ACP-103-069 
 
 Abbreviations: ASD=autism spectrum disorder; EOT=end of treatment; ET=early termination; yrs=years 
a 
Subjects who complete the 6-week Treatment Period may be eligible to enroll in a 52-week, open-label extension study (Study ACP-103-070). 
Subjects entering ACP-103-070 will not complete a follow-up telephone call as they will be immediately enrolled in ACP-103-070. 


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Table S–1 
Schedule of Events and Assessments for ACP-103-069 
Period 
Screening 
 
Double-blind treatment period 
Follow-up 
 
 
Baseline 
 
 
 
 
 
EOT/ETr Unscheduleda 
Safety  
follow-upb 
Visit Week 
-4 to 0 
0 
1 
2 
3 
4 
5 
6 
 
10 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
 
9 
Visit window (days) 
+7c 
 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
 
+3d 
Type of visite  
Clinic 
Clinic 
Clinic 
Clinic/ 
Remote 
Clinic 
Clinic 
Clinic/ 
Remote 
Clinic 
Clinic 
Telephone 
Informed consent/assent  
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
Xf 
 
 
 
 
 
 
 
 
Medical history and demographics 
X 
 
 
 
 
 
 
 
 
 
Autism disease history 
X 
 
 
 
 
 
 
 
 
 
HBV, HCV and HIV history 
X 
 
 
 
 
 
 
 
 
 
COVID-19 historyt 
X 
 
 
 
 
 
 
 
 
 
ADI-Ru, bb 
X 
 
 
 
 
 
 
 
 
 
MINI-KIDu 
X 
 
 
 
 
 
 
 
 
 
Capsule swallowing testg 
X 
X 
 
 
 
 
 
 
 
 
Medication history 
X 
X 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
 
X 
 
 
X 
 
 
Vital signs  
X 
X 
X 
Xv 
X 
X 
Xv 
X 
X 
 
Heightw, weight, and BMI 
X 
X 
X 
Xv 
X 
X 
Xv 
X 
X 
 
12-lead ECGh, i, q 
X 
X 
 
 
X 
 
 
X 
 
 
Pharmacokinetic sample collectioni, j, q 
 
Xk 
X 
 
X 
 
 
X 
Xl 
 
Clinical laboratory tests i, q, s, aa 
X 
X 
 
 
X 
 
 
X 
 
 
Thyroid function tests i 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test i, m 
X 
X 
 
 
X 
 
 
X 
 
 
Table continues on next page 


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Table S-1 
Schedule of Events and Assessments for ACP-103-069 (continued) 
Period 
Screening 
 
Double-blind treatment Period 
Follow-up 
 
 
Baseline 
 
 
 
 
 
EOT/ETr Unscheduleda 
Safety  
follow-upb 
Visit Week 
-4 to 0 
0 
1 
2 
3 
4 
5 
6 
 
10 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
 
9 
Visit window (days) 
+7c 
 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
 
+3d 
Type of visite 
Clinic 
Clinic 
Clinic 
Clinic/ 
Remote 
Clinic 
Clinic 
Clinic/ 
Remote 
Clinic 
Clinic 
Telephone 
Urine toxicology (drug) screen 
(UDS)n 
X 
X 
 
 
X  
 
 
X 
 
 
ABCu 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
CGI-S of irritability 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
CGI-I of irritability 
 
 
X 
X 
X 
X 
X 
X 
 
 
RBS-Ru 
X 
X 
 
 
X 
 
 
X 
 
 
VABS-Socializationu 
 
X 
 
 
X 
 
 
X 
 
 
CGSQu 
X 
X 
 
X 
 
X 
 
X 
 
 
C-SSRSu 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ESRS-Au, x 
X 
X 
X 
X x 
X 
X 
Xx   
X 
X 
 
Accurate Symptom Reporting (ASR) 
Trainingu 
X 
 
 
 
 
 
 
 
 
 
Assessment of concomitant 
medicationst  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of syncope occurrencey 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of somnolence 
occurrencez 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Study drug dispensation 
 
X 
X 
 
X 
X 
 
 
Xo 
 
Study drug return and accountabilityp 
 
 
X 
X 
X 
X 
X 
X 
X 
 


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Abbreviations: ABC=Aberrant Behavior Checklist; ADI-R=Autism Diagnostic Interview–Revised; AE=adverse event; ASR=accurate symptom reporting; 
BMI=body mass index; CGI-I=Clinical Global Impression–Improvement; CGI-S=Clinical Global Impression–Severity; CGSQ=Caregiver Strain 
Questionnaire; COVID-19=coronavirus disease 2019; C-SSRS=Columbia–Suicide Severity Rating Scale; ECG=electrocardiogram; EOT=end of treatment; 
ESRS-A=Extrapyramidal Symptom Rating Scale–Abbreviated; ET=early termination; LAR=legally acceptable representative; MINI-KID=Mini 
International Neuropsychiatric Interview for Children and Adolescents; PK=pharmacokinetic; RBS-R=Repetitive Behavior Scale–Revised; SAE=serious 
adverse event; 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 discontinue treatment prematurely from the study or who do not participate in the 
long-term extension 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 
The Screening Period can be extended up to an additional 7 days (i.e., for a total of 5 weeks) before the Baseline visit, after discussion with the Medical 
Monitor. Discussion between the Investigator and Medical Monitor about eligibility is encouraged, to ensure that scientifically informed eligibility decisions 
are being made with all the necessary information, and in an objective and homogenous manner consistent with the protocol. Following the discussion, the 
Principal Investigator will document and sign off on the final eligibility decision. 
d 
Visit timing and windows are relative to the Baseline visit, not relative to the previous visit. 
e 
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. Remote visits are permitted for Week 2 (Visit 4) and Week 5 (Visit 7). For all other 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. 
f 
All assessments must be completed and subject must meet required eligibility criteria before being randomized. 
g 
Subjects will be assessed for their ability to swallow a test capsule (i.e., placebo). If the subject is unable to swallow a test capsule at the Screening visit, they 
may take some capsules home to practice, and will be re-assessed at the Baseline visit. 
h 
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 that can 
occur either at Screening or Baseline. 
i 
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. 
j 
For all PK samples (scheduled and unscheduled, and except at the Baseline visit) the dates and times of administration of the last three doses of the study 
drug should be recorded. 
k 
At the Baseline visit, a PK sample is drawn predose. 
l 
Every effort should be made to collect a PK sample at an unscheduled visit because of an SAE, or an AE leading to discontinuation. 


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m 
For female subjects of childbearing potential, a serum pregnancy test will be completed at the Screening visit; urine pregnancy dipstick tests will be 
completed at all other scheduled timepoints. 
n 
A urine toxicology dipstick should be used in addition to the urine toxicology screen at both the Baseline visit and Visit 8 (to confirm eligibility in 
Study ACP-103-070). A rapid UDS dipstick will be used at Visit 3.  
o 
Study drug may be dispensed to the subject at unscheduled visits if needed. 
p 
If visit is remote, accountability will be assessed verbally with the caregiver, and verified at the next clinic visit. 
q 
The involvement of experienced personnel in the conduction of routine procedures such as blood drawing and ECG recording in this population is strongly 
recommended. 
r 
The ET visit will not be done if the subject withdraws consent to participate in all parts of the study and withdrawal of consent happens before that 
timepoint. 
s 
Prolactin results should be blinded to the Investigator and the Sponsor after Baseline. Results will be monitored by an independent Medical Monitor from the 
Contract Research Organization (CRO). 
t 
Including COVID-19 vaccination. 
u 
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, that 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. The ASR training should be done at Screening before the caregiver completes any scales, and 
repeated whenever there is a change in caregiver or if the site feels a caregiver requires retraining. 
v 
If visit is conducted remotely, vital signs, height, weight, and BMI are optional. 
w 
As measured by stadiometer. 
x 
The ESRS-A will only be conducted at clinic visits and not at remote visits. 
y 
If the caregiver reports an occurrence of syncope, the investigator should ask the “syncope adverse event questions”, as a tool to guide diagnosis, in 
Appendix G. 
z 
If the caregiver reports an occurrence of somnolence, the investigator should ask the “somnolence adverse event questions”, as a tool to guide diagnosis, in 
Appendix H.  
aa 
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. 
bb 
If an ADI-R has been completed for the subject by a certified rater (certified by Dr. 
 and approved by the Sponsor) within 6 months prior to the 
Screening visit and if the original complete ADI-R response booklet with the subject’s answers is available as source data, then there is no need to conduct 
the ADI-R at Screening. The ADI-R can be administered remotely. 
 
PPD


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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ............................................................................................... 2 
DECLARATION OF INVESTIGATOR ................................................................................... 4 
PROTOCOL SYNOPSIS........................................................................................................... 5 
TABLE OF CONTENTS ......................................................................................................... 29 
LIST OF TABLES ................................................................................................................... 35 
LIST OF FIGURES ................................................................................................................. 35 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................. 36 
1 
INTRODUCTION................................................................................................... 38 
1.1 
Background Information ......................................................................................... 38 
1.1.1 
Autism Spectrum Disorder ...................................................................................... 38 
1.1.2 
Current Treatments for Irritability Associated With Autism Spectrum Disorder .... 38 
1.1.3 
Scientific Rationale ................................................................................................. 39 
1.2 
Investigational Product............................................................................................ 41 
1.3 
Previous Clinical Experience .................................................................................. 41 
1.3.1 
Studies in Adults With Schizophrenia ..................................................................... 42 
1.3.2 
Phase 1 Study in Adolescents With Psychiatric Disorders...................................... 44 
1.4 
Study Rationale ....................................................................................................... 44 
1.4.1 
Rationale for Study Design ..................................................................................... 44 
1.4.2 
Rationale for Dose Selection ................................................................................... 45 
1.5 
Benefit/Risk Assessment ......................................................................................... 46 
1.5.1 
Known Potential Risks ............................................................................................ 46 
1.5.2 
Known Potential Benefits ....................................................................................... 47 
2 
STUDY OBJECTIVES AND ENDPOINTS .......................................................... 47 
2.1 
Primary Efficacy Objective ..................................................................................... 47 
2.1.1 
Primary Endpoint .................................................................................................... 47 
2.2 
Secondary Objectives .............................................................................................. 47 
2.2.1 
Secondary Endpoints ............................................................................................... 47 
2.3 
Safety Objectives .................................................................................................... 48 
2.3.1 
Safety Endpoints ..................................................................................................... 48 
2.4 
Pharmacokinetic Objective ..................................................................................... 48 
2.4.1 
Pharmacokinetic Endpoints ..................................................................................... 48 
2.5 
Pharmacokinetic/Pharmacodynamic Objective....................................................... 49 
2.5.1 
Pharmacokinetic/Pharmacodynamic Endpoint ....................................................... 49 


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3 
STUDY DESCRIPTION......................................................................................... 49 
3.1 
Overview of Study Design ...................................................................................... 49 
3.1.1 
Screening Period (3-28 Days) ................................................................................. 49 
3.1.2 
Double-blind Treatment Period (6 Weeks).............................................................. 50 
3.1.3 
Safety Follow-up Period (30 Days)......................................................................... 50 
4 
SUBJECT ELIGIBILITY AND WITHDRAWAL CRITERIA ............................... 51 
4.1 
Inclusion Criteria ..................................................................................................... 51 
4.2 
Exclusion Criteria.................................................................................................... 53 
4.3 
Screen Failures ........................................................................................................ 57 
4.4 
Subject Withdrawal of Consent ............................................................................... 57 
4.5 
Subject Discontinuation .......................................................................................... 58 
4.5.1 
Handling of Subject Discontinuation During the Treatment Period ....................... 58 
4.6 
Subject Lost to Follow-up ....................................................................................... 59 
4.7 
Study Discontinuation ............................................................................................. 59 
4.8 
Prior and Concomitant Therapy .............................................................................. 59 
4.8.1 
Prior Medication...................................................................................................... 59 
4.8.2 
Concomitant Medication ......................................................................................... 59 
4.8.2.1 
Permitted, Restricted, and Prohibited Medications ................................................. 60 
4.8.3 
Rescue Medications, Treatments, and Procedures .................................................. 60 
5 
INVESTIGATIONAL PRODUCT.......................................................................... 60 
5.1 
Investigational Product Description ........................................................................ 60 
5.1.1 
Formulation, Appearance, Packaging, and Labeling............................................... 61 
5.1.2 
Product Storage and Stability .................................................................................. 62 
5.1.3 
Dosing and Administration ..................................................................................... 62 
5.1.4 
Method of Assigning Subjects to Treatment Groups .............................................. 62 
5.1.5 
Blinding ................................................................................................................... 62 
5.1.6 
Study Drug Compliance .......................................................................................... 63 
5.1.7 
Overdose ................................................................................................................. 63 
5.2 
Investigational Product Accountability Procedures ................................................ 63 
6 
STUDY ASSESSMENTS ....................................................................................... 64 
6.1 
Screening Assessments............................................................................................ 64 
6.1.1 
Demography ............................................................................................................ 64 
6.1.2 
Medical History ....................................................................................................... 64 
6.1.3 
Autism Disease History........................................................................................... 64 
6.1.4 
Autism Diagnostic Interview–Revised.................................................................... 65 


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6.1.5 
Mini International Neuropsychiatric Interview for Children and Adolescents ....... 65 
6.1.6 
Capsule Swallowing Test ........................................................................................ 66 
6.1.7 
Medication History.................................................................................................. 66 
6.1.8 
Physical Examination .............................................................................................. 66 
6.1.9 
Vital Signs ............................................................................................................... 66 
6.1.10 
Height, Weight, and Body Mass Index.................................................................... 66 
6.1.11 
12-lead ECG ............................................................................................................ 66 
6.1.12 
Clinical Laboratory Tests ........................................................................................ 66 
6.1.13 
Pregnancy Test ........................................................................................................ 66 
6.1.14 
Urine Toxicology (Drug) Screen ............................................................................. 66 
6.1.15 
Aberrant Behavior Checklist ................................................................................... 66 
6.1.16 
CGI-S ...................................................................................................................... 66 
6.1.17 
RBS-R ..................................................................................................................... 66 
6.1.18 
VABS-Socialization ................................................................................................ 66 
6.1.19 
CGSQ ...................................................................................................................... 67 
6.1.20 
C-SSRS ................................................................................................................... 67 
6.1.21 
Concomitant Medications and Adverse Events....................................................... 67 
6.2 
Efficacy Assessments .............................................................................................. 67 
6.2.1 
Aberrant Behavior Checklist ................................................................................... 67 
6.2.2 
CGI-S ...................................................................................................................... 68 
6.2.3 
CGI-I ....................................................................................................................... 68 
6.2.4 
Repetitive Behavior Scale–Revised ........................................................................ 68 
6.2.5 
Vineland Adaptive Behavior Scales–Socialization ................................................. 69 
6.2.6 
Caregiver Strain Questionnaire ............................................................................... 69 
6.3 
Safety Scales ........................................................................................................... 70 
6.3.1 
Columbia–Suicide Severity Rating Scale ............................................................... 70 
6.3.2 
Extrapyramidal Symptom Rating Scale–Abbreviated ............................................ 70 
6.4 
Safety Assessments ................................................................................................. 71 
6.4.1 
Medication History.................................................................................................. 71 
6.4.2 
Physical Examination .............................................................................................. 71 
6.4.3 
Vital Signs ............................................................................................................... 72 
6.4.4 
Electrocardiograms ................................................................................................. 72 
6.4.5 
Laboratory Evaluations ........................................................................................... 73 
6.4.6 
Syncope ................................................................................................................... 75 
6.4.7 
Somnolence ............................................................................................................. 76 
6.5 
Pharmacokinetic Assessments ................................................................................. 76 
6.6 
Blood Sampling....................................................................................................... 76 


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6.7 
Safety Follow-up ..................................................................................................... 79 
6.8 
Unscheduled Visits .................................................................................................. 79 
6.9 
Remote Assessments or Visits ................................................................................. 80 
7 
ADVERSE EVENTS .............................................................................................. 80 
7.1 
Specification of Safety Parameters ......................................................................... 80 
7.1.1 
Definition of Adverse Event.................................................................................... 80 
7.1.2 
Definition of Serious Adverse Event....................................................................... 81 
7.2 
Classification of an Adverse Event ......................................................................... 82 
7.2.1 
Severity of Event ..................................................................................................... 82 
7.2.2 
Relationship to Study Drug ..................................................................................... 83 
7.2.3 
Duration................................................................................................................... 83 
7.2.4 
Frequency ................................................................................................................ 83 
7.2.5 
Action Taken with Study Drug................................................................................ 83 
7.2.6 
Therapy ................................................................................................................... 84 
7.2.7 
Outcome .................................................................................................................. 84 
7.2.8 
Seriousness .............................................................................................................. 84 
7.2.9 
Definition of Unexpectedness ................................................................................. 84 
7.3 
Time Period and Frequency for Event Assessment and Follow-up ........................ 84 
7.4 
Reporting Procedures .............................................................................................. 85 
7.4.1 
Adverse Event Reporting ........................................................................................ 85 
7.4.2 
Serious Adverse Event Reporting ........................................................................... 85 
7.4.3 
Reporting of Pregnancy........................................................................................... 86 
7.4.4 
Reporting of Overdose ............................................................................................ 87 
8 
MONITORING ....................................................................................................... 87 
9 
STATISTICAL METHODS AND DATA ANALYSIS ........................................... 87 
9.1 
Statistical and Analytical Plans ............................................................................... 87 
9.2 
Statistical Hypotheses ............................................................................................. 87 
9.3 
Sample Size Determination ..................................................................................... 88 
9.4 
Population Analysis Sets ......................................................................................... 88 
9.5 
Statistical Analyses.................................................................................................. 88 
9.5.1 
Primary Endpoint Analysis ..................................................................................... 89 
9.5.1.1 
Estimand.................................................................................................................. 89 
9.5.1.2 
Primary Estimator ................................................................................................... 90 
9.5.2 
Secondary Endpoint Analyses ................................................................................. 90 
9.5.3 
Safety Endpoints ..................................................................................................... 92 
9.5.3.1 
Treatment-emergent Adverse Events ...................................................................... 92 


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9.5.3.2 
Vital Signs, Weight, and Body Mass Index ............................................................. 92 
9.5.3.3 
12-lead Electrocardiograms..................................................................................... 92 
9.5.3.4 
Physical Examination Results ................................................................................. 92 
9.5.3.5 
Clinical Laboratory Tests and Hormonal Assessments ........................................... 92 
9.5.3.6 
Columbia-Suicide Severity Rating Scale ................................................................ 93 
9.5.3.7 
Extrapyramidal Symptom Rating Scale–Abbreviated ............................................ 93 
9.5.4 
Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analyses ..................... 93 
9.5.5 
Subgroup Analyses .................................................................................................. 93 
9.6 
Interim Analyses...................................................................................................... 93 
9.7 
Data and Safety Monitoring Board ......................................................................... 93 
9.8 
Measures to Minimize Bias ..................................................................................... 93 
9.9 
Breaking the Study Blind/Subject Code ................................................................. 94 
10 
STUDY MANAGEMENT AND DATA COLLECTION ....................................... 94 
10.1 
Data Collection and Management Responsibilities ................................................ 94 
10.2 
Source Documents .................................................................................................. 95 
10.3 
Case Report Forms .................................................................................................. 95 
10.4 
Confidentiality......................................................................................................... 95 
10.5 
Study Records Retention ......................................................................................... 95 
10.6 
Protocol Exceptions and Deviations ....................................................................... 96 
10.7 
Protocol Amendments ............................................................................................. 96 
11 
QUALITY MANAGEMENT ................................................................................. 96 
11.1 
Risk Management.................................................................................................... 96 
11.2 
Quality Control and Quality Assurance .................................................................. 97 
12 
ETHICAL CONSIDERATIONS............................................................................. 98 
12.1 
Ethical Standard ...................................................................................................... 98 
12.2 
Institutional Review Board/Ethics Committee........................................................ 98 
12.3 
Informed Consent/Assent Process........................................................................... 98 
12.3.1 
Subject Assent Form ............................................................................................... 99 
12.3.2 
Parent and Legally Acceptable Representative Informed Consent ......................... 99 
12.3.3 
Consent and Other Informational Documents Provided to Subjects....................... 99 
12.3.4 
Consent Procedures and Documentation................................................................. 99 
12.3.4.1 Remote Consent Procedures and Documentation ................................................. 100 
13 
PUBLICATION PLAN ......................................................................................... 100 
14 
CONFLICT OF INTEREST POLICY .................................................................. 101 
14.1 
Finance, Insurance, and Indemnity ....................................................................... 101 


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15 
LITERATURE REFERENCES ............................................................................ 102 
16 
APPENDICES....................................................................................................... 104 
Appendix A Prohibited and Restricted Medicationsa.......................................................... 104 
Appendix B Prohibited and Restricted Concomitant Medications: Inhibitors and 
Inducers of Cytochrome P450 Enzyme 3A4 .................................................. 109 
Appendix C Criteria for Identifying Potentially Clinically Important Laboratory Values . 111 
Appendix D Criteria for Potentially Clinically Important ECG Values.............................. 112 
Appendix E Criteria for Identifying Additional ECG Measurements of Potential 
Clinical Relevance. To be Used for Medical Monitoring Purposes ................ 113 
Appendix F Criteria for Potentially Clinically Important Vital Signs ................................ 115 
Appendix G Syncope Adverse Event Questions ................................................................. 116 
Appendix H Somnolence Adverse Event Questions ........................................................... 117 
 
 
 


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LIST OF TABLES 
Table S–1 
Schedule of Events and Assessments for ACP-103-069.................................. 25 
Table 6–1 
Safety Laboratory Evaluations......................................................................... 75 
Table 6–2 
Blood Collection Volume Limits in Affected Children ................................... 78 
Table 6–3 
Blood Collection Volumes for Safety Labs and Pharmacokinetic Samples 
(6- through 17-year-olds) ................................................................................. 78 
Table 6–4 
Blood Collection Volumes for Safety Labs and Pharmacokinetic Samples 
(5-year-olds)..................................................................................................... 79 
 
LIST OF FIGURES 
Figure S–1 
Schematic of Study Design for ACP-103-069 ................................................. 24 
 


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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 
ADHD 
attention-deficit hyperactivity disorder 
ADI-R 
Autism Diagnostic Interview–Revised 
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 
CDC 
Centers for Disease Control and Prevention 
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 
COVID-19 
coronavirus disease 2019 
C-SSRS 
Columbia–Suicide Severity Rating Scale 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition 
DSMB 
data and safety monitoring board 
DSM-IV 
Diagnostic and Statistical Manual of Mental Disorders, Fourth 
Edition 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOT 
end of treatment 
ESRS-A 
Extrapyramidal Symptom Rating Scale–Abbreviated 


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Term 
Definition 
ET 
early termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HbA1c 
glycosylated hemoglobin 
HDL 
high-density lipoprotein 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICE 
intercurrent event 
ICH 
International Council for Harmonisation  
IRB 
institutional review board 
LAR 
legally acceptable representative 
MINI-KID 
Mini International Neuropsychiatric Interview for Children and 
Adolescents 
MMRM 
mixed-effect model repeated measures 
NSA-16 
Negative Symptom Assessment–16 
PANSS 
Positive and Negative Syndrome Scale 
PDP 
Parkinson’s disease psychosis 
PK 
pharmacokinetic(s) 
PK/PD 
pharmacokinetic/pharmacodynamic 
QD 
once daily 
QRS 
QRS interval on ECG 
QT 
QT interval on ECG 
QTc 
corrected QT interval on ECG 
QTcB 
corrected QT interval using Bazett’s correction method 
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 
ULN 
upper limit of normal 
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 


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phenotypes with shared underlying pathophysiology to develop targeted treatment, 
management of irritability and maladaptive, self-injurious behaviors 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 


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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 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. 


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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 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. 


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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, respectively. 
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 at 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 at Week 6 in Clinical 
Global Impression–Severity (CGI-S) score. 


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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 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 at 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. 


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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). 
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 
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 
Based on the precedent of the two atypical antipsychotics approved for treatment of 
irritability associated with ASD, this is a 6-week, Phase 2, fixed dose, randomized, 


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double-blind, placebo-controlled study in pediatric patients (5 through 17 years of age) with a 
diagnosis of ASD according to the DSM-5 criteria experiencing irritability, agitation, or 
self-injurious behaviors. A three-arm (high pimavanserin dose, low pimavanserin dose, or 
placebo), fixed-dose design allows for testing of efficacy, safety, and tolerability of 
pimavanserin by dose level. The primary endpoint is change from Baseline at Week 6 in the 
caregiver-rated ABC–Irritability (ABC-I) subscale score (Aman et al. 1985; Kaat et al. 2014). 
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 (Cmax and 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. 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. 
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 


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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. 
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 prolongation. Pimavanserin prolongs the QT interval. 
The use of pimavanserin should be avoided in patients with known QT prolongation or in 
combination with other drugs known to prolong QT interval including Class 1A 
antiarrhythmics (e.g., quinidine, procainamide) or Class 3 antiarrhythmics (e.g., amiodarone, 
sotalol), certain antipsychotic medications (e.g., ziprasidone, chlorpromazine, thioridazine), 
and certain antibiotics (e.g., gatifloxacin, moxifloxacin). Pimavanserin should also be 
avoided in patients with a history of cardiac arrhythmias, as well as other circumstances that 
may increase the risk of the occurrence of torsade de pointes and/or sudden death, including 
symptomatic bradycardia, hypokalemia or hypomagnesemia, and the presence of congenital 
prolongation of the QT interval. 
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. 


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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 indication 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. Subjects may benefit from the 
increased medical care and attention for the study duration and will be given an opportunity to 
roll over into the open label extension. 
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 Efficacy Objective 
• To evaluate the efficacy of pimavanserin compared with placebo in the treatment of 
irritability associated with ASD in children and adolescents 
2.1.1 
Primary Endpoint 
• Change from Baseline at Week 6 in the caregiver-rated Aberrant Behavior Checklist 
(ABC) Irritability subscale score 
2.2 
Secondary Objectives 
• To evaluate the efficacy of pimavanserin compared with placebo, in the treatment of 
non-irritability symptoms, the magnitude of improvement in irritability, and the 
response rate, in children and adolescents with ASD.  
2.2.1 
Secondary Endpoints 
• Change from Baseline at Week 6 in the caregiver-rated ABC subscale scores 
o Stereotypic behavior 
o Lethargy 
o Hyperactivity 
o Inappropriate speech 
• Change from Baseline at Week 6 in the Clinical Global Impression–Severity (CGI-S) 
of irritability score 
• Clinical Global Impression–Improvement (CGI-I) of irritability score at Week 6 
• Change from Baseline at Week 6 in the Repetitive Behavior Scale–Revised (RBS-R) 
scores 


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• Change from Baseline at Week 6 in the Vineland Adaptive Behavior Scales (VABS)–
Socialization subscale score 
• Change from Baseline at Week 6 in the Caregiver Strain Questionnaire (CGSQ) 
scores 
• Proportion of subjects who have at least 25% reduction from Baseline in the ABC–
Irritability subscale score at Week 6 
• Proportion of subjects who have CGI-I of irritability score of 1 (very much improved) 
or 2 (much improved) at Week 6 
• Proportion of subjects who have at least 25% reduction from Baseline in the ABC–
Irritability subscale score AND a CGI-I of irritability score of 1 (very much 
improved) or 2 (much improved) at Week 6 
2.3 
Safety Objectives 
• To evaluate the safety and tolerability of pimavanserin compared with placebo in the 
treatment of irritability associated with ASD in children and adolescents 
2.3.1 
Safety Endpoints 
Safety will be evaluated by analyses of the following: 
• Treatment-emergent adverse events  
• 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) 
2.4 
Pharmacokinetic Objective 
• To characterize the pharmacokinetics (PK) of pimavanserin in children and 
adolescents with ASD 
2.4.1 
Pharmacokinetic Endpoints 
• Plasma concentrations of pimavanserin, and AC-279 
• Pimavanserin PK parameters such as, but not limited to, Cmax and AUC, using a 
population PK approach 


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2.5 
Pharmacokinetic/Pharmacodynamic Objective 
• To characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship of 
pimavanserin for the treatment of irritability associated with ASD in children and 
adolescents 
2.5.1 
Pharmacokinetic/Pharmacodynamic Endpoint 
• PK/PD using appropriate PK/PD analysis methods (e.g., evaluate the relationship 
between exposure and efficacy/safety endpoints) 
3 STUDY DESCRIPTION 
3.1 
Overview of Study Design 
This study will be conducted as a 6-week, randomized, double-blind, fixed-dose, 
placebo-controlled, parallel group study in children and adolescents (5 through 17 years of 
age) with ASD with irritability, agitation, or self-injurious behaviors. Approximately 
60 global sites and approximately eight countries will participate in this study.  
The study will have three periods:  
• Screening period: 3-28 days 
• Double-blind treatment period: 6 weeks 
• Safety follow-up period: 30(+3) days for those subjects who discontinue prematurely 
from the study or who do not enroll in the 52-week, open-label extension study 
(Study ACP-103-070). 
The study design schematic is provided in Figure S–1. 
The study start date is defined as the date the first subject is randomized. 
The primary completion date is the last date that subject data was collected for the primary 
outcome measure. 
The study completion date (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. 
3.1.1 
Screening Period (3-28 Days) 
During the screening period, subjects will be assessed for study eligibility, the ability to 
swallow a test capsule (i.e., placebo), and prohibited medications will be discontinued if 
medically appropriate. If the subject is unable to swallow a test capsule at the Screening visit, 
they may take some capsules home to practice, and will be re-assessed at the Baseline visit. 


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Discussion between the Investigator and Medical Monitor about eligibility is encouraged, to 
ensure that scientifically informed eligibility decisions are being made with all the necessary 
information, and in an objective and homogenous manner consistent with the protocol. 
Following the discussion, the Principal Investigator will document and sign off on the final 
eligibility decision. 
Medications should only be discontinued if it is deemed clinically appropriate to do so and in 
consultation with the treating physician (e.g., symptoms are not well controlled or the subject 
cannot tolerate the current medication). Investigators should not withdraw a subject’s 
prohibited medication solely for the purpose of making them eligible to enroll into the study. 
The screening period may be extended up to 7 days to confirm subject eligibility when 
discussed with the Medical Monitor in advance. 
A single rescreening of individuals who fail screening is permitted with the approval of the 
Sponsor’s Medical Monitor. 
3.1.2 
Double-blind Treatment Period (6 Weeks) 
The Baseline visit (Visit 2) may occur as soon as screening procedures are completed and 
subject eligibility has been confirmed by the Investigator. At Visit 2, subjects within each age 
group (5 through 12 years old or 13 through 17 years old) and region (US or rest of world) 
will be randomized in a 1:1:1 ratio to pimavanserin low dose, pimavanserin high dose, or 
placebo. For the 5- through 12-year-olds, the subjects who are randomized to the low dose 
group will receive 10 mg/day pimavanserin and the subjects who are randomized to the high 
dose group will receive 20 mg/day pimavanserin. For the 13- through 17-year-olds, the 
subjects who are randomized to the low dose group will receive 20 mg/day pimavanserin and 
the subjects who are randomized to the high dose group will receive 34 mg/day 
pimavanserin. Every attempt will be made to recruit equal numbers of subjects from both age 
groups. The total study sample size will be comprised of at least 35% subjects in the younger 
age group. Assessments will be conducted at Weeks 0 (Baseline), 1, 2, 3, 4, 5, and 6/early 
termination (ET). 
3.1.3 
Safety Follow-up Period (30 Days) 
Subjects who successfully complete the 6-week Treatment Period may enroll in a 52-week, 
open-label extension study (Study ACP-103-070) if they qualify and if the subjects have 
presented to the clinic in person to sign the ACP-103-070 informed consent form (ICF) and 
have all ACP-103-069 end-of-treatment procedures. For subjects who discontinue treatment 
prematurely from the study or who do not enroll in the extension study 
(Study ACP-103-070), in addition to the EOT or ET visit performed at time of 
discontinuation, a safety follow-up telephone call will occur 30(+3) days after the last dose of 


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study drug. Those who roll over into the 52-week open-label extension study, or have 
withdrawn consent to participate in all parts of the study, or who have well documented “lost 
to follow-up” status will be exempt. For subjects who discontinue prematurely or who do not 
continue into the extension study, the Investigator must ensure that the subject is 
appropriately transitioned to standard of care and/or followed for additional care per the 
Investigator or physician’s clinical judgment. 
The schedule of assessments is provided in Table S–1. 
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. 
4.1 
Inclusion Criteria 
A subject must meet all of the following inclusion criteria at Screening and Baseline to be 
eligible for participation in the study: 
Study Population 
1. Is a male or female 5 through 17 years of age at Screening and Baseline visits 
2. Is within the 5th to 95th percentile for gender specific weight for-age and 
height-for-age growth charts from the National Center for Health Statistics 
3. 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/legally acceptable representative (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. 


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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.  
4. 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 
5. Is able to swallow the test placebo capsule without difficulty during the Screening 
or Baseline visits  
6. Has a mental age of ≥2 years as determined by Investigator based upon school 
evaluation social history or medical records documented at any time before or at 
Screening 
Psychiatric Diagnosis and Concomitant Medications 
7. Meets Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
(DSM-5) criteria for a primary diagnosis of ASD (APA 2013) and the diagnosis is 
confirmed by the Autism Diagnostic Interview–Revised (ADI-R) 
8. Has a score ≥18 on the Irritability subscale of the Aberrant Behavior Checklist 
(ABC) at Screening and Baseline. If the ABC–Irritability score at Baseline exceeds 
≥20% improvement from Screening, the patient will not be randomized and will be 
screen failed. 
9. Has a score ≥4 (moderate or greater severity) on the Clinical Global Impression–
Severity (CGI-S) of irritability score at Screening and Baseline  
10. Has no current comorbid psychiatric disorder other than attention-deficit 
hyperactivity disorder (ADHD), or anxiety disorder 
11. Is drug-naïve to antipsychotic treatment (OR had less than 2 weeks antipsychotic 
treatment for any reason), OR had prior lack of tolerability to adequate dose of any 
duration of antipsychotic confirmed by caregiver and medical records review when 
available. 
12. Has been discontinued from previous treatments for irritability associated with ASD 
and washed out for at least 5 drug half-lives or 2 weeks (whichever is longer) prior 
to Baseline 


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13. Is able to discontinue all prohibited concomitant medications to meet protocol 
requirements prior to and during the study period (for further information see 
Appendix A and Appendix B). Investigators should not withdraw a subject’s 
medication solely for the purpose of enrolling them into the study unless 
discontinuation of the medication is deemed to be clinically appropriate 
(e.g., symptoms are not well controlled or the subject cannot tolerate the current 
medication). 
14. If subject is undergoing concurrent behavioral therapy for autism related symptoms 
or behaviors, this non-pharmacological treatment regimen has been stable for at 
least 4 weeks prior to Screening, and will be consistent throughout the study 
15. Is judged by the Investigator to be clinically stable (i.e., no psychiatric 
hospitalization, unless it took place exclusively for social reasons, within 12 weeks 
prior to Screening) and not at imminent risk of suicide or injury to self, others, or 
property 
Contraceptives 
16. Female subjects who participate in this study must either be unable to become 
pregnant (e.g., premenarchal, surgically sterile, etc.) -OR- agree to use a highly 
effective non-hormonal method of contraception (e.g., intrauterine device, condom 
or diaphragm with spermicides, or contraceptive sponge) from 28 days before 
Baseline to 45 days after last dose (if subject does not roll over into the open-label 
extension study). 
Females of childbearing potential must have a negative serum human chorionic 
gonadotropin (hCG) pregnancy test at Screening and a negative urine hCG 
pregnancy test at Baseline. 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: 
Central Nervous System, Psychiatric, and Illicit Drug Use Criteria 
1. 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) 


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2. Subjects who have had changes in medications or medication doses (for medical 
and allowed comorbid psychiatric conditions) within 4 weeks of Baseline 
3. Any history as reported by the caregiver or documented by medical records, when 
available, of angioedema, serotonin or neuroleptic malignant syndromes, dystonic 
reaction, or tardive dyskinesia, due to an antipsychotic or psychotropic medication. 
4. 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 [current or over last 
6 months]) at Screening or Baseline and including more than one life-threatening 
suicide attempt (positive answer to suicidal behavior questions [over last 6 months])  
5. 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 
6. Has a positive urine drug test at Screening or Baseline or positive urine drug 
dipstick test result at Baseline (Day 1). For study eligibility, the urine toxicology 
(drug) screen (UDS) must be negative for any substance of which the subject does 
not have a valid prescription. 
7. Has met DSM-5 criteria for substance use disorders within the last 6 months prior to 
Baseline 
8. Has been treated once or several times for ≥2 weeks for irritability with an adequate 
dose of any antipsychotic treatment including off-label medication and has 
discontinued due to lack of efficacy as confirmed by caregiver reports and medical 
records when available. Discontinuation due to lack of tolerability for antipsychotic 
treatments of any duration is not exclusionary. 
9. Has a current comorbid diagnosis of bipolar disorder, schizophrenia, major 
depressive disorder, substance use disorder, Rett syndrome, or fragile-X syndrome, 
as confirmed by the Mini International Neuropsychiatric Interview for Children and 
Adolescents (MINI-KID) at Screening. ADHD and anxiety disorders are 
exclusionary if they are the primary disorder, or are not stable or adequately treated. 
Medical Criteria 
10. Has any of the following: 
a. a confirmed genetic disorder associated with ASD 


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b. a cognitive and/or behavioral disturbance or profound intellectual 
disability (IQ≤50) documented at any time before or at Screening 
(measured and documented standardized, individualized, test of 
intelligence) 
11. Has a history of seizures, unless seizure-free and off epileptic drugs for at least 
6 months prior to Screening 
12. Has any condition that, in the opinion of the Investigator, would interfere with the 
ability to comply with study instructions, or that might confound the interpretation 
of the study results or put the subject at undue risk 
13. Has current evidence, or history within the previous 12 weeks prior to Screening, of 
a serious and/or unstable psychiatric, neurologic, cardiovascular, respiratory, 
gastrointestinal, renal, hepatic, hematologic, or other medical disorder, including 
cancer or malignancies that in the judgment of the Investigator would jeopardize the 
safe participation of the subject in the study 
14. Clinically significant finding(s) on physical examination determined by the 
Investigator to pose a health concern to the subject while on study  
15. Weight <15 kg 
16. 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 Screening or 
Baseline. For age ≥13 years a resting position (sitting or supine) SBP ≥120 mmHg 
and/or a DBP ≥80 mmHg, at Screening or Baseline.  
17. Has a clinically significant abnormal ECG at Screening or at Baseline.  
18. Has a history or presence on at least one ECG at Screening or at Baseline, of any of 
the following cardiac conduction abnormalities: 
a. QTcF ≥450 ms 
b. PR interval >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 >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 


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i. Resting heart rate <50 beats per minute 
For the Baseline visit, the decision to allow study entry should be based on the 
Investigator’s interpretation of the ECG tracing collected on the study-provided 
ECG device during the visit and that the QTcF interval is not exclusionary.  
One repeat set of triplicate ECGs is allowed that can occur either at Screening or 
Baseline. 
19. Has a known family or personal history or symptoms of long QT syndrome or has a 
history of cardiac arrhythmias or risk factors for torsade de pointes and/or sudden 
death, including symptomatic bradycardia, hypokalemia or hypomagnesemia, and 
the presence of congenital prolongation of the QT interval 
20. Has a known history of hepatitis B virus (HBV), hepatitis C virus (HCV), or human 
immunodeficiency virus (HIV). Subjects with a history of hepatitis B are eligible if 
there is documentation of a negative test for hepatitis B surface antigen and a 
positive test for antibodies to the HBV surface antigen. Subjects with a history of 
hepatitis C are eligible if there is documentation of a negative HCV RNA test.  
21. The subject, or any member of the household, has suffered from coronavirus disease 
2019 (COVID-19) or had a COVID-19 (PCR or immunoglobulin) positive test in 
the last 4 weeks before Screening 
22. Has had greater than 10% blood loss within 60 days prior to study drug 
administration 
23. Has one or more clinical laboratory test value(s) at Screening outside the limits 
specified below, or any other clinically significant laboratory abnormality as 
determined by the Investigator: 
a. Hemoglobin value of less than the lower limit of normal per central lab 
normal ranges  
b. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
value more than 2 × the upper limit of normal (ULN) 
c. Total bilirubin value of more than 25.7 µmol/L (1.5 mg/dL) except in 
subjects with documented diagnosis of Gilbert’s syndrome. 
d. Serum creatinine more than 2 × ULN 
e. Creatine kinase more than 1000 U/L  
24. Has unstable diabetes mellitus (DM) as measured by a glycosylated hemoglobin 
(HbA1c) ≥7% at Screening 


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25. Has a clinically significant thyroid function test result at Screening (as measured by 
thyroid stimulating hormone [TSH] and reflex free thyroxine [T4]). If TSH is 
abnormal and the reflex free T4 is normal, the subject may be randomized 
26. Has a prolactin concentration greater than or equal to 100 ng/mL at Screening 
27. Is breastfeeding or lactating, or has a positive pregnancy test result (for subjects 
who are of childbearing potential) 
28. Has a sensitivity to any compound present in pimavanserin or any metabolites or 
compounds listed as being present in this medication 
29. Has received any other investigational (either approved or unapproved) drug within 
30 days or five half-lives (whichever is longer) prior to Screening 
30. Is participating in another clinical study of any investigational drug, device, or 
intervention 
31. Has participated in greater than two interventional pharmaceutical clinical research 
studies within 6 months of Screening 
32. Has a family member who is an employee of Acadia 
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. Basic 
demographic data will be collected from screen failures. 
A single rescreening of individuals who fail screening is permitted with the approval of the 
Sponsor’s Medical Monitor. 
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 


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subject’s reason for wanting to discontinue treatment and the agreement to continue with the 
applicable assessments for study termination must be documented. 
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
•
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 8/ET and the safety follow-up visit 
(as outlined in Table S–1) if a subject discontinues prematurely during the treatment period of 
the study. All information will be reported on the applicable pages of the electronic case 
report form (eCRF). Every effort should be made to collect a PK sample at any ET visit, or 
the visit immediately following any SAE, or following any AE leading to discontinuation, 
even if it is an unscheduled visit. 
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, 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. 


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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. 
4.8 
Prior and Concomitant Therapy 
All medications used from study screening 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). 


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4.8.2.1 
Permitted, Restricted, and Prohibited Medications 
Prohibitions and restrictions for concomitant medications should be followed between the 
initial screening visit and Visit 8 (EOT)/ET as specified in Appendix A and Appendix B. 
These appendices do not constitute an exhaustive list and any questions regarding prohibited 
and restricted medications should be discussed with the Medical Monitor or designee. 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. 
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), pimavanserin 34 mg (provided as 


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1×34 mg capsule), or matching placebo (1×placebo capsule). Placebo capsules will be size- 
and color-matched to the pimavanserin capsules. Capsules will be administered orally as a 
single dose QD. 
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) 
Placebo (provided as 1×placebo capsule) 
5.1.1 
Formulation, Appearance, Packaging, and Labeling 
The Sponsor will supply pimavanserin 10 mg, 20 mg, and 34 mg capsules, and matching 
placebo capsules. 
Pimavanserin 10 mg, 20 mg, and 34 mg capsules, and placebo 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.  
Inactive ingredients include magnesium stearate, microcrystalline cellulose, and the 
components of the capsule shell (hypromellose and titanium dioxide). 
Placebo capsules contain all of the same excipients as pimavanserin capsules but do not 
contain any pimavanserin tartrate. 
Pimavanserin capsules and placebo capsules are manufactured under current Good 
Manufacturing Practice. 
Pimavanserin capsules and placebo capsules will be provided in kits containing 10 count 
blister strips. Each kit will be labeled as required per country requirement. 
Placebo capsules will also be provided in 35 count high density polyethylene (HDPE) bottles 
as open label supplies for purpose of performing a swallow test at Screening and/or Baseline 
(in case the subject fails the capsule swallowing test at Screening). 
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.  


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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 
The first dose of study drug will be administered at the clinic at the Baseline visit. Study drug 
kits will be dispensed to the subject to take home. 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. 
For all PK samples (scheduled and unscheduled), the dates and times of administration of the 
last three doses of the study drug should be recorded. 
5.1.4 
Method of Assigning Subjects to Treatment Groups 
At the Baseline visit, subjects will be stratified by age group (5- through 12-year-olds or 
13- through 17-year-olds) and region (US or rest of world). Within each stratum, eligible 
subjects will be randomized in a 1:1:1 ratio to pimavanserin low dose, pimavanserin high 
dose, or placebo using an interactive response technology (IRT) system. The assignments will 
be based on a pre-generated permuted-block randomization schedule. For the 5- through 
12-year-olds, the subjects who are randomized to the low dose group will receive 10 mg/day 
pimavanserin and the subjects who are randomized to the high dose group will receive 
20 mg/day pimavanserin. For the 13- through 17-year-olds, the subjects who are randomized 
to the low dose group will receive 20 mg/day pimavanserin and the subjects who are 
randomized to the high dose group will receive 34 mg/day pimavanserin. 
5.1.5 
Blinding 
Treatment assignments will be blinded to all study subjects, parents/LARs, Investigators, 
raters, site personnel, and Sponsor personnel. In the event of a potential suspected unexpected 
serious adverse reaction (SUSAR), in accordance with current health authority guidance, 
treatment assignments for the affected subject may be unblinded to a controlled group of the 
Sponsor’s Safety and/or Regulatory personnel for reporting purposes.  
If pregnancy occurs during the study, the pregnant subject should be withdrawn and 
unblinded so that counseling may be offered based on whether the fetus was exposed to the 
active drug or placebo. 
Details regarding medical emergency unblinding procedures are provided in Section 9.9. 


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5.1.6 
Study Drug Compliance 
The Investigator or designated study center personnel will maintain a log of all study drug 
dispensed and returned during the study. Study drug supplies for each subject will be 
inventoried and accounted for throughout the study to verify the subject’s compliance with 
the dosage regimen. Subjects will be counseled regarding compliance at every visit. Subjects 
who have <80% or >120% compliance may be discontinued from the study. If a subject 
shows significant undercompliance (<80%) between any two scheduled visits, the Medical 
Monitor should be notified to determine if the subject remains eligible for the study and 
whether the incident should be considered a protocol deviation. 
If a subject misses one dose of study drug, he or she should not take an extra dose the next 
day. 
5.1.7 
Overdose 
An overdose is a deliberate or inadvertent administration of a treatment at a dose higher than 
the maximum recommended dose per protocol. It must be reported using the Sponsor’s 
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. If visit is remote, accountability will be assessed verbally with the 
caregiver, and verified at the next clinic visit. Any study drug supplied is for use in this study 
only and should not be used for any other purpose. 
At appropriate intervals during the study, study drug reconciliation will be performed by the 
Sponsor (or designee) who may return appropriate unused study drug and used and unused 
packaging to the Sponsor’s designee for destruction. 
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. 


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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 
contact with the subject participating in the study, that 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. The ASR training should be done at 
Screening 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 
Screening Assessments 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. 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. 
6.1.1 
Demography 
Demographic information, including date of birth, age at Screening, gender, race, and 
ethnicity will be recorded.  
6.1.2 
Medical History 
A complete medical history will be obtained from each potential subject at Screening. Any 
new medical condition beginning after the ICF has been signed will be captured as an AE. 
Subjects may be asked to provide pharmacy or medical records to substantiate the medication 
history. The subject’s, and subject’s family history of, risk factors for syncope of any etiology 
will be reviewed (as per the American Academy of Child and Adolescent Psychiatry physical 
assessments). A review of any history of HIV, hepatitis B, or hepatitis C will also be 
performed. 
6.1.3 
Autism Disease History 
Details of the subject’s autism history and treatment will be collected at Screening. 


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6.1.4 
Autism Diagnostic Interview–Revised 
The ADI-R is an Investigator-based interview for caregivers of children or adults for whom 
autism or pervasive developmental disorders is a possible diagnosis (Lord et al. 1994; 
Rutter et al. 2003).  
The ADI-R consists of 93 questions in five sections: 
x opening questions 
x communication (both early and current) 
x social development and play (both early and current) 
x repetitive and restrictive behaviors (all scored for both current and ever judgments) 
x general behavior problems 
An ADI-R diagnosis of autism is conferred on the basis of an algorithm that is scored on 
three dimensional clusters of items: communication, social development and play, and 
repetitive and restrictive behaviors. The algorithm, based on International Classification of 
Diseases-10 (ICD-10)/DSM-IV guidelines, specifies a cutoff score of 8 on communication 
items for verbal subjects (who, as in the original ADI, were operationally defined as 
individuals scoring 0 on the "level of language" item, indicating use of three-word phrases, 
spontaneous or echoed, that sometimes contain a verb) and a cutoff of 7 for nonverbal 
subjects. For all subjects, a minimum score of 10 on social items and 3 for restricted and 
repetitive behaviors was identified. An autism diagnosis is indicated when scores in all three 
behavioral areas meet or exceed the specified minimum cutoff scores.  
The ADI-R, which takes approximately 1.5 hours, will be administered at Screening, and can 
be conducted remotely. If an ADI-R has been completed for the subject by a certified rater 
(certified by Dr. 
 and approved by the Sponsor) within 6 months prior to the Screening 
visit and if the original complete ADI-R response booklet with the subject’s answers is 
available as source data, then there is no need to conduct the ADI-R at Screening.  
6.1.5 
Mini International Neuropsychiatric Interview for Children and Adolescents 
The MINI-KID is a structured clinical diagnostic interview designed to assess the presence of 
current psychiatric disorders in children and adolescents (Sheehan et al. 2010). The 
instrument is administered to the child/adolescent together with the parent(s)/caregiver. The 
MINI-KID is organized in diagnostic sections or modules. Using branching tree logic, the 
instrument asks 2 to 4 screening questions for each disorder. The instrument screens for 
24 DSM-5 and ICD-10 psychiatric disorders and suicidality. 
The MINI-KID, which takes approximately half an hour, will be administered at Screening. 
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6.1.6 
Capsule Swallowing Test 
At the Screening visit, subjects will be assessed for their ability to swallow a test capsule 
(i.e., placebo). Subjects must be able to swallow the test capsule in order to be eligible for 
study entry. If the subject is unable to swallow a test capsule at the Screening visit, they may 
take some capsules home to practice, and will be re-assessed at the Baseline visit. 
6.1.7 
Medication History 
See Section 6.4.1. 
6.1.8 
Physical Examination 
See Section 6.4.2. 
6.1.9 
Vital Signs 
See Section 6.4.3. 
6.1.10 
Height, Weight, and Body Mass Index 
See Section 6.4.2. 
6.1.11 
12-lead ECG 
See Section 6.4.4. 
6.1.12 
Clinical Laboratory Tests 
See Section 6.4.5. 
6.1.13 
Pregnancy Test 
See Section 6.4.5. 
6.1.14 
Urine Toxicology (Drug) Screen 
See Section 6.4.5. 
6.1.15 
Aberrant Behavior Checklist 
See Section 6.2.1. 
6.1.16 
CGI-S 
See Section 6.2.2. 
6.1.17 
RBS-R 
See Section 6.2.4. 
6.1.18 
VABS-Socialization 
See Section 6.2.5. 


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6.1.19 
CGSQ 
See Section 6.2.6. 
6.1.20 
C-SSRS 
See Section 6.3.1. 
6.1.21 
Concomitant Medications and Adverse Events 
All medications used from study screening until completion of the safety follow up visit are 
to be recorded (Sections 4.8 and 6.4.1).  
All adverse events (Section 7) from study screening 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) 
The ABC will be administered at Screening and Baseline, and at all post-Baseline visits from 
Week 1 through Week 6. 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 screening 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 10-20 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. 


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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 Screening and 
Baseline, and at all visits from Week 1 through Week 6. 
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). The CGI-I of irritability will 
be administered at all visits from Week 1 through Week 6. 
The same clinician should administer the CGI-I of irritability throughout the study as 
established at the Week 1 visit. 
6.2.4 
Repetitive Behavior Scale–Revised 
The 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) 
• 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 Screening and Baseline, and at the Week 3 and Week 6 
visits. This scale will take approximately 20-30 minutes to complete. 


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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 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 3 and Week 6 
visits. 
The same rater or clinician should perform the VABS-Socialization together with the same 
caregiver throughout the study as established at the Baseline visit. 
6.2.6 
Caregiver Strain Questionnaire  
The Caregiver Strain Questionnaire (CGSQ) (Brannan et al. 1997) is a 21-item 
parent/caregiver-facing questionnaire of self-reported strain experienced in the past 6 weeks 
(Screening visit), or since last visit (all other visits), 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 
• disruption of social/community life 
• worry and guilt 
• fatigue and strain 
• embarrassment 
• child-caregiver relationship 
The CGSQ will be administered at Screening and Baseline, and at the Week 2, Week 4, and 
Week 6 visits. 


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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 Baseline/Screening 
version will be administered at Screening, and the Since Last Visit version will be 
administered at subsequent visits. The C-SSRS results for each subject should be reviewed by 
the Investigator at each visit. If at any time the C-SSRS results for a given subject reveal 
potential suicidality, then the Investigator should assess the clinical significance of such 
results. If a clinically significant risk of suicidality is identified for a subject, then the 
Investigator should discontinue the subject and implement appropriate treatment 
(Sections 4.4 and 3.1.3). 
The C-SSRS will be administered at Screening and Baseline, at all visits from Week 1 
through Week 6, 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 the study to monitor for any worsening in extrapyramidal 
symptoms or signs at scheduled and unscheduled visits. 
The ESRS-A will be administered at Screening and Baseline; at all visits from Week 1 
through Week 6; and at unscheduled visits. The ESRS-A will only be conducted at clinic 
visits and not at remote visits. 
The same rater or clinician should perform the ESRS-A together with the same caregiver 
throughout the study as established at Baseline visit. 


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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 
Medication History 
Current and past treatments, medication history, or therapies that are specific to their 
diagnosis will be recorded. A careful review of current, recent, and past medications with 
each subject will also be performed. Medication history will be collected at the Screening and 
Baseline visits 
6.4.2 
Physical Examination 
A general physical examination will be conducted at Screening and Baseline, at Week 3 and 
Week 6 visits. 
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. 
Height (as measured by a stadiometer) and weight will also be measured at all visits from 
Week 1 through Week 6, and at unscheduled visits. Height and weight measurements are 
optional at the Week 2 and Week 5 visits if these are conducted remotely. 


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6.4.3 
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 
Screening and Baseline, at all visits from Week 1 through Week 6, and at unscheduled visits. 
Vital signs are optional at the Week 2 and Week 5 visits if these are conducted remotely.  
6.4.4 
Electrocardiograms 
All 12-lead electrocardiograms (ECGs) will be complete, standardized recordings, performed 
in sequential triplicate whenever possible at Screening, Baseline, Week 3, and Week 6 
(EOT/ET). 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) 
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 


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interpreted by a qualified clinician. ECG tracings and results (ventricular rate, PR, QRS, QT, 
QTcF, and QTcB intervals) will be included in the subject's study records. 
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 that can occur either at Screening or 
Baseline.  
• If the ECG was repeated during the Screening period and the central ECG read during 
Baseline evaluation contains any of the exclusionary abnormalities, the subject should 
be withdrawn from study 
• If the ECG was not repeated at Screening and the central ECG read at Baseline 
contains any of the exclusionary abnormalities, the Baseline ECG may be repeated. 
6.4.5 
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 
o Alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), total 
bilirubin (TBIL), lactate dehydrogenase (LDH) 
o Lipid panel 
 Total cholesterol, high-density lipoprotein (HDL)-cholesterol, triglycerides, 
low-density lipoprotein (LDL)-cholesterol, cholesterol/HDL ratio, non-HDL 
cholesterol 
o HbA1c  
o Mg 
 Mg should only be performed at Visit 1 (Screening) 
o Thyroid function tests 


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 Thyroid stimulating hormone (TSH) and reflex free T4 
 Thyroid function tests should only be performed at Visit 1 (Screening) 
o Vitamin B12 
 Vitamin B12 should only be performed at Visit 1 (Screening) 
o Prolactin 
 Prolactin results should be blinded to the Investigator and the Sponsor after 
Baseline. Results will be monitored by an independent Medical Monitor from 
the Contract Research Organization (CRO). 
o Creatine kinase (CK)/creatine phosphokinase (CPK) 
• Pregnancy test 
o A serum pregnancy test should only be performed at Visit 1 (Table 6–1) for 
women of childbearing potential 
o A urine pregnancy test should be performed at all designated visits after Visit 1 
(Table 6–1) for women of child-bearing potential 
 If urine cannot be obtained in women of childbearing potential, a serum 
pregnancy test should be done in its place 
• Hematology tests 
o Complete blood count (CBC) including: 
 White blood cell (WBC) count 
 Complete differential (relative and absolute) 
 Hematocrit (Hct), hemoglobin, red blood cells (RBC), platelets 
 Reticulocyte count 
• Urinalysis 
o Blood, 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. 


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• Urine toxicology (drug) screen 
o Urine toxicology (drug) 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]). Negative drug screens are required 
for study eligibility. 
o A urine toxicology dipstick should be used at the Baseline and Week 3 visits. At 
the Baseline visit, the urine toxicology dipstick should be performed before 
randomization. 
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 (Screening) 
CHEM, CBC, UA, urine toxicology screen, and serum pregnancy 
test 
Visit 2 (Baseline) 
CHEM, CBC, UA, urine toxicology screen and dipstick, urine 
pregnancy test, and PK blood draws 
Visit 3 (Week 1) 
PK blood draws  
Visit 5 (Week 3) 
CHEM, CBC, UA, urine toxicology dipstick, urine pregnancy 
test, and PK blood draws 
Visit 8 (ET/EOT)  
CHEM, CBC, UA, urine toxicology screen and dipstick, urine 
pregnancy test, and PK blood draws 
Abbreviations: CBC=complete blood count; CHEM=clinical chemistry serum tests; EOT=end of treatment; 
ET=early termination; PK=pharmacokinetic; UA=urinalysis 
6.4.6 
Syncope 
Medical history of syncope will be recorded at screening. 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. 


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6.4.7 
Somnolence 
Medical history of somnolence will be recorded at screening. At each study visit, the 
investigator should query the caregiver for occurrences of somnolence from 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. 
6.5 
Pharmacokinetic Assessments 
At each predefined timepoint, PK samples will be obtained for measurement of 
concentrations of pimavanserin and its metabolite AC-279. When possible, an additional 
PK sample will be collected from subjects at any ET visit, or who experience a serious 
adverse event (SAE) or an adverse event (AE) leading to discontinuation, as soon as possible 
after the occurrence of that event. 
For all PK samples (scheduled and unscheduled), the dates and times of administration of the 
last three doses of the study drug should be recorded. For samples collected from subjects 
who experience an SAE or an AE leading to discontinuation, the date and time of the last 
dose prior to the SAE or AE should also be recorded. 
Pimavanserin and AC-279 plasma concentration data will remain blinded until the unblinding 
of the clinical database at the end of the study. 
At the Baseline visit, a PK sample is drawn predose. 
At Visit 3, Visit 5, Visit 8, or upon ET, a single PK sample will be collected at each visit 
within one of the following time intervals: 
• 1-3 hours after dosing 
• 4-7 hours after dosing 
• 8-11 hours after dosing 
Every effort should be made to collect a PK sample within each of the specified time 
intervals (1-3 hours after dosing, 4-7 hours after dosing, and 8-11 hours after dosing) over the 
course of the study visits that require a PK sample collection. 
6.6 
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 


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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. 
A total of approximately four 2 mL venous blood samples will be collected from each subject 
for measurement of plasma pimavanserin and AC-279. 
In addition, blood samples (one 2 mL sample) for determination of plasma concentrations of 
pimavanserin (and AC-279) will be collected in the event of ET, an SAE, or an AE leading to 
withdrawal. 
Detailed procedures for collection, handling, and storage of plasma specimens are provided 
in the PK Laboratory Manual. Validated, sensitive, and specific high performance liquid 
chromatography-tandem mass spectroscopy (LC-MS/MS) assays will be used to measure 
pimavanserin and its metabolites in plasma. 
An indwelling intravenous cannula may be used for collection of serial PK blood samples 
(saline is to be used to flush the indwelling cannula); otherwise, PK blood samples will be 
obtained via standard venipuncture procedures. The date and actual time of PK blood 
collection must be collected and recorded in the subject’s eCRF. Each label will state the 
study number, subject number, analyte (plasma), study day, and scheduled sample time 
(plasma). 
Each PK sample requires collection of 2 mL of venous blood. A single 2 mL venous blood 
sample will be collected for PK sampling from each subject at the Baseline visit. A single 
2 mL venous blood sample will be collected from each subject on each subsequent day of PK 
sampling. 
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. 
The total amount of blood to be obtained from each subject for PK analysis (approximately 
8 mL) and safety laboratory blood samples (approximately 33 mL and 26.2 mL for 6- through 
17-year-olds and 5-year-olds, respectively) during the course of this study will not exceed 
approximately 41 mL (6- through 17-year-olds) and 34.2 mL (5-year-olds). Note: this total 
amount does not account for additional blood samples that may be collected (e.g., to verify 


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eligibility, in the event of an SAE or an AE leading to withdrawal [see Section 7.4.2], to 
verify elevated laboratory results, etc.).  
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 
Table 6–3 
Blood Collection Volumes for Safety Labs and Pharmacokinetic 
Samples (6- through 17-year-olds) 
 
Screening 
Visit 
Baseline 
Visit 
Visit 3 
(Week 1) 
Visit 5 
(Week 3) 
Visit 8 
(Week 6) 
Total safety labs each study visit 
9 mL 
8 mL 
- - 
8 mL 
8 mL 
PK - predose 
- - 
2 mL 
- - 
- - 
- - 
PK - postdose 
- - 
- -  
2 mL 
2 mL 
2 mL 
Total PK samples each study visit 
- - 
2 mL 
2 mL 
2 mL 
2 mL 
Total volume in any 24-hour period 
(Safety and PK) 
9 mL 
10 mL 
2 mL 
10 mL 
10 mL 
Total volume in any 30-day period (Safety and PK) 
Screening and Baseline 
---------19 mL---------- 
 
 
 
Screening, Baseline, Week 1, and 
Week 3 
---------------31 mL-------------- 
 
Baseline, Week 1, and Week 3 
 
---------------22 mL--------------- 
 
Week 1 and Week 3 
 
 
---------12 mL--------- 
 
Week 3 and Week 6 
 
 
 
---------20 mL--------- 
Abbreviation: PK=pharmacokinetics 


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Table 6–4 
Blood Collection Volumes for Safety Labs and Pharmacokinetic 
Samples (5-year-olds) 
 
Screening 
Visit 
Baseline 
Visit 
Visit 3 
(Week 1) 
Visit 5 
(Week 3) 
Visit 8 
(Week 6) 
Total safety labs each study visit 
8.5 mL 
5.9 mL 
- - 
5.9 mL 
5.9 mL 
PK - predose 
- - 
2 mL 
- - 
- - 
- - 
PK - postdose 
- - 
- -  
2 mL 
2 mL 
2 mL 
Total PK samples each study visit 
- - 
2 mL 
2 mL 
2 mL 
2 mL 
Total volume in any 24-hour period 
(Safety and PK) 
8.5 mL 
7.9 mL 
2 mL 
7.9 mL 
7.9 mL 
Total volume in any 30-day period (Safety and PK) 
Screening and Baseline 
---------16.4 mL---------- 
 
 
 
Screening, Baseline, Week 1, and 
Week 3 
---------------26.3 mL-------------- 
 
Baseline, Week 1, and Week 3 
 
---------------17.8 mL--------------- 
 
Week 1 and Week 3 
 
 
---------9.9 mL--------- 
 
Week 3 and Week 6 
 
 
 
---------15.8 mL--------- 
Abbreviation: PK=pharmacokinetics 
 
6.7 
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 and decide not to continue into the open-label study or are 
not eligible for the open-label study, as well as those who discontinue prematurely from the 
study. Subjects 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 
• Assessment of somnolence 
6.8 
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 


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of the C-SSRS. The Investigator may perform any additional safety evaluations deemed by 
the Investigator to be clinically indicated. 
Every effort should be made to collect a PK sample at an unscheduled visit because of an 
SAE, or an AE leading to discontinuation. 
6.9 
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 may not be 
possible. In those cases, assessments may be performed offsite by raters either in person, or 
via video technology or telephone where possible. Remote visits are permitted for Week 2 
(Visit 4) and Week 5 (Visit 7). For all other 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). The location of the collected assessments should be captured in the eCRF.  
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. 
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 


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• 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 
For subjects who enroll into the open-label extension study, AEs will be recorded from the 
time informed consent is obtained in the present study until the first dose of study drug in the 
open-label study.  
For subjects who discontinue from the study or do not enroll into the open-label extension, 
AEs will be recorded from the time informed consent is obtained until 30 days after the last 
dose of study drug. 
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. 


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Definition of Hospitalization 
Hospitalization is defined by the Sponsor as a full admission to the hospital for diagnosis and 
treatment. This includes prolongation of an existing inpatient hospitalization.  
Examples of visits to a hospital facility that do not meet the serious criteria for 
hospitalization include: 
• Emergency room visits (that do not result in a full hospital admission) 
• Outpatient surgery 
• Preplanned or elective procedures 
• Protocol procedures 
• Social hospitalization, defined as admission to the hospital as a result of inadequate 
family support or care at the subject’s primary residence  
Definition of Disability or Permanent Damage 
Disability is defined as a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions. 
Definition of Medically Significant 
Important medical events (medically significant events) that may not result in death, be life 
threatening, or require hospitalization may be considered to be an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject or may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. Examples of 
such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias, convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse. 
An SAE may also include any other event that the Investigator or Medical Monitor judges to 
be serious or that suggests a significant hazard, contraindication, side effect, or precaution. 
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 


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• Severe: incapacitating and/or preventing normal everyday activities 
7.2.2 
Relationship to Study Drug 
The causality of each AE should be assessed and classified by the Investigator as “related” or 
“not related.” An event is considered related if there is a reasonable possibility that the event 
may have been caused by the product under investigation (i.e., there are facts, evidence, or 
arguments to suggest possible causation). 
Consider the following when assessing causality: 
• Temporal associations between the agent and the event 
• Response to drug cessation (de-challenge) or re-challenge 
• Compatibility with known class effect 
• Known effects of concomitant medications 
• Pre-existing risk factors 
• A plausible mechanism 
• Concurrent illnesses 
• Past medical history 
7.2.3 
Duration 
The start and stop dates for AEs will be recorded using the following criteria: 
• Start: Date of the first episode of the AE or date of worsening in severity  
• Stop: Date when AE recovered or resolved, recovered or resolved with sequelae, or 
worsened in severity 
7.2.4 
Frequency 
The frequency of the AE should be indicated according to the following definitions: 
• Single: Experienced once, without recurrence at same severity 
• Recurrent: More than one discrete episode with the same severity 
7.2.5 
Action Taken with Study Drug 
• Dose not changed: No change in study drug 
• Drug interrupted: Study drug temporarily stopped 
• Drug withdrawn: Study drug discontinued permanently 


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• Not applicable 
• Unknown 
7.2.6 
Therapy 
• None: No new treatment instituted 
• Medication: New treatment initiated as a direct result of AE 
• Other: Other action required 
7.2.7 
Outcome 
• Recovered/resolved: Recovered or resolved 
• Recovered/resolved with sequelae: Recovered or resolved with sequelae 
• Not recovered/not resolved: Not recovered or not resolved 
• Fatal: Death due to an AE 
• Unknown: Unknown 
7.2.8 
Seriousness 
• Not serious 
• Serious (see Section 7.1.2) 
7.2.9 
Definition of Unexpectedness 
An AE, the nature or severity of which is not consistent with the information provided in the 
Reference Safety Information section of the current pimavanserin Investigator’s Brochure. 
7.3 
Time Period and Frequency for Event Assessment and Follow-up 
Adverse events will be recorded from the time informed consent is obtained through the 
study safety follow-up period. If an AE is ongoing at the end of the study safety follow-up 
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. If the 
subject rolls over into the open-label study, any ongoing AEs will be followed in the 
open-label study. 
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). 


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7.4 
Reporting Procedures 
7.4.1 
Adverse Event Reporting 
The Investigator must record all observed AEs and all reported AEs. At each visit, the 
Investigator should ask the subject a nonspecific question (e.g., “Have you noticed anything 
different since your last visit?”) to assess whether any AEs have been experienced since the 
last report or visit. 
Note that any use of medication (and specifically any newly prescribed medication) during 
the course of a study may indicate the occurrence of an AE that may need to be recorded on 
both the AE and the concomitant medication page. 
All AEs, serious and not serious, will be recorded on the AE eCRF page using appropriate 
medical terminology. Severity and relationship to study drug will be assessed by the 
Investigator. 
When possible, clinical AEs should be described by diagnosis and not by symptoms 
(e.g., “cold” or “seasonal allergies” instead of “runny nose”). 
All AEs, whether or not related to the study drug, must be fully and completely documented 
on the AE eCRF and in the subject’s notes. 
7.4.2 
Serious Adverse Event Reporting 
The reporting of SAEs by the Sponsor or designee to the regulatory authorities is a regulatory 
requirement. Each regulatory authority has established a timetable for reporting SAEs based 
upon established criteria. 
Serious AEs must be reported within 24 hours of discovery to the Sponsor or its designee; 
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. 


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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. 
In the event of any SAE (other than death), the study subject will be instructed to contact the 
Investigator (or designee) using the telephone number provided in the ICF. All subjects 
experiencing an SAE will be seen by the Investigator or designee as soon as is feasible 
following the report of the SAE. 
Serious AEs occurring after the safety follow-up period (i.e., 30[+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. 
If pregnancy occurs during the study, the pregnant subject should be unblinded so that 
counseling may be offered based on whether the fetus was exposed to the active drug or 
placebo. 
Any AEs that are the consequence of pregnancy and which meet the criteria for serious 
should also be reported via the SAE form. 
7.4.3.1 Reporting Paternal 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. 


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7.4.4 
Reporting of Overdose 
An overdose is a deliberate or inadvertent administration of a treatment at a dose higher than 
the maximum recommended dose per protocol. It must be reported to the Sponsor or 
designee on the Sponsor Overdose Reporting form within 24 hours of discovery. In addition, 
all events of overdose are to be captured as protocol deviations (see Section 5.1.7). 
8 MONITORING  
Routine monitoring of study sites is described in Section 11. 
Clinical site monitoring is conducted to ensure that the rights and well-being of human 
subjects are protected, that the reported study data are accurate, complete, and verifiable, and 
that the conduct of the study is in compliance with the currently approved protocol and 
amendment(s) as applicable, with GCP, and with applicable regulatory requirements. Details 
of the study site monitoring process are described in a separate clinical monitoring plan 
document. 
9 STATISTICAL METHODS AND DATA ANALYSIS 
9.1 
Statistical and Analytical Plans 
Statistical methods will be documented in detail in a statistical analysis plan (SAP) to be 
approved by the Sponsor prior to database lock. Deviations from the approved SAP, if any, 
will be described and justified in the final clinical study report. 
9.2 
Statistical Hypotheses 
The primary endpoint is the Change from Baseline at Week 6 in the caregiver-rated ABC-I 
subscale score. The primary analysis will be based on the Full Analysis Set. 
Let Δ be the difference in the mean Change from Baseline at Week 6 in the ABC-I subscale 
score between either pimavanserin dose group and the placebo group: 
The null hypothesis for the primary efficacy endpoint is:  
 
Δ=0 
The alternative hypothesis for the primary efficacy endpoint is:  
Δ≠0 
The hypothesis testing for pimavanserin high dose versus placebo and pimavanserin low dose 
versus placebo will be tested in a sequential order. That is, if there is no evidence to show the 
superiority of the pimavanserin high-dose treatment to the placebo with respect to the 
primary efficacy endpoint at the significance level of 0.05, no further testing will be 
performed for pimavanserin low-dose treatment versus placebo. 


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9.3 
Sample Size Determination 
The planned sample size is a total of 228 subjects for both age groups combined (76 subjects 
randomized to each of the three treatment groups of equal sample sizes: pimavanserin high 
dose group, pimavanserin low dose group, and the placebo group). The total study sample 
size will be comprised of at least 35% (80) subjects in the younger age group (5 through 
12 years old). 
Assuming the true difference in the mean change in the ABC-I subscale score from Baseline 
to Week 6 is 5 points between each pimavanserin dose group and the placebo group, and 
assuming the common standard deviation is 10 points, 64 evaluable subjects per treatment 
group will provide 80% power to detect the difference between either pimavanserin dose 
group and the placebo group at a significance level of 0.05, using a 2-sided t-test. Adjusting 
for a potential discontinuation rate of up to 15%, approximately 76 subjects per treatment 
group or 228 total subjects will be randomized. 
9.4 
Population Analysis Sets  
The Safety Analysis Set will include all randomized subjects who received at least one dose 
of study drug (pimavanserin or placebo). Subjects will be analyzed based on the treatment 
that they actually received. The Safety Analysis Set will be used for all safety analyses. 
The Full Analysis Set will include all randomized subjects who received at least one dose of 
study drug and who have both a baseline value and at least one post-Baseline value for the 
ABC-I subscale score. Subjects will be analyzed based on their randomized treatment. The 
Full Analysis Set will be used for the analysis of all efficacy endpoints. 
The Pharmacokinetics Analysis Set will include subjects in the Safety Analysis Set with at 
least one measurable plasma concentration. The Pharmacokinetics Analysis Set will be used 
for pimavanserin and AC-279 plasma concentration summaries. 
Any other analysis sets, if necessary, will be defined in the SAP. 
9.5 
Statistical Analyses 
Continuous measurement results will be reported using the number of subjects with data 
values, mean, standard error of the mean, standard deviation, minimum, maximum, and 
median. For each categorical outcome, the number and percentage of subjects in each 
category will be reported. 
Handling of missing values will be described in detail in the SAP. 


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9.5.1 
Primary Endpoint Analysis 
9.5.1.1 
Estimand 
The primary clinical question of interest for the primary objective is: what is the difference in 
the mean changes from Baseline to Week 6 in the ABC-I score comparing pimavanserin high 
dose versus placebo, and pimavanserin low dose versus placebo, in subjects with ASD with 
irritability, agitation, or self-injurious behaviors, assuming all subjects complete 6 weeks of 
treatment without extended use of rescue medications or use of prohibited medications? 
The estimand is described by the following attributes: 
Population: subjects diagnosed of ASD with irritability, agitation, or self-injurious behaviors 
as defined by the inclusion/exclusion criteria of the study. 
Variable (primary endpoint): Change from Baseline at Week 6 in the ABC-I score. 
Treatment condition: pimavanserin high dose, pimavanserin low dose, and placebo without 
extended use of rescue medications or use of prohibited medications. 
Intercurrent events and strategies:  
• The two intercurrent events (ICEs) “treatment discontinuation due to COVID-19”, 
“treatment discontinuation not due to COVID-19” will be addressed by the 
hypothetical strategy (i.e., assuming that subjects with these ICEs evolve in the same 
way after ICE occurrence as the subjects in the same treatment group who complete 
the treatment).  
• The intercurrent events “use of rescue medications beyond maximum allowed period” 
and “use of prohibited medications” (as listed in the Appendices A and B) will be 
addressed by the treatment condition attribute following the hypothetical strategy 
(i.e., considering measurements of the primary efficacy endpoint, if collected, as 
missing from the point of these ICE occurrence onward and assuming that subjects 
with this ICE evolve in the same way after ICE occurrence as the subjects in the same 
treatment group without these ICEs). 
• The intercurrent event “remote assessments” will be addressed by the treatment 
policy strategy, i.e., utilizing measurements of the primary efficacy endpoint 
regardless of the occurrence of this ICE. 
• Alternative approaches to handling intercurrent events will be addressed in the 
sensitivity analyses. Details on the sensitivity analyses will be provided in the SAP. 
Population-level summary: difference (pimavanserin high dose vs. placebo, pimavanserin 
low dose vs. placebo) in the mean changes from Baseline to Week 6 in the ABC-I score. 


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9.5.1.2 
Primary Estimator 
The primary efficacy endpoint, Change from Baseline at Week 6 in the ABC-I score, will be 
analyzed using MMRM model. The model will include effects for the age group (5 through 
12 years old or 13 through 17 years old; categories based on age at screening), region (US or 
rest of world), treatment group (pimavanserin high dose, pimavanserin low dose, or placebo), 
visit (Week 1, Week 2, Week 3, Week 4, Week 5, or Week 6), the treatment-by-visit 
interaction, and the Baseline ABC-I score. An unstructured covariance matrix and Kenward-
Roger approximation for the denominator degrees of freedom will be used. The primary 
treatment comparisons will be based on the difference in least squares means at Week 6 
between each pimavanserin dose group and the placebo group using the Full Analysis Set. 
A hierarchical testing procedure will be used to control the Type 1 error rate across the 
two treatment comparisons (pimavanserin high dose vs. placebo and pimavanserin low dose 
vs. placebo) for the primary endpoint. The hypotheses testing will be conducted in sequential 
order: 1. pimavanserin high dose versus placebo, 2. pimavanserin low dose versus placebo. 
If the first comparison fails to reach statistical significance at the 2-sided 0.05 level, the 
subsequent comparison will be declared as not statistically significant regardless of the 
associated nominal p-value. The study-wise Type 1 error rate will be maintained at the 
significance level of 0.05. 
In addition to the primary treatment comparisons for the Week 6 timepoint, the treatment 
groups will also be compared at each of the other timepoints (Weeks 1, 2, 3, 4, and 5) using 
the same MMRM model described above. These other comparisons will be considered 
exploratory. 
9.5.2 
Secondary Endpoint Analyses 
Secondary endpoints are the following: 
• Change from Baseline at Week 6 in the caregiver-rated ABC subscale scores 
o Stereotypic behavior 
o Lethargy 
o Hyperactivity 
o Inappropriate speech 
• Change from Baseline at Week 6 in the Clinical Global Impression–Severity (CGI-S) 
of irritability score 
• Clinical Global Impression–Improvement (CGI-I) of irritability score at Week 6  
• Change from Baseline at Week 6 in the Repetitive Behavior Scale–Revised (RBS-R) 
scores 


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• Change from Baseline at Week 6 in the Vineland Adaptive Behavior Scales (VABS)–
Socialization subscale score 
• Change From Baseline at Week 6 in the Caregiver Strain Questionnaire (CGSQ) 
scores 
• Proportion of subjects who have at least 25% reduction from Baseline in the ABC-I 
subscale score (ABC-I responders) at Week 6 
• Proportion of subjects who have CGI-I of irritability score of 1 (very much improved) 
or 2 (much improved) (CGI-I of irritability responders) at Week 6 
• Proportion of subjects who have at least 25% reduction from Baseline in the ABC–
Irritability subscale score AND a CGI-I of irritability score of 1 (very much 
improved) or 2 (much improved) at Week 6 
The change from Baseline to each post-Baseline timepoint in the ABC subscale scores 
(lethargy, stereotypic behavior, hyperactivity, inappropriate speech) and the CGI-S of 
irritability score will be analyzed using an MMRM model similar to that described above for 
the primary endpoint, except that the Baseline value of the endpoint being analyzed will be 
included in the model instead of the Baseline ABC-I subscale score. 
The CGI-I of irritability score at each post-Baseline timepoint will be analyzed using an 
MMRM model. The dependent variable will be the CGI-I of irritability score. The 
independent variables in the model will include the following: age group, region, treatment 
group (pimavanserin high dose, pimavanserin low dose, or placebo), visit (Week 1, Week 2, 
Week 3, Week 4, Week 5, or Week 6), the treatment-by-visit interaction, and the Baseline 
CGI-S of irritability score. 
The change from Baseline to each post-Baseline timepoint in the RBS-R scores, the 
VABS-Socialization subscale score, and the CGSQ scores will be analyzed using an MMRM 
model similar to that described above for the primary endpoint, except that the Baseline value 
of the endpoint being analyzed will be included in the model instead of the Baseline ABC-I 
subscale score, also the visit variable included in the model will reflect the visits scheduled 
for the respective endpoints. 
The proportion of subjects with ≥25% reduction in the ABC-I subscale score, the proportion 
of subjects with a CGI-I of irritability score of 1 or 2, and the proportion of subjects with 
≥25% reduction in the ABC-I subscale score AND a CGI-I of irritability score of 1 or 2 will 
be summarized at each post-Baseline timepoint. The proportions will be compared between 
each pimavanserin dose group and the placebo group using Cochran-Mantel-Haenszel test 
stratified by age group and region. 


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9.5.3 
Safety Endpoints 
Safety results will be summarized by treatment group using descriptive statistics. No formal 
statistical testing will be performed for any of the safety endpoints. 
9.5.3.1 
Treatment-emergent Adverse Events 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
coding dictionary. All AEs will be listed and treatment-emergent adverse events (TEAEs) will 
be summarized by system organ class and preferred term. A TEAE is defined as an AE that 
started after first study dose administration and no later than last study dose date + 30 days. 
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.  
9.5.3.2 
Vital Signs, Weight, and Body Mass Index 
The vital signs, body weight, and BMI at Baseline and each post-Baseline timepoint will be 
summarized by treatment group. Change from Baseline values at each post-Baseline 
timepoint will also be summarized. 
The number and percentage of subjects with changes from Baseline (increases and decreases 
separately) in body weight of 7% or more will also be provided. 
9.5.3.3 
12-lead Electrocardiograms 
The measurement values of ECG parameters at Baseline and each post-Baseline timepoint 
will be summarized by treatment group. Change from Baseline values at each post-Baseline 
timepoint will also be summarized. 
Categorical analyses will be conducted on the incidence of subjects with prolonged QTc 
intervals and changes in QTc intervals in accordance with ICH guidelines and based on the 
FDA E14 Guidance Document. 
9.5.3.4 
Physical Examination Results 
The results of the physical examinations at each visit will be tabulated by treatment group. 
9.5.3.5 
Clinical Laboratory Tests and Hormonal Assessments 
The serum clinical chemistry, hematology, urinalysis and hormonal assessment results at 
Baseline and each post-Baseline timepoint will be summarized by treatment group. Change 
from Baseline values at each post-Baseline timepoint will also be summarized. 
The number and percentage of subjects with potentially clinically important post-baseline 
laboratory values will be summarized by treatment group for selected parameters. The criteria 


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for potentially clinically important values are presented in Appendix C, Appendix D, and 
Appendix F. 
9.5.3.6 
Columbia-Suicide Severity Rating Scale 
For the C-SSRS, the number and percentage of subjects with suicidal ideation or suicidal 
behavior during the study will be tabulated. 
9.5.3.7 
Extrapyramidal Symptom Rating Scale–Abbreviated 
ESRS-A total scores and the four individual global CGI-S of irritability scores at Baseline 
and each post-Baseline timepoint will be summarized by treatment group. Change from 
Baseline values at each post-Baseline timepoint will also be summarized. 
9.5.4 
Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analyses 
Plasma concentration data for pimavanserin and its metabolite (AC-279) will be listed and 
summarized using standard summary statistics. 
If data allow, population PK and PK/PD analyses will be performed to further characterize 
the PK profile and exposure response relationship of pimavanserin and its metabolite using 
measures of safety, and efficacy parameters. The results of population PK and PK/PD 
modeling will be presented in a separate report. Pimavanserin plasma concentration data will 
remain blinded until the unblinding of the clinical database at the end of the study. 
9.5.5 
Subgroup Analyses 
Selected analyses will be performed in age subgroups (5 through 12 years old or 13 through 
17 years old; categories based on age at screening). Additional subgroup analyses may be 
specified 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. 
9.8 
Measures to Minimize Bias 
Subjects will be stratified by age group (5- through 12-year-olds or 13- through 17-year-olds) 
and region (US or rest of world). Within each stratum, eligible subjects will be randomized 


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into one of three treatment groups (pimavanserin high dose, pimavanserin low dose, or 
placebo) in a 1:1:1 ratio using an interactive response technology (IRT) system. The 
assignments will be based on a pre-generated permuted-block randomization schedule. 
Blinding will be assured by restricting access of Investigators and Sponsor personnel and/or 
designee to the treatment codes, and providing identical capsules and packaging for the three 
treatment groups. 
9.9 
Breaking the Study Blind/Subject Code 
For the final analysis, the treatment codes for all subjects will be released to the Sponsor after 
all subjects have completed the study and the clinical database is locked. 
For DSMB safety reviews, the treatment codes will be released to an independent statistical 
group to produce unblinded statistical outputs. The Sponsor and the Investigators will remain 
blinded. 
In case of an emergency, the Investigator has the sole responsibility for determining if 
unblinding of a participants’ intervention assignment is warranted. Participant safety must 
always be the first consideration in making such a determination. If the Investigator decides 
that unblinding is warranted, the Investigator should make every effort to contact the sponsor 
prior to unblinding a participant’s intervention assignment unless this could delay emergency 
treatment of the participant. If a participant’s intervention assignment is unblinded, the 
sponsor must be notified within 24 hours after breaking the blind. 
If pregnancy occurs during the study, the pregnant subject should be withdrawn and 
unblinded so that counseling may be offered based on whether the fetus was exposed to the 
active drug or placebo. 
10 STUDY MANAGEMENT AND DATA COLLECTION 
10.1 Data Collection and Management Responsibilities 
All documents required for the conduct of the study as specified in the ICH GCP guidelines 
will be maintained by the Investigator in an orderly manner and made available for 
monitoring and/or auditing by the Sponsor and regulatory authorities. 
The Investigator and institution must permit authorized representatives of the Sponsor or 
designees (including monitors and auditors), regulatory authorities (including inspectors), 
and the IRB/EC direct 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 


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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 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, 


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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 6.7). The Investigator must report any 
protocol deviation to the Sponsor and, if required, to the IRB/EC in accordance with local 
regulations, within reasonable time. 
10.7 Protocol Amendments 
Changes to the protocol may be made only by the Sponsor (with or without consultation with 
the Investigator). All protocol modifications must be submitted to the site IRB/EC in 
accordance with local requirements and, if required, to regulatory authorities, as either an 
amendment or a notification. Approval for amendments must be awaited before any changes 
can be implemented, except for changes necessary to eliminate an immediate hazard to trial 
subjects, or when the changes involve only logistical or administrative aspects of the trial. 
No approval is required for notifications. 
11 QUALITY MANAGEMENT 
11.1 Risk Management 
The Sponsor utilizes the ICH E6 (GCP) Revision 2 risk management approach that includes 
methods to assure and control the quality of the trial proportionate to the risks inherent in the 
trial and the importance of the information collected. The intent is that all aspects of this trial 
are operationally feasible and that any unnecessary complexity, procedures, and data 
collection are avoided. The Sponsor’s risk management approach includes the following 
documented activities:  


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• 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, drug storage areas, and laboratories) and review of study-related records may 


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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 screening procedures.  


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The informed consent must, at a minimum, include the elements of consent described in the 
ICH guidance on GCP and the US CFR 21 part 50.25. A copy of the ICF planned for use will 
be reviewed by the Sponsor or designee for acceptability and must be submitted by the 
Investigator or designee together with the protocol, to the appropriate IRB/EC for review and 
approval prior to the start of the study at that investigational site. Consent forms must be in a 
language fully comprehensible to the prospective subject 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 


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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 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. 


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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 
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autism spectrum disorder. J Autism Dev Disord. 2019;49(6):2417-2425.  
Acadia Pharmaceuticals Inc. NUPLAZID® [package insert]. 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. 
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 
Fifth Edition: DSM-5. American Psychiatric Association Publishing; 2013. 
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(1):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. 


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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.  
Levy SE, Mandell DS, Schultz RT. Autism. Lancet. 2009;374(9701):1627-1638. 
Lord C, Rutter M, Le Couteur A. Autism Diagnostic Interview-Revised: a revised version of 
a diagnostic interview for caregivers of individuals with possible pervasive developmental 
disorders. J Autism Dev Disord. 1994;24(5):659-685. 
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. 
Rutter, M, Le Couteur A, Lord C. ADI-R Autism Diagnostic Interview – Revised. WPS 
Edition. Manual. Western Psychological Services; 2003. 
Sharma SR, Gonda X, Tarazi FI. Autism spectrum disorder: classification, diagnosis and 
therapy. Pharmacol Ther. 2018;190:91-104. 
Sheehan DV, Sheehan KH, Shytle RD, et al. Reliability and validity of the Mini International 
Neuropsychiatric Interview for children and adolescents (MINI-KID). J Clin Psychiatry. 
2010;71(3):313-326. 
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) 
carbamide (2R,3R)-dihydroxybutanedioate (2:1) (ACP-103), a novel 5-
hydroxytryptamine(2A) receptor inverse agonist. J Pharmacol Exp Ther. 2006;317(2):910-
918. 


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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 study entry and throughout the treatment 
period 
Anticholinergics 
PROHIBITED 
• Centrally acting 
anticholinergics 
o biperiden 
Centrally acting anticholinergic medications are 
prohibited throughout the treatment period and must be 
washed out and discontinued at least 2 weeks or 5 
half-lives (whichever is longer) prior to Baseline 


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Medication Class 
Medicationa 
Prohibition/restrictions 
o trihexiphenidyl 
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 
• Must be washed out at least 2 weeks or 5 half-lives 
(whichever is longer) prior to Baseline 
• Prohibited throughout the treatment period 
• If subject has a history of seizures, must be seizure-
free and off epileptic drugs for at least 6 months 
prior to Screening 
Antidepressants 
PROHIBITED 
• amitriptyline 
• citalopram 
• clomipramine 
• desipramine 
• desvenlafaxine 
• doxepin 
• duloxetine 
• escitalopram 
• esketamine  
• fluvoxamine 
• imipramine 
• ketamine 
• mianserin 
• mirtazapine 
• nefazadone 
• nortriptyline 
• sertraline 
• trazodone 
• trimipramine 
• Prohibited throughout the treatment period 
• Must be discontinued at least 2 weeks or 5 half-lives 
(whichever is longer) prior to the Baseline visit 


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Medication Class 
Medicationa 
Prohibition/restrictions 
• venlafaxine 
Antimanic agents 
PROHIBITED 
• lithium 
• valproate 
Prohibited at study entry and throughout the treatment 
period 
Antimicrobials, 
antifungals, and 
antimalarials 
PROHIBITED 
• clarithromycin 
• erythromycin 
• levofloxacin 
• moxifloxacin 
• pentamidine 
• roxithromycin 
Prohibited at study entry and throughout the treatment 
period 
RESTRICTED 
• artenimol/piperaquine 
• azithromycin 
• bedaquiline 
• ciprofloxacin 
• fluconazole 
• gemifloxacin 
• norfloxacin 
• ofloxacin 
• telavancin 
• telithromycin 
• Prohibited at Baseline but may be used during the 
course of the study to treat a bacterial infection (e.g., 
urinary tract infection, respiratory infection), 
post-Baseline at the discretion of the Investigator 
• 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 
• Must be washed out 2 weeks or 5 half-lives 
(whichever is longer) prior to Baseline 
• Prohibited throughout the treatment period 
Anxiolytics 
PROHIBITED 
• chlordiazepoxide 
• diazepam 
• flurazepam 
Prohibited at study entry and throughout the treatment 
period 
RESTRICTED 
• alprazolam 
• lorazepam 
• midazolam 
• oxazepam 
• temazepam 
• triazolam 
• 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. 


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Medication Class 
Medicationa 
Prohibition/restrictions 
• 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 at study entry and throughout the treatment 
period 
Centrally-acting 
alpha-agonist 
hypotensive agents 
PROHIBITED 
• clonidine 
Prohibited at study entry and throughout the treatment 
period 
Centrally-acting 
alpha2A adrenergic 
receptor agonists  
PROHIBITED 
• guanfacine 
Prohibited at study entry and throughout the treatment 
period 
Hypnotics and 
sleeping agents 
PROHIBITED 
• eszopiclone 
• zolpidem 
• zopiclone 
Prohibited at study entry and 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 for at least 12 weeks prior to 
Screening and the dose is expected to remain the same 
throughout the duration of the study  
Opioids 
PROHIBITED 
• methadone 
Prohibited at study entry and throughout the treatment 
period 
Serotonin 
antagonists  
PROHIBITED 
• cyproheptadine 
• Prohibited throughout the treatment period 
• Must be discontinued at least 3 weeks prior to the 
Baseline visit 
Stimulants and 
wake-promoting 
agents 
RESTRICTED 
• amphetamine salts 
• armodafinil 
Allowed if stable for at least 12 weeks prior to 
Screening and the dose is expected to remain the same 
throughout the duration of the study 


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Medication Class 
Medicationa 
Prohibition/restrictions 
• lisdexamfetamine 
• methylphenidate 
• modafinil 
Abbreviations: ADHD=attention-deficit hyperactivity disorder; ECG=electrocardiogram; QTcF=corrected QT 
interval using Fridericia’s correction method; QRS=QRS interval on ECG;  
a 
Medications within each class include but are not limited to the examples listed in this table. 


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Appendix B Prohibited and Restricted Concomitant Medications: Inhibitors and 
Inducers of Cytochrome P450 Enzyme 3A4 
The information presented here is intended to provide guidance and does not constitute an 
exhaustive list of strong CYP 3A4 enzyme (CYP3A4) inhibitors and inducers. Any questions 
should be discussed with the Medical Monitor or appropriate designee.  
Subjects who require current treatment with a prohibited medication will be withdrawn from 
the study. 
Subjects who have previously taken a prohibited medication during the study will be 
withdrawn from the study unless:  
• the prohibited medication has been discontinued AND  
• withdrawal from the study presents an unacceptable medical risk to the subject 
The justification to allow the subject to continue in the study will be made by the 
Sponsor/Medical Monitor with medical input from the Investigator, and will be documented. 
If allowed to remain in the study, this will be reported as a major protocol deviation and not a 
waiver. 
The metabolism of pimavanserin is affected by strong CYP3A4 inhibitors, resulting in an 
increase in maximum plasma concentration (Cmax) and area under the plasma 
concentration-time curve (AUC) of approximately 3-fold.  
Strong inhibitors of CYP3A4 are to be stopped at least 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 
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) 


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Pak™) 
− combination treatments 
including ritonavir, such as: 
danoprevir and ritonavir 
elvitegravir and ritonavir 
indinavir and ritonavir 
lopinavir and ritonavir 
paritaprevir and ritonavir and 
ombitasvir (and/or dasabuvir) 
saquinavir and ritonavir 
tipranavir and ritonavirsaquinavir 
(Invirase®) 
telaprevir (Incivek®) 
telithromycin (Ketek®) 
troleandomycin 
voriconazole (Vfend®) 
fluconazole (Diflucan®) 
fluvoxamine (Luvox®) 
fosamprenavir (Lexiva®) 
imatinib (Gleevec®) 
isavuconazole 
tofisopam 
verapamil (Calan®) 
STRONG 
INDUCERS 
apalutamide 
avasimibe 
carbamazepine (Tegretol®) 
enzalutamide 
ivosidenib 
lumacaftor 
mitotanephenytoin (Dilantin®)  
rifampin (Rifadin®, Rifadin® IV, 
Rimactane®) 
St. John's Wort 
MODERATE 
INDUCERS 
bosentan (Tracleer®) 
cenobamate 
dabrafenib 
efavirenz (Sustiva®) 
etravirine (Intelence®) 
lorlatinib 
modafinil (Provigil®) 
nafcillin (Unipen®, Nallpen®)  
pexidartinib 
phenobarbital (Luminal®, 
Solfoton®) 
primidone 
sotorasib 
a 
The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-
dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain 
preparation was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when another 
preparation was used (e.g., low dose, single strength). (FDA Drug Development and Drug Interactions 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabelin
g/ucm093664.htm#classInhibit). 


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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 
HbA1c 
% 
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-103-069 
 
Final Version: 1.0 
Clinical Study Protocol Amendment 4 
 
Date: 21 December 2022 
 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc. 
Page 112 of 117 
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-103-069 
 
Final Version: 1.0 
Clinical Study Protocol Amendment 4 
 
Date: 21 December 2022 
 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc. 
Page 113 of 117 
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) 


Study: ACP-103-069 
 
Final Version: 1.0 
Clinical Study Protocol Amendment 4 
 
Date: 21 December 2022 
 
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Page 114 of 117 
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-103-069 
 
Final Version: 1.0 
Clinical Study Protocol Amendment 4 
 
Date: 21 December 2022 
 
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Page 115 of 117 
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-103-069 
 
Final Version: 1.0 
Clinical Study Protocol Amendment 4 
 
Date: 21 December 2022 
 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc. 
Page 116 of 117 
Appendix G Syncope Adverse Event Questions 
• Was there a trigger? 
• 
Did the subject experience any strong emotion, pain, exercise etc. that may 
have triggered the syncope? 
• Was there a prodrome? 
• 
Did the subject have pre-syncope symptoms such as feeling faint, dizzy, 
sick, visual disturbances and ringing in the ears (tinnitus)? 
• Did the subject change color? 
• 
Did the subject have a pallor or blue color? 
• Did the subject lose consciousness?  
• 
If so, how long did the unconsciousness last? 
• Were there other symptoms associated with syncope such as nausea, sweating, feeling 
faint. 
• 
Did the subject experience bradycardia or tachycardia during the syncope? 
• Does the subject/family have history of syncope? 
• To rule out seizure please indicate the following: 
• 
Was there a convulsion? 
• 
Was there tongue biting? 
• 
Was there urinary incontinence? 
• How long did the syncope take for full recovery? 
• What is the possible underlying cause of the syncope? 
• 
In your judgment, do you consider the event of syncope to be situational, 
vasovagal, neural, orthostatic, or arrhythmic syncope? 
• Does the subject require therapy for the syncope? 
• What is the risk for further events? 
• Will the subject be referred to a specialist for further investigation? 
• In your judgment, do you consider that the adverse event of syncope may place the 
subject at safety risk if he/she continues to participate in the study? 


Study: ACP-103-069 
 
Final Version: 1.0 
Clinical Study Protocol Amendment 4 
 
Date: 21 December 2022 
 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc. 
Page 117 of 117 
Appendix H Somnolence Adverse Event Questions 
• What is the probable cause for the somnolence? 
 
• Is the subject on any concomitant medication that is known to produce somnolence? 
 
• How soon does the subject experience somnolence after taking study medication? 
 
• How often does the subject experience somnolence during the day?  
 
• Does the subject need to take a nap with each episode of somnolence? 
 
• Does the subject take several naps during the day? 
 
• Does the subject go to bed late watching TV or playing video games? 
 
• Does the subject have insomnia/nightmare during the night that prevents him/her 
from sleeping well? 
 
• How many hours does the subject sleep at night? 
 
• Is the somnolence interfering with concentration at school and other the daily 
activities? 
 
• Has narcolepsy or other sleep disorder been ruled-out? 
 
• In your opinion, does the subject require therapy/medication to alleviate the 
somnolence? 
 
• In your judgment, do you consider that the adverse event of somnolence may place 
the subject at safety risk if he/she continues to participate in the study? 

SAP_001.pdf: 
 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc. 
Page 1 of 4 
 
 
 
STATISTICAL ANALYSIS PLAN ADDENDUM 
 
Protocol No.: 
ACP-103-069 
Protocol Title: 
A Phase 2, Randomized, Double-blind, 
Placebo-controlled Study to Evaluate the Efficacy and 
Safety of Pimavanserin for the Treatment of Irritability 
Associated With Autism Spectrum Disorder 
Drug: 
Pimavanserin 
Sponsor:  
Acadia Pharmaceuticals Inc. 
Version Date 
October 12, 2024 
 
 
 
 
 
 
 
 
 


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Protocol ACP-103-069 
Version 1.0 
Statistical Analysis Plan Addendum 
12 October 2024 
 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc. 
Page 3 of 4 
TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................3 
1 
INTRODUCTION ........................................................................................................4 
2 
EFFICACY ANALYSES .............................................................................................4 
 
 
 


Protocol ACP-103-069 
Version 1.0 
Statistical Analysis Plan Addendum 
12 October 2024 
 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc. 
Page 4 of 4 
1 INTRODUCTION 
This statistical analysis plan (SAP) addendum provides further details per the Food and Drug 
Administration (FDA) comments on the SAP (Version 3) of Study ACP-103-069 dated 29 July 
2024 for IND 157863. 
2 EFFICACY ANALYSES 
Section 12.4 Multiple Comparisons / Multiplicity (Page 27): 
In response to the FDA's comments, the hierarchical testing procedure has been reverted to the 
testing procedures outlined in the previous version of the SAP, dated December 22, 2022, which 
is consistent with the protocol. 
A hierarchical testing procedure will be used to control the Type I error rate across the two 
treatment comparisons (pimavanserin high dose vs. placebo and pimavanserin low dose vs. 
placebo) for the primary endpoint. The hypotheses testing will be conducted in sequential order: 
1. pimavanserin high dose versus placebo, 2. pimavanserin low dose versus placebo. If the first 
comparison fails to reach statistical significance at the 2-sided 0.05 level, the subsequent 
comparison will be declared as not statistically significant regardless of the associated nominal 
p-value. The study-wise Type I error rate will be maintained at the significance level of 0.05. 
Section 13.1.2.2 Tipping Point Analyses (Page 32):  
In response to the FDA's comments, the tipping point analyses have been updated to remove the 
limitation on the delta value, allowing it to exceed 100% until the conclusion of the primary 
analysis is overturned. 
This sensitivity analysis of the tipping point analysis will be implemented for Full Analysis Set 
using delta adjustment imputation. This MNAR (missing not at random) sensitivity analysis is to 
departure from MAR (missing at random) assumption by progressively increasing the delta until 
conclusion from the primary analysis is overturned. The delta value is 0% to 100%, 200%,.... in 
5% increments of the observed treatment difference between a pimavanserin high dose and 
placebo, pimavanserin low dose and placebo, from the primary analysis of MMRM (mixed 
model for repeated measures) model until conclusion of the primary analysis is overturned. 


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Confidential and Proprietary Information of Acadia Pharmaceuticals Inc. 
Page 1 of 52 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Protocol No.: 
ACP-103-069 
Protocol Title: 
A Phase 2, Randomized, Double-blind, 
Placebo-controlled Study to Evaluate the Efficacy and 
Safety of Pimavanserin for the Treatment of Irritability 
Associated With Autism Spectrum Disorder 
Drug: 
Pimavanserin 
Sponsor:  
Acadia Pharmaceuticals Inc. 
Version No. and Date 
Version 3.0, July 29, 2024 
 
 
 
 
 
 
 
 
 
 


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Protocol ACP-103-069
Version 3.0
Statistical Analysis Plan
 29 July 2024
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc.
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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF TABLES ...........................................................................................................................7 
LIST OF FIGURES .........................................................................................................................7 
LIST OF ABBREVIATIONS ..........................................................................................................8 
1 
INTRODUCTION ......................................................................................................10 
2 
OBJECTIVES .............................................................................................................10 
2.1 
Primary Objective .......................................................................................................10 
2.2 
Secondary Objective ...................................................................................................10 
3 
STUDY DESIGN .......................................................................................................10 
3.1 
General Study Design .................................................................................................10 
3.2 
Schedule of Assessments ............................................................................................13 
3.3 
Randomization ............................................................................................................13 
3.4 
Blinding ......................................................................................................................13 
3.5 
Determination of Sample Size ....................................................................................13 
3.6 
Coronavirus Disease 2019 ..........................................................................................14 
4 
ANALYSIS SETS ......................................................................................................14 
5 
GENERAL CONSIDERATIONS FOR DATA ANALYSES ...................................14 
5.1 
Data Presentation Conventions ...................................................................................14 
5.2 
Derived Variables .......................................................................................................15 
5.2.1 
Aberrant Behavior Checklist ......................................................................................15 
5.2.2 
CGI-S ..........................................................................................................................16 
5.2.3 
CGI-I ...........................................................................................................................16 
5.2.4 
Repetitive Behavior Scale-Revised (RBS-R) .............................................................16 
5.2.5 
Vineland Adaptive Behavior Scales–Socialization (VABS-Socialization) ................17 
5.2.6 
Caregiver Strain Questionnaire ...................................................................................17 
5.2.7 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................18 
5.2.8 
Extrapyramidal Symptom Rating Scale–Abbreviated (ESRS-A) ..............................19 
5.3 
Analysis Visits ............................................................................................................19 
5.3.1 
Study Day ...................................................................................................................19 
5.3.2 
Analysis Visit Windows .............................................................................................20 
5.3.3 
Unscheduled Assessments ..........................................................................................20 


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5.3.4 
Multiple Measurements within Visit Windows ..........................................................20 
5.4 
Missing Data ...............................................................................................................21 
5.4.1 
Missing or Incomplete Date for Last Dose of Study Drug .........................................21 
5.4.2 
Missing or Incomplete Dates for Prior or Concomitant Medications .........................22 
5.4.3 
Missing or Incomplete Dates for Adverse Events ......................................................22 
5.4.4 
Missing Severity Assessment for Adverse Events .....................................................22 
5.4.5 
Missing Relationship to Study Drug for Adverse Events ...........................................22 
5.5 
Character Values of Clinical Laboratory Variables ....................................................22 
6 
SUBJECT DISPOSITION ..........................................................................................22 
7 
PROTOCOL DEVIATIONS ......................................................................................23 
8 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ...................24 
8.1 
Demographics and Other Baseline Characteristics .....................................................24 
8.2 
Baseline Disease Characteristics ................................................................................24 
9 
MEDICAL HISTORY ................................................................................................24 
10 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE ...........................24 
10.1 
Exposure to Study drug ..............................................................................................25 
10.2 
Measurement of Treatment Compliance ....................................................................25 
11 
PRIOR, CONCOMITANT AND POST-TREATMENT MEDICATION .................25 
12 
EFFICACY ANALYSIS CONSIDERATIONS.........................................................26 
12.1 
Efficacy Variables ......................................................................................................26 
12.2 
Adjustment for Covariates ..........................................................................................27 
12.3 
Handling of Missing Data ...........................................................................................27 
12.4 
Multiple Comparisons / Multiplicity ..........................................................................27 
12.5 
Examination of Subgroups .........................................................................................27 
13 
METHODS OF EFFICACY ANALYSES .................................................................28 
13.1 
Primary Efficacy Endpoints ........................................................................................28 
13.1.1 
Primary Analysis ........................................................................................................28 
13.1.2 
Sensitivity Analysis ....................................................................................................31 
13.2 
Secondary and Exploratory Efficacy Analyses ..........................................................33 
14 
SAFETY ANALYSES ...............................................................................................34 
14.1 
Adverse Events ...........................................................................................................34 
14.2 
Clinical Laboratory Variables .....................................................................................35 


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14.2.1 
Analysis of Clinical Laboratory Variables .................................................................37 
14.3 
Vital Signs, Height, Weight, and BMI .......................................................................40 
14.4 
Electrocardiogram (ECG) ...........................................................................................41 
14.5 
Physical Examination .................................................................................................42 
14.6 
Syncope and somnolence ............................................................................................43 
14.7 
Other Safety Variables ................................................................................................43 
14.7.1 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................43 
14.7.2 
Extrapyramidal Symptom Rating Scale–Abbreviated (ESRS-A) ..............................43 
15 
CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC 
ANALYSES ...............................................................................................................43 
16 
INTERIM ANALYSIS ...............................................................................................44 
17 
DATA MONITORING/REVIEW COMMITTEE .....................................................44 
18 
COMPUTER METHODS ..........................................................................................44 
19 
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL .....................................44 
20 
REFERENCES ...........................................................................................................45 
21 
APPENDICES ............................................................................................................46 
21.1 
Schedule of Events and Assessments .........................................................................46 
21.2 
SAS Programming Code for MMRM Model .............................................................50 
21.3 
SAS Programming Code for Multiple Imputation under MNAR ..............................51 
21.4 
Summary of Version Changes ....................................................................................52 
 
 


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LIST OF TABLES 
Table 1 
Analysis Visit Windows ........................................................................................ 20 
Table 2 
Criteria for Potentially Clinically Important Laboratory Values – Hematology 
and Chemistry ....................................................................................................... 39 
Table 3 
Criteria for Potentially Clinically Important Laboratory Values - Urinalysis ....... 40 
Table 4 
Criteria for Potentially Clinically Important Vital Signs ...................................... 41 
Table 5 
Criteria for Potentially Clinically Important ECG Values .................................... 42 
 
LIST OF FIGURES 
Figure 1 
Schematic of Study Design ................................................................................... 12 
 


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LIST OF ABBREVIATIONS 
Terms 
Definitions 
ABC 
Aberrant Behavior Checklist 
ABC-I 
Aberrant Behavior Checklist-Irritability 
ABC-L 
Aberrant Behavior Checklist-Lethargy (lethargy and social withdrawal) 
AC-279 
N-desmethyl-pimavanserin, major metabolite of pimavanserin 
ADI-R 
Autism Diagnostic Interview–Revised 
AE 
adverse event 
ASD 
autism spectrum disorder 
ASR 
Accurate symptom reporting 
CGI-I 
Clinical Global Impression–Improvement 
CGI-S 
Clinical Global Impression–Severity 
CGSQ 
Caregiver Strain Questionnaire 
COVID-19 
coronavirus disease 2019 
C-SSRS 
Columbia–Suicide Severity Rating Scale 
DSMB 
data and safety monitoring board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
ESRS-A 
Extrapyramidal Symptom Rating Scale–Abbreviated 
ET 
early termination 
EOT 
end of treatment 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GSD 
Guidance for Site Documentation and Data Management Querying of Data 
Impacted by COVID-19 
HbA1c 
glycosylated hemoglobin 
HIV 
human immunodeficiency virus 
ICE  
intercurrent event 
IQ 
intelligence quotient 
MAR 
missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation 


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Terms 
Definitions 
MINI-KID 
Mini International Neuropsychiatric Interview for Children and 
Adolescents 
MMRM 
mixed model for repeated measures 
MNAR 
missing not at random 
Msec 
milliseconds 
PCI 
potentially clinically important 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
QRS 
QRS interval of ECG 
QT 
QT interval for heart rate of ECG 
QTc 
corrected QT interval of ECG for heart rate 
QTcB 
corrected QT interval using Bazett’s correction method 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RBS-R 
Repetitive Behavior Scale–Revised 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SE 
standard error 
SOC 
system organ class 
TEAE   
treatment-emergent adverse event 
ULN 
upper limit of normal 
US 
United States 
VABS 
Vineland Adaptive Behavior Scales 


Protocol ACP-103-069 
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Statistical Analysis Plan 
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1 INTRODUCTION 
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the statistical 
analyses of efficacy and safety data based on the study protocol Amendment 4.0 dated 
21 December 2022, and the electronic case report form (eCRF). The SAP will be finalized and 
approved before database lock of the final analysis.  
For Italy, a country-specific protocol amendment (Amendment 4-IT finalized 12 July 2023) 
added the details of the Schwartz equation and modified the exclusion criterion #23 to also 
exclude patients whose estimated glomerular filtration rate (eGFR) is <30 mL/min as calculated 
by the bedside Schwartz equation.  
Specifications for tables, figures, and listings will be provided in a separate document. Statistical 
analyses for population pharmacokinetic (PK) and PK/pharmacodynamics (PD) modeling will be 
presented in a separate report and therefore will not be included in this SAP. 
2 OBJECTIVES 
2.1 
Primary Objective 
To evaluate the efficacy of pimavanserin compared with placebo in the treatment of irritability 
associated with Autism Spectrum Disorder (ASD) in children and adolescents. 
2.2 
Secondary Objective 
To evaluate the efficacy of pimavanserin compared with placebo, in the treatment of 
non-irritability symptoms, the magnitude of improvement in irritability, and the response rate, in 
children and adolescents with ASD. 
3 STUDY DESIGN 
3.1 
General Study Design 
This study will be conducted as a 6-week, randomized, double-blind, fixed-dose, 
placebo-controlled, parallel group study in children and adolescents (5 through 17 years of age) 
with irritability, agitation, or self-injurious behaviors associated to ASD. Approximately 
60 global sites and eight countries will participate in this study. 
The study will have three periods: 
• Screening period: 3-28 days 
• Double-blind treatment period: 6 weeks 


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• Safety follow-up period: 30 (+3) days for those subjects who discontinue prematurely 
from the study or who do not enroll in the 52-week, open-label extension study 
(Study ACP-103-070) 
The study design schematic is provided in Figure 1. 


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Figure 1 
Schematic of Study Design 
 
Abbreviations: ASD=autism spectrum disorder; EOT=end of treatment; ET=early termination; yrs=years   
a 
Subjects who complete the 6-week Treatment Period may be eligible to enroll in a 52-week, open-label extension study (Study ACP-103-070).  Subjects 
entering ACP-103-070 will not complete a follow-up telephone call as they will be immediately enrolled in ACP-103-070. 


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3.2 
Schedule of Assessments 
The schedule of events and assessments for the study is presented in Appendix 21.1. 
3.3 
Randomization 
Eligible subjects will be randomized in a 1:1:1 ratio to pimavanserin low dose, pimavanserin 
high dose, or placebo using an interactive response technology (IRT) system. The randomization 
will be stratified by age group (5- through 12-year-olds or 13- through 17-year-olds) and region 
(U.S. or rest of world). For the 5- through 12-year-olds, the subjects who are randomized to the 
low dose group will receive 10 mg/day pimavanserin and the subjects who are randomized to the 
high dose group will receive 20 mg/day pimavanserin. For the 13- through 17-year-olds, the 
subjects who are randomized to the low dose group will receive 20 mg/day pimavanserin and the 
subjects who are randomized to the high dose group will receive 34 mg/day pimavanserin. The 
assignments will be based on a pre-generated permuted-block randomization schedule. 
3.4 
Blinding 
This is a double-blind study. Blinding will be assured by restricting access of Investigators and 
Sponsor personnel and/or designee to the treatment codes and providing identical capsules and 
packaging for the adjunctive pimavanserin and adjunctive placebo treatments. Neither the 
subjects nor the study personnel at the clinical sites will know which treatment is administered to 
each subject. 
3.5 
Determination of Sample Size 
The planned sample size is a total of 228 subjects for both age groups combined (76 subjects 
randomized to each of the three treatment groups of equal sample sizes: pimavanserin high dose 
group, pimavanserin low dose group, and the placebo group). The total study sample size will be 
comprised of at least 35% (80) subjects in the younger age group (5- through 12-year-olds).  
Assuming the true difference in the mean change in the ABC-Irritability (ABC-I) subscale score 
from Baseline at Week 6 is 5 points between each pimavanserin dose group and the placebo 
group, and assuming the common standard deviation is 10 points, 64 evaluable subjects per 
treatment group will provide 80% power to detect the difference between either pimavanserin 
dose group and the placebo group at a significance level of 0.05, using a 2-sided t-test. Adjusting 
for a potential discontinuation rate of up to 15%, approximately 76 subjects per treatment group, 
or 228 total subjects, will be randomized. 


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3.6 
Coronavirus Disease 2019  
In the context of the global COVID-19 pandemic or other natural disaster, the mechanisms to 
record information on the potential impact of the COVID-19 pandemic on data itself, as well as 
data collection and integrity, will be implemented. The impact of COVID-19 on the statistical 
analysis is discussed in each of the relevant sections of this SAP. 
4 ANALYSIS SETS 
Randomized Analysis Set 
The Randomized Analysis Set will include all unique subjects who were randomized. Subjects 
will be analyzed based on their randomized treatment.  
Safety Analysis Set 
The Safety Analysis Set will include all randomized subjects who received at least one dose of 
study drug (pimavanserin or placebo). Subjects will be analyzed based on the treatment that they 
actually received. If a subject received wrong kit, the actual treatment group will be determined 
based on the majority of treatment the subject received. The Safety Analysis Set will be used for 
all safety analyses. 
Full Analysis Set 
The Full Analysis Set will include all randomized subjects who received at least one dose of 
study drug and who have both a baseline value and at least one post-baseline value for the ABC-I 
subscale score. Subjects will be analyzed based on their randomized treatment. The Full Analysis 
Set will be used for the analysis of all efficacy endpoints. 
Pharmacokinetics Analysis Set 
The Pharmacokinetics Analysis Set will include subjects in the Safety Analysis Set with at least 
one measurable plasma concentration. The Pharmacokinetics Analysis Set will be used for 
pimavanserin and AC-279 plasma concentration summaries. 
5 GENERAL CONSIDERATIONS FOR DATA ANALYSES 
5.1 
Data Presentation Conventions 
For continuous variables, the following summary statistics will be provided: number of subjects, 
mean, standard error of the mean (SE), standard deviation (SD), minimum, maximum, and 
median. Unless specified otherwise, means, medians, and confidence intervals (CIs) will be 
presented to one more decimal place than the raw data, and the SDs and SEs will be presented to 
2 more decimal places than the raw data. Unless otherwise specified, the maximum number of 


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decimal places is 4 and values will be truncated to 4 decimal places in situations where there are 
more than 4 decimal places. Wherever possible data will be decimal aligned. 
For categorical variables, summaries will include the number and percentage of subjects in each 
category. For demographic and baseline characteristics, the number of subjects and the 
percentage of subjects with missing data will be summarized (if applicable), and the denominator 
for percentages will be the total number of subjects in the given treatment group, unless 
otherwise specified. Categories with zero counts will not have zero percentages displayed. 
Percentages will be presented to 1 decimal place. 
All data captured in the Electronic Data Capture (EDC) system will be presented in the listings.  
Unless specified otherwise, all statistical tests will be 2-sided hypothesis tests performed at the 
significance level of 0.05  for main effects and all confidence intervals (CIs) will be 2-sided 
95% CIs. P-values will generally be presented to 4 decimal places; values less than 0.0001 will 
be presented as <0.0001. 
Values that are collected with “<” or “>” signs will generally be analysed as the numerical value 
without the sign in tables and figures. In listings, these data will be reported as collected with the 
sign. 
Duration in years is calculated as number of days/365.25 and will be rounded to 1 digit after the 
decimal point (tenths) for presentation purposes. 
Duration in months is calculated as (number of days/365.25)×12 and will be rounded to 1 digit 
after the decimal point (tenths) for presentation purposes. 
5.2 
Derived Variables 
In general, the assessment scale total scores and subscores will be derived within the analysis 
datasets, if those scores are not automatically generated in EDC. In the event that total scores 
and/or subscores are also collected on the eCRF, the derived values will be used for all analyses. 
Both the raw and derived scores will be presented in the listings. 
5.2.1 
Aberrant Behavior Checklist 
The Aberrant Behavior Checklist (ABC) is a parent/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) 


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IV. Hyperactivity (hyperactivity and noncompliance) (16 items) 
V. 
Inappropriate Speech (4 items) 
The ABC will be administered at Screening and Baseline, and at all post-baseline visits from 
Week 1 through Week 6. Items are rated on a 4-point Likert scale ranging from 0 (not at all a 
problem) to 3 (the problem is severe), with higher scores indicating more severe problems. 
Subscale scores are calculated by summing the items within that subscale.  
Missing ABC item scores will not be imputed. If any item is missing within a subscale, then that 
particular subscale score will be missing.  
5.2.2 
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 study 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 Screening and Baseline, and at all visits from 
Week 1 through Week 6. The possible scores are 1=normal, not ill, 2=minimally ill, 3=mildly ill, 
4=moderately ill, 5=markedly ill, 6=severely ill, 7=among the most extremely ill. 
Missing CGI-S of irritability scores will not be imputed. 
5.2.3 
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 study irritability associated with ASD, has improved or worsened relative to a 
baseline state at the beginning of the intervention, i.e., status at Baseline (Guy 1976). The CGI-I 
of irritability will be administered at all visits from Week 1 through Week 6. The possible scores 
are 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 
5=minimally worse, 6=much worse, 7=very much worse. 
Missing CGI-I of irritability scores will not be imputed. 
5.2.4 
Repetitive Behavior Scale-Revised (RBS-R) 
The 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): 6 items 
• self-injurious behavior (actions that cause or have the potential to cause redness, 
bruising, or other injury to the body): 8 items 


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• compulsive behavior (behavior that is repeated and performed according to a rule or 
involves things being done “just so”): 8 items 
• ritualistic behavior (performing activities of daily living in a similar manner): 6 items 
• sameness behavior (resistance to change, insisting that things stay the same): 11 items 
• restricted behavior (limited range of focus, interest, or activity): 4 items 
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 total RBS-R score is calculated as the sum of all subscale scores. 
Missing RBS-R item scores will not be imputed.  
The RBS-R will be administered at Screening and Baseline, and at the Week 3 and Week 6 visits. 
5.2.5 
Vineland Adaptive Behavior Scales–Socialization (VABS-Socialization)  
The 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 socialization domain is a 112 item questionnaire with 3 subdomains: interpersonal 
relationships, play and leisure, and coping skills. Items are rated in a 0,1,2 scale. 2 (behavior is 
usually performed), 1 (behavior is sometimes performed), 0 (behavior is never performed). 
Missing VABS-Socialization item scores will not be imputed.  
The VABS–Socialization will be administered at Baseline and at the Week 3 and Week 6 visits. 
5.2.6 
Caregiver Strain Questionnaire  
The Caregiver Strain Questionnaire (CGSQ) (Brannan et al. 1997) is a 21-item 
parent/caregiver-facing questionnaire of self-reported strain experienced in the past 6 weeks 
(Screening visit), or since last visit (all other visits) by parents/caregivers and families of 
children and adolescents with serious emotional and behavioral disorders. 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 


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• sacrifice 
• disruption of social/community life 
• worry and guilt 
• fatigue and strain 
• embarrassment 
• child-caregiver relationship 
The total score is sum of the following three subscale scores: 
• objective strain (mean of items 1-11),  
• subjective internalized strain (mean of items 12, 16-18, 20-21), and  
• subjective externalized strain (mean of items 13, 14 reversed, 15, 19). 
The CGSQ will be administered at Screening and Baseline, and at the Week 2, Week 4, and 
Week 6 visits.  
Missing CGSQ item scores will not be imputed.  
5.2.7 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS will be administered at Screening and Baseline, at all visits from Week 1 through 
Week 6, and at unscheduled visits. The C-SSRS monitors changes in suicidal thinking and 
behavior over time, in order to determine risk (Posner et al. 2011). Four constructs are measured: 
the severity of ideation, the intensity of ideation, behavior, and lethality. The Baseline/Screening 
version (Lifetime and past 6 months) will be administered at Screening, and the Since Last Visit 
version will be administered at subsequent visits including Baseline visit. 
There are 5 questions about suicidal ideation, representing 5 types of suicidal ideation: wish to be 
dead; non-specific active suicidal thoughts; active suicidal ideation with any methods (not plan) 
without intent to act; active suicidal ideation with some intent to act, without specific plan; active 
suicidal ideation with specific plan and intent. If a subject/caregiver answers “yes” to any of 
these 5 questions, this subject will be counted as having suicidal ideation. 
There are 5 questions about suicidal behavior, representing 5 types of suicidal behavior: 
preparatory acts or behavior; aborted attempt; interrupted attempt; actual attempt; suicide. If a 
subject answers “yes” to any of these 5 questions, this subject/caregiver will be counted as 
having suicidal behavior. 
Missing C-SSRS item scores will not be imputed. 


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5.2.8 
Extrapyramidal Symptom Rating Scale–Abbreviated (ESRS-A) 
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 
the study to monitor for any worsening in extrapyramidal symptoms or signs at scheduled and 
unscheduled visits. 
ESRS-A consists of 4 subscales and 4 clinical global impression movement severity scales of 
Parkinsonism, dyskinesia, dystonia, and akathisia. The Parkinsonism subscale consists of 
10 items, the dyskinesia subscale consists of 6 items, the dystonia subscale consists of 6 items, 
and the akathisia subscale consists of 2 items. Each item is scored on a 6-point scale (0=absent, 
1=minimal, 2=mild, 3=moderate, 4=severe, 5=extreme). The ESRS-A total score is the sum of 
the 24 item scores with a possible range of 0 to 120. Higher scores denote more severe symptoms 
of a movement disorder. 
Missing ESRS-A item scores of the 4 subscales will not be imputed. The ESRS-A total score will 
be missing if any item score of the 4 subscales is missing. 
Each clinical global impression movement severity scale of Parkinsonism, dyskinesia, dystonia, 
and akathisia is a single-item 6-point scale (0=absent, 1=minimal, 2=mild, 3=moderate, 
4=severe, 5=extreme). The score ranges from 0 to 5, with higher scores indicating more severe 
movement disorders. Missing clinical global impression movement severity score will not be 
imputed. 
The ESRS-A will be administered at Screening, Baseline, Week 1, Week 2, Week 3, Week 4, 
Week 5, and Week 6 visits; and at unscheduled visits. The ESRS-A will only be conducted at 
clinic visits and not at remote visits. 
5.3 
Analysis Visits 
5.3.1 
Study Day  
Study Day 1 is defined as the first dose date of study drug (pimavanserin or placebo). If the date 
of assessment occurs on or after the first dose date, then study day will be calculated as (date of 
assessment – date of first dose) + 1. If the date of assessment occurs prior to the first dose date, 
then study day will be calculated as (date of assessment – date of first dose). 


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5.3.2 
Analysis Visit Windows  
The Baseline value is defined as the most recent non-missing value collected prior to the 
administration of the first dose. 
Efficacy, safety and PK assessments will be summarized by analysis visits as presented in 
Table 1 below. 
Table 1 
Analysis Visit Windows 
Analysis Visit Name 
Target Study Day 
Study Day Interval 
Baseline  
1 
≤ 1 
Week 1 
8 
2 to 11 
Week 2 
15 
12 to 18 
Week 3 
22 
19 to 25 
Week 4 
29 
26 to 32 
Week 5 
36 
33 to 39 
Week 6 
43 
≥40  
 
5.3.3 
Unscheduled Assessments 
Both scheduled and unscheduled assessments, including early termination visits, will be 
considered for planned timepoint analyses based on the above analysis visit windowing rules. 
All assessments will be presented in data listings. 
5.3.4 
Multiple Measurements within Visit Windows 
If multiple non-missing continuous measurements exist in an analysis window, the 
measurements will be selected based on the following rules if a single value is needed: 
• For Baseline visit, the assessment closest to and prior to the time of the first dose, 
whether scheduled or unscheduled, will be used as the baseline value. If multiple 
measurements occur on the same day at the same time or the time is not available, the one 
with later nominal visit (scheduled visits take precedence over unscheduled visit) will be 
selected. 
• For post-baseline visits, the assessment closest to the target study day will be selected for 
the by-visit analyses. In these analyses, if two assessments are equidistant from the target 
day then the chronologically last assessment will be used. If two assessments have the 
same date/time, the one with later nominal visit (scheduled visits take precedence over 
unscheduled visit) will be selected. 


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If multiple non-missing categorical measurements exist in an analysis window, the 
measurements will be selected based on the following rules if a single value is needed: 
• For Baseline visit, the assessment closest to and prior to the time of the first dose, 
whether scheduled or unscheduled, will be used as the baseline value. If multiple 
measurements occur on the same day at the same time or the time is not available, the 
value with the lowest severity will be selected. 
• For post-baseline visits, the assessment closest to the target study day will be selected for 
the by-visit analyses. In these analyses, if two assessments are equidistant from the target 
day then the chronologically last assessment will be used. Exceptions may be made for 
incomplete assessments, in which case, more complete assessments may be given 
priority. If multiple measurements occur on the same day, the value with the highest 
severity will be selected. 
For safety analysis where the most extreme values should be selected (e.g. overall post-baseline 
minimum, overall post-baseline maximum, and potentially clinically important values), all 
non-missing post-baseline values should be considered, regardless of whether the value is 
selected for the by-visit summaries. All results will be presented in data listings. 
When ECG is collected in triplicate, the average of the triplicate will be considered as one 
assessment for the analyses. 
5.4 
Missing Data 
In general, missing data will not be imputed unless specified in this document. Handling of 
missing data in the efficacy analyses are described separately in Section 12.3. 
5.4.1 
Missing or Incomplete Date for Last Dose of Study Drug 
The missing last dose date of study drug for a subject who completed or early terminated from 
the study will be imputed using the last expected dosing date, which is defined as the minimum 
of the non-missing drug return date of the last dispensed drug kits, the last drug dispensed date 
plus the number of days that the dosing would continue per protocol or the end-of-
treatment/early termination visit (EOT/ET) date, whichever occurs earlier. For the incomplete 
last dose date of the study drug, the imputation will be compared against the last expected dosing 
date defined as above. Details will be provided in a separate specifications document. The 
missing or incomplete dates will be displayed in the data listings as reported on the eCRF rather 
than the imputed dates. 
For data summarization before final database lock, if a subject is still ongoing at the time of 
analysis, then this subject’s last dose date will be imputed using the database extract date. 


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5.4.2 
Missing or Incomplete Dates for Prior or Concomitant Medications 
Missing or incomplete medication start or end dates will be imputed for the purpose of 
determining whether the medications are taken concomitantly (see Section 11 for definition). 
When the chronological order of medication use relative to the study drug treatment period is 
unclear due to missing or incomplete date(s), the medication will be considered as concomitant. 
The imputation algorithms will be provided in a separate specifications document. The missing 
or incomplete dates will be displayed in the data listings as reported on the eCRF rather than the 
imputed dates. 
5.4.3 
Missing or Incomplete Dates for Adverse Events  
Missing or incomplete adverse event (AE) start dates will be imputed for the purpose of 
determining whether the AEs are treatment-emergent (see Section 14.1 for definition). When the 
chronological order of an AE onset relative to the study drug treatment period is unclear due to 
missing or incomplete date(s), the AE will be considered as treatment-emergent. The imputation 
algorithms will be provided in a separate specifications document. The missing or incomplete 
dates will be displayed in the data listings as reported on the eCRF rather than the imputed dates. 
5.4.4 
Missing Severity Assessment for Adverse Events 
If the severity is missing for an AE starting on or after the date of the first dose of study drug, 
then a severity of “Severe” will be assigned. The imputed values for severity assessment will be 
used for incidence summaries, and the actual values will be presented in data listings. 
5.4.5 
Missing Relationship to Study Drug for Adverse Events 
If the relationship to study drug is missing for an AE starting on or after the date of the first dose 
of study drug, a causality of “Related” will be assigned. The imputed values for relationship to 
study drug will be used for incidence summaries, and the actual values will be presented in data 
listings. 
5.5 
Character Values of Clinical Laboratory Variables  
If the reported value of a clinical laboratory variable cannot be used in a statistical analysis due 
to, for example, a character string reported for a numeric variable, an appropriately determined 
coded value will be used in the statistical analysis. The coding algorithms will be provided in a 
separate specifications document. The actual values as reported in the database will be presented 
in data listings. 
6 SUBJECT DISPOSITION 
For subjects who participate in the screening phase but are not randomized (screen failures), their 
demographics information (including age, sex, and primary race), screen failure reasons (the 


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specific inclusion/exclusion criterion (or criteria) not met or other reason including the reason 
due to coronavirus disease 2019 [COVID-19]) and protocol version will be provided in a listing. 
If a subject is re-screened, then the re-screening subject ID and the final enrollment status 
(whether eventually enrolled) will also be displayed in this listing. In addition, the frequency that 
the screen failure reasons are reported will also be summarized. Note that one subject may be 
deemed ineligible for multiple inclusion/exclusion criteria. A single rescreening of individuals 
who fail screening is permitted with the approval of the Sponsor’s Medical Monitor. 
The number of sites that screened at least one subject, number of sites that randomized at least 
one subject, number of subjects screened, number of unique subjects screened, and number of 
randomized subjects will be summarized. 
For randomized subjects, number and percentage of subjects in Safety Analysis Set, Full 
Analysis Set, and PK Analysis Set will be summarized by treatment group and overall. A listing 
will be provided displaying all subjects excluded from the Safety or Full Analysis Sets, and will 
include reason(s) for exclusion. 
In addition, the number of subjects randomized at each site will also be tabulated by Analysis Set 
and by treatment group and overall. 
For Randomized Analysis Set and Full Analysis Set, the number and percentage of subjects who 
completed the study or discontinued (all discontinued and by primary discontinuation reason 
including  the reason due to COVID-19) will also be summarized by treatment group and overall. 
A listing will be provided on the reasons for premature study drug/study discontinuation. 
7 PROTOCOL DEVIATIONS 
Protocol deviations will be reviewed regularly over the course of the study. The review process, 
definition of the deviation categories, and the classification of a deviation as major or minor are 
detailed in the Protocol Deviation Management Plan. Protocol deviations will also be assessed 
with respect to relationship to COVID-19. 
A summary of the number and percentage of subjects with major protocol deviations for each 
deviation category will be presented by treatment group and overall in three ways: all protocol 
deviations, COVID-19 related protocol deviations, and non COVID-19 related protocol 
deviations. 
Two listings of protocol deviations will be provided: all deviations and COVID-19 related 
protocol deviations. 


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8 DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
8.1 
Demographics and Other Baseline Characteristics 
Demographics and baseline characteristics will be summarized by treatment group and overall, 
for Randomized Analysis Set and Full Analysis Sets using descriptive statistics. Variables 
include age, age category (5-12 years and 13-17 years), mental age, sex, primary race (subjects 
of multi-racial background can only identify/select one primary race on eCRF, or choose “other” 
and specify), ethnicity, height, weight, body mass index (BMI), intelligence quotient (IQ), IQ 
categories (<70 and ≥70), region, and caregiver relationship. 
The reported age reflects a subject’s age at the informed consent date. Age will be presented both 
as continuous and categorical (5 through 12 years old or 13 through 17 years old). If there are 
discrepancies in the values between the IRT system and the clinical database, categories based on 
the IRT system and clinical database will each be presented separately. 
8.2 
Baseline Disease Characteristics 
Disease characteristics at Baseline will be summarized for the Randomized Analysis Set and Full 
Analysis Set using descriptive statistics. Baseline ABC subscale scores, CGI-S of irritability 
score, RBS-R score, VABS-Socialization score, CGSQ score, ADI-R, MINI-KID, and ESRS-A 
score will be presented as continuous variables. CGI-S of irritability score will also be presented 
as a categorical variable using discrete categories. Subject history of syncope, family history of 
syncope, subject history of somnolence will be summarized using yes/no counts. 
9 MEDICAL HISTORY 
Medical and surgical history data will be coded using Medical Dictionary for Regulatory 
activities (MedDRA) version 24.0 or higher. The subject incidence will be summarized for each 
system organ class (SOC) and preferred term by treatment group and overall, for Safety Analysis 
Set. A subject will be counted only once per SOC or per preferred term for the summary. 
A listing of the SOC, preferred term, body system, verbatim term for the medical history 
condition/event, start and stop dates (when available), and an indicator for whether or not the 
condition is ongoing will be provided. 
10 EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE 
Summaries of exposure and compliance to study drug will be provided for the Safety Analysis 
Set. 


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10.1 Exposure to Study drug  
For each subject, the duration of exposure to study drug (last dose date – first dose date + 1), will 
be calculated and summarized by treatment group. Duration of exposure will also be summarized 
with number and percentage of subjects in each of the following categories: <1 week 
(1 to 7 days), 1 to <2 weeks (8 to 14 days), 2 to <3 weeks (15 to 21 days), 3 to <4 weeks 
(22 to 28 days), 4 to <5 weeks (29 to 35 days), 5 to <6 weeks (36 to 42 days), and >6 weeks 
(43 days or longer). 
The pimavanserin dose levels are expressed as free base.  
10.2 Measurement of Treatment Compliance 
Study drug dosing compliance (in percentage) for a subject is defined as the total number of 
capsules actually taken divided by the number of capsules expected to be taken and then 
multiplied by 100. The total number of capsules actually taken is calculated by the total number 
of capsules dispensed minus the total number of capsules returned. The number of capsules 
expected to be taken is calculated as the duration of exposure (days) × 1 (number of tablets taken 
per day). Additional details for handling missing number of capsules returned will be provided in 
a separate specification document. 
 
Compliance will be summarized as both continuous and categorical variables by treatment 
groups. For categorical presentation, the number and percentage of subjects in each of the 
following categories will be presented: <80%, 80 to 120%, and >120%. 
Listings of study drug accountability will be provided separately. 
11 PRIOR, CONCOMITANT AND POST-TREATMENT MEDICATION 
For a subject, prior medication is defined as any medication with stop date prior to the date of the 
first dose of study drug. Concomitant medication is defined as any medication that is ongoing at 
the first dose of study drug or with a start date between the dates of the first and last doses of 
study drug, inclusive.  Any medication with a start date after the date of the last dose of study 
drug will be considered as post-treatment medication. Prior, concomitant, or post-treatment 
medications will be summarized separately. Medications will be coded using WHO Drug 
Dictionary 2021 March or newer version. The number and percentage of subjects taking each 
drug class (ATC Level 3) and medication preferred term will be tabulated by treatment group and 
overall, for Safety Analysis Set. Multiple medication usage by a subject in the same category will 
be counted only once. 
Relationship to COVID-19 will be assessed for selected medications as detailed in the Guidance 
for Site Documentation and Data Management Querying of Data Impacted by COVID-19 (GSD) 


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and provided in a listing. Listings of the prior, concomitant, or post-treatment medications will 
be provided. 
12 EFFICACY ANALYSIS CONSIDERATIONS 
All efficacy analyses will be performed using the planned treatment assignments based on the 
randomization schedule for the Full Analysis Set. 
12.1 Efficacy Variables 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from Baseline at Week 6 in the ABC-I score. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are the following: 
• Change from Baseline at Week 6 in the caregiver-rated ABC subscale scores 
o Stereotypic behavior 
o Lethargy 
o Hyperactivity 
o Inappropriate speech 
• Change from Baseline at Week 6 in the Clinical Global Impression–Severity (CGI-S) of 
irritability score 
• Clinical Global Impression–Improvement (CGI-I) of irritability score at Week 6 
• Change from Baseline at Week 6 in the Repetitive Behavior Scale–Revised (RBS-R) 
scores 
• Change from Baseline at Week 6 in the Vineland Adaptive Behavior Scales (VABS)–
Socialization subscale score 
• Change from Baseline at Week 6 in the Caregiver Strain Questionnaire (CGSQ) Since 
last visit scores 
• Proportion of subjects who have at least 25% reduction from Baseline in the ABC 
Irritability subscale score at Week 6 
• Proportion of subjects who have CGI-I of irritability score of 1 (very much improved) or 
2 (much improved) at Week 6 (CGI-I of irritability responders)  
• Proportion of subjects who have at least 25% reduction from Baseline in the ABC 
Irritability subscale score AND a CGI-I of irritability score of 1 (very much improved) or 
2 (much improved) at Week 6 


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12.2 Adjustment for Covariates 
For continuous variables analyzed using the mixed model for repeated measures (MMRM), the 
stratification factors (age group and region) and the baseline value of the endpoint being 
analyzed will be included as covariates as described in Section 13. For CGI-I of irritability score, 
the Baseline CGI-S of irritability score will be included in the MMRM analysis. 
12.3 Handling of Missing Data 
The primary analysis of the primary efficacy variable will be performed assuming missing at 
random (MAR) using an MMRM method. ABC-I scores that are missing (based on approaches 
described in Section 5.2.1) will not be imputed. The MMRM method is unbiased in the 
estimation of treatment effect under the MAR assumption and can be thought of as aiming to 
estimate the treatment effect that could have been observed if all subjects had continued on 
treatment for the protocol planned treatment duration (EMA, 2009). Sensitivity analyses of the 
primary efficacy variable will be performed as described in Section 13. 
12.4 Multiple Comparisons / Multiplicity 
A hierarchical testing procedure will be used to control the Type I error rate across the two 
treatment comparisons (pimavanserin high dose vs. placebo and pimavanserin low dose vs. 
placebo) for the primary endpoint and an important secondary endpoint CGI-S. The hypotheses 
testing will be conducted in sequential order:  
1. pimavanserin high dose versus placebo on change from Baseline to Week 6 ABC-I score 
2. pimavanserin low dose versus placebo on change from Baseline to Week 6 ABC-I score  
3. pimavanserin high dose versus placebo on change from Baseline to Week 6 CGI-S score   
4. pimavanserin low dose versus placebo on change from Baseline to Week 6 CGI-S score  
If the proceeding comparison fails to reach statistical significance at the 2-sided 0.05 level, the 
subsequent comparison(s) will be declared as not statistically significant regardless of the 
associated nominal p-value. The study-wise Type I error rate will be maintained at the 
significance level of 0.05. 
No statistical inference will be made for any other secondary endpoints. 
12.5 Examination of Subgroups 
Treatment comparisons will be made with respect to the primary efficacy variable using the 
MMRM analysis described in Section 13.1.1 separately for each subgroup by: 
• age group (5 through 12 years old or 13 through 17 years old) 


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o  Only the  region stratification factor (U.S. or rest of world) will be included 
in the MMRM model for this analysis 
• sex (male or female) 
• primary race (white or non-white) 
• IQ (<70 or ≥70) 
• region (U.S.A. or rest of world) 
o Only the age group stratification factor (5 through 12 years old or 13 through 
17 years old) will be included in the MMRM model for this analysis 
• severity of ABC-I at entry (<25 or ≥25) 
• severity of ABC-Lethargy at entry (ABC-L) (<20 or ≥20) 
• stimulants (defined as ATC level 3 =’ PSYCHOSTIMULANTS, AGENTS USED FOR 
ADHD AND NOOTROPICS’) use during treatment period (yes or no) 
 
The LS mean differences with corresponding 95% CIs from the subgroups will also be 
graphically presented in forest plots for the primary efficacy variable. 
13 METHODS OF EFFICACY ANALYSES 
13.1 Primary Efficacy Endpoints  
13.1.1 Primary Analysis  
Estimand 
The primary clinical question of interest for the primary objective is: what is the difference in the 
mean changes from Baseline at Week 6 in the ABC-I score comparing pimavanserin high dose 
vs. placebo, and pimavanserin low dose versus placebo, in subjects with ASD with irritability, 
agitation, or self-injurious behaviors, assuming all subjects complete 6 weeks of treatment 
without extended use of rescue medication or use of prohibited medications? 
The primary estimand defining the treatment effect of interest in this study uses the hypothetical 
strategy specified in the ICH E9 (R1) Addendum. The estimand, or target of estimation, 
following the hypothetical strategy is the pharmacological effect seen, had no study treatment 
discontinuation occurred. This hypothetical estimand is justifiable in this case, since the focus is 
on the pharmacological effect of the drug additional to non-specific effects. Subjects who 
discontinue from a study treatment either could have lost their treatment effect or could have had 
their treatment effect confounded by other medication taken after the discontinuation of study 


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treatment. This means that any observations taken after subjects stop study drug will most likely 
not contribute relevant information about the pharmacological effect of the study drug.  
By this strategy, the last collected efficacy assessment after premature treatment discontinuation 
will be done only at the early termination (ET) visit. Every effort will be made to complete the 
ET evaluations prior to administering any additional medications for the treatment of irritability 
associated with Autism Spectrum Disorder (ASD) or other prohibited medications. In the case of 
lost to follow-up events or death, no ET evaluations are expected, and only scheduled 
assessments performed before such an event are expected.  
In this hypothetical strategy, the event of premature discontinuation of study medication is 
considered missing at random (MAR), and the primary endpoint of the study could be considered 
as a combination of the responses of on-treatment completers at Week 6 and the imputation of 
the endpoint to Week 6 following the trend in each treatment group using the mixed-effect model 
repeated measures (MMRM) method for subjects who discontinuation study drug during the 
study. All data collected in study will be used for statistical analysis. Under the MAR 
assumption, MMRM provides an unbiased estimate of treatment effect for the treatment period. 
The estimand is described by the following attributes: 
Target Population: subjects diagnosed with ASD with irritability, agitation, or self-injurious 
behaviors as defined by the inclusion/exclusion criteria of the study. 
Variable (primary endpoint): change from Baseline at Week 6 in the ABC-I score. 
Treatment condition: pimavanserin high dose, pimavanserin low dose, and placebo, daily for 
6 weeks, without extended use of rescue medications or use of prohibited medications. 
Intercurrent events (ICE) and strategies:  
Note that in the following discussion of ICEs, the primary reason for treatment discontinuation 
is used to classify ICEs rather than secondary reasons for discontinuation (if any are recorded).  
• 
The two intercurrent events (ICEs) “premature treatment discontinuation due to 
COVID-19”, “premature treatment discontinuation not due to COVID-19” (i.e. early 
dropout prior to Week 6) will be addressed by the hypothetical strategy, i.e., assuming 
that subjects with these ICEs evolve in the same way after ICE occurrence as the subjects 
in the same treatment group who complete the treatment. 
• 
If “use of rescue medications beyond maximum allowed period” and “use of prohibited 
medications” (as listed in the Protocol Appendices A and B ) resulted in treatment 
discontinuation, then the event will be considered as an ICE of treatment discontinuation 
and will be handled in the analyses according to the strategy for treatment discontinuation 
ICEs. 


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• The intercurrent event “remote assessments” will be addressed by the treatment policy 
strategy, i.e., utilizing measurements of the primary efficacy endpoint regardless of the 
occurrence of this ICE. 
Alternative approaches to handling intercurrent events will be addressed in the sensitivity 
analyses. 
Population-level summary: difference (pimavanserin high dose vs. placebo, pimavanserin low 
dose vs. placebo) in the mean changes from Baseline at Week 6 in the ABC-I score. 
Hypotheses 
Let Δ be the difference in the mean change from Baseline at Week 6 in the ABC-I subscale score 
between either pimavanserin dose group and the placebo group: 
The null hypothesis for the primary efficacy endpoint is:  
 
Δ = 0 
The alternative hypothesis for the primary efficacy endpoint is:  
Δ ≠ 0 
The hierarchical testing procedure for the hypothesis testing is described in Section 12.4. 
Primary Estimator 
The hypothesis testing will be performed for Full Analysis Set using the direct likelihood 
MMRM method assuming all missing data are missing at random (MAR). The dependent 
variable will be the change from Baseline in the ABC-I score. The independent variables in the 
model will include the following: age group (5 through 12 years old or 13 through 17 years old), 
region (U.S. or rest of world), treatment group (pimavanserin high dose, pimavanserin low dose, 
or placebo), visit (Week 1, Week 2, Week 3, Week 4, Week 5, or Week 6), treatment-by-visit 
interaction, and the Baseline ABC-I score. An unstructured covariance matrix will be used, and 
the Kenward-Roger approximation will be used to adjust the denominator degrees of freedom. 
Observed cases will be analyzed in the model and the least squares (LS) means will be estimated 
using observed margins. Sample SAS® code for MMRM analysis is provided in Appendix 21.2. 
In the event that the model fails to converge using the unstructured covariance matrix, the 
following alternative covariance structures will be modeled in the order given: heterogeneous 
Toeplitz, heterogeneous compound symmetry, heterogeneous autoregressive (1), Toeplitz, 
compound symmetry, autoregressive (1), variance components. The first alternative covariance 
structure that allows for convergence will be selected for the final model, and the sandwich 
estimator (Diggle 1994) will be used to estimate the standard errors of the fixed effects 
parameters. 
At each visit, the effect size (Cohen’s d) for the change from Baseline between the treatment 
groups will be calculated using the following formula: 


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𝐸𝑓𝑓𝑒𝑐𝑡 𝑠𝑖𝑧𝑒= 𝐿𝑆 𝑚𝑒𝑎𝑛 𝑑𝑖𝑓𝑓𝑒𝑟𝑒𝑛𝑐𝑒
√𝑣𝑎𝑟𝑖𝑎𝑛𝑐𝑒
 
The variance at a given visit will be obtained from the covariance matrix estimated for the 
MMRM model. The sign (+ or -) of the effect size will be chosen so that a positive value favors 
pimavanserin. 
Summary statistics for the ABC-I score (observed and change from baseline) will be presented 
for all visits from Baseline through Week 6. For change from Baseline values at each 
post-baseline visit, LS means and standard errors (SE), the between-group difference in 
LS means with the corresponding 95% confidence interval, p-value (2-sided) and effect size will 
also be presented. In addition, LS mean ± SE over time for the change from Baseline values by 
treatment group will also be presented in line plots. 
The hypothesis testing will be performed based on the difference in LS means at Week 6 and will 
be tested at the significance level of 0.05, following the hierarchical testing procedure described 
in Section 12.4. The treatment-group comparisons at each of the other timepoints (Weeks 1, 2, 3, 
4, or 5) using the same MMRM model will be considered exploratory.  
The LS mean differences with corresponding 95% CIs from the primary analysis and sensitivity 
analyses below will also be graphically presented in a forest plot. 
13.1.2 Sensitivity Analysis  
The following sensitivity analyses of the primary efficacy endpoint are planned to account for 
intercurrent events. 
13.1.2.1 
Pattern-Mixture Models Assuming Missing Not At Random (MNAR) Using 
Multiple Imputation (MI) 
MMRM assumes data are MAR, which is a reasonable assumption in longitudinal clinical trials. 
However, the possibility of missing not at random (MNAR) data can never be ruled out. In order 
to further evaluate robustness of the primary results to deviations from MAR assumptions, 
additional sensitivity analyses may be conducted.  
Placebo Based Imputation Methods  
Similar to “Standard” multiple imputations, except parameters for imputation model obtained 
from only the placebo (control) group. Missing data for both placebo and pimavanserin high and 
low dose groups are imputed based on the imputation model derived from placebo data within 
each stage. If pimavanserin high and/or low doses improved outcomes prior to dropout, this 
benefit is carried into subsequent imputed values, but will diminish over time in accordance with 
the correlation structure. 


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13.1.2.2 
Tipping Point Analyses 
Sensitivity analyses based on pattern-mixture model (PMM) using MI will be performed in order 
to explore data missing mechanisms of MNAR and investigate the response profile of dropout 
reasons for the following scenarios: 
1) Dropout reason due to Adverse Event (AE) as MNAR 
2) Dropout reasons due to AE, lack of efficacy (LOE), COVID-19, use of prohibited 
medication as MNAR 
3) All dropouts not due to COVID-19 as MNAR 
4) All dropouts as MNAR 
This sensitivity analysis will be implemented for Full Analysis Set using delta adjustment 
imputation. This MNAR sensitivity analysis is to departure from MAR assumption by 
progressively increasing the delta until conclusion from the primary analysis is overturned. The 
delta is 0%, 5%, 10%, 15%,  .., 100% of the observed treatment difference between a 
pimavanserin high dose and placebo, pimavanserin low dose and placebo, from the primary 
analysis of MMRM model until conclusion of the primary analysis is overturned. When delta = 0 
the missing data are assumed to be MAR. When delta > 0, the missing data are assumed to be 
MNAR.  
1) Using Monte Carlo Markov Chain (MCMC) methodology from PROC MI to impute the 
intermittent missing data to a monotone missing pattern 
2) Using a standard MAR-based multiple imputation approach from PROC MI to impute the 
monotone missingness data 
3) For subjects in the pimavanserin group with a dropout reason due to AE, LOE, subject 
withdraw consent, COVID-19, use of prohibited medication, a delta will be added for all 
the values after the dropout time 
4) Using MMRM model in the primary analysis to analyze the completed data using PROC 
MIXED on the multiple imputed data  
5) Obtaining the overall results using PROC MIANALYZE.  
 
13.1.2.3 
Sensitivity Analysis Using Randomized Analysis Set  
This sensitivity analysis using MI assuming MAR will be performed using the Randomized 
Analysis Set. 


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13.1.2.4 
Remote Assessments 
To assess the impact of the intercurrent events of remote assessments on the primary analysis, an 
indicator variable will be assigned to flag subjects that had assessments done remotely for the 
primary efficacy endpoint at any visit including baseline (Yes/No). The remote visit flag 
indicator variable and the interaction between treatment group and remote visit flag indicator 
variable will be included as factors in the MMRM mode. 
13.2 Secondary and Exploratory Efficacy Analyses 
The change from Baseline at each post-baseline timepoint in the ABC subscale scores (lethargy, 
stereotypic behavior, hyperactivity, inappropriate speech), the CGI-S of irritability score and the 
CGI-I of irritability score will be analyzed using an MMRM model similar to the primary 
analysis described above for the primary endpoint, except that the Baseline covariate of the 
endpoint being analyzed will be included in the model instead of the Baseline ABC-I subscale 
score. For CGI-I of irritability score, the Baseline covariate include in the MMRM model will be 
the Baseline CGI-S of irritability score 
The change from Baseline at each post-baseline timepoint in the RBS-R scores, the 
VABS-Socialization subscale score, and the CGSQ scores will be analyzed using an MMRM 
model similar to the primary analysis described above for the primary endpoint, except that the 
Baseline value of the endpoint being analyzed will be included in the model instead of the 
Baseline ABC-I subscale score, also the visit variable included in the model will reflect the visits 
scheduled for the respective endpoints. 
The proportion of subjects with ≥25% reduction in the ABC-I subscale score, the proportion of 
subjects with a CGI-I of irritability score of 1 or 2, and the proportion of subjects with ≥25% 
reduction in the ABC-I subscale score and a CGI-I of irritability score of 1 or 2 will be 
summarized at each post-Baseline timepoint. The proportions will be compared between each 
pimavanserin dose group and the placebo group using Cochran-Mantel-Haenszel test stratified 
by age group and region; Newcombe’s 95% CI stratified by age group and region will be 
presented. Subjects with missing score at a given visit are considered as non-responders for that 
visit. 
In addition to the treatment comparisons for the Week 6 timepoint, the treatment groups will also 
be compared at each of the other timepoints (Weeks 1, 2, 3, 4, or 5). These comparisons will be 
considered exploratory.  


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14 SAFETY ANALYSES 
The safety analysis will be performed on the Safety Analysis Set based on the actual treatment 
received. Safety results will be summarized by treatment group using descriptive statistics. 
No formal statistical testing will be performed for any of the safety endpoints. 
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. 
14.1 Adverse Events  
All Adverse events (AEs) will be coded using MedDRA version 24.0 or higher. 
An AE (classified by preferred term) will be considered a treatment-emergent AE (TEAE) if it 
starts after the first study dose administration and no later than last study dose date + 30 days. 
AEs reported on Day 1 based on Baseline (pre-dose) findings (e.g. clinically significantly 
abnormal vital signs, laboratory test results, or electrocardiogram parameters) will not be 
considered as TEAEs. 
The event counts and the number and percentage of subjects reporting TEAEs in each treatment 
group, and the two pimavanserin groups combined will be tabulated by SOC and preferred term; 
and, by SOC, preferred term, and maximum severity. If more than one AE occurs with the same 
preferred term for the same subject, the subject will be counted only once for that preferred term 
using the most severe and more related occurrence for the summarization by severity and by 
relationship to study drug, respectively. The display in these tables will be sorted alphabetically 
by SOC, and then by frequency of the two pimavanserin groups combined within each SOC. 
The event counts and the number and percentage of subjects with any TEAEs will also be 
tabulated by preferred term without SOCs within each treatment group and sorted by frequency 
of the two pimavanserin groups combined. 
The incidence of most frequently reported (preferred terms reported by  5% of subjects in any 
treatment group) TEAEs, TEAEs leading to discontinuation, TEAEs related to study drug, 
TEAEs by maximum severity, fatal TEAEs (i.e., events that cause death), serious TEAEs, and 
serious TEAEs related to study drug, will be summarized by SOC, preferred term, and treatment 
group. In addition, TEAEs by SOC, preferred term, and stimulant use will be summarized. 


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The relationship of selected AEs to COVID-19 will be assessed as detailed in the GSD and 
provided in the listing. Additional summaries of relationship to COVID-19 may be provided. 
An AE listing by subject will display all events, including those which are not 
treatment-emergent, and will include the verbatim term in addition to the MedDRA SOC and 
preferred term. This listing will also include all relevant eCRF data associated with the event: 
e.g. date of onset, date resolved, date of last dose, severity, frequency, outcome, relationship to 
study drug, action taken with study drug, and required therapy. When a date is presented, the 
study day associated with the date will also be displayed. Separate listings will be provided for 
TEAEs leading to discontinuation, TEAEs related to study drug, SAEs, and fatal AEs. 
14.2 Clinical Laboratory Variables 
Clinical laboratory tests are performed at Screening, Baseline, Week 3 and Week 6/ET visits. 
Due to COVID-19 disruptions it is possible that some test results may be collected from a local 
laboratory. Local laboratory results and the associated normal ranges will be converted to 
SI units; the local laboratory results, in SI units, will then be normalized to central lab ranges to 
be included in summary data analysis together with the central laboratory results. The 
normalization will be performed using the following scale transformation equation: 
𝑠= 𝐿. + (⸮−⸮௫) ⸮௦−⸮௦
⸮௫−⸮௫
 
where s is the normalized individual laboratory value to be used for summary; x is the original 
value from the local lab; Lx and Ux are the lower and upper limits from the local lab; Ls and Us 
are the lower and upper limits from the central lab. 
For labs with only a single upper (or lower) limit, the following scale transformation equation 
will be used: 
⸮= ⸮⸮௦
⸮௫
 
where s is the normalized individual laboratory value to be used for summary; x is the original 
value from the local lab; Us is the upper (or lower) limit from the central lab; Ux is the upper 
(or lower) limit from the local laboratory. Local laboratory results and normalized results will be 
included in data listings. Only central lab and normalized local lab results will be used for 
summary of change from baseline, shift, and potentially clinically important (PCI) analyses. 
Clinical laboratory tests include the following: 
• Clinical chemistry serum tests 


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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 
o Alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl 
transpeptidase (GGT), alkaline phosphatase (ALP), total bilirubin (TBIL), lactate 
dehydrogenase (LDH) 
o Lipid panel 
 Total cholesterol, high-density lipoprotein (HDL)-cholesterol, triglycerides, 
low-density lipoprotein (LDL)-cholesterol, cholesterol/HDL ratio, non-HDL 
cholesterol 
o HbA1c 
o Magnesium (Mg), Vitamin B12 (only at Visit 1 [Screening]) 
o Thyroid function tests (only at Visit 1 [Screening]) 
 Thyroid stimulating hormone (TSH) and reflex free T4 
o Prolactin 
 Prolactin results should be blinded to the Investigator and the Sponsor after 
Baseline. Results will be monitored by an independent Medical Monitor from the 
Clinical Research Organization (CRO) 
o Creatine kinase (CK)/creatine phosphokinase (CPK) 
• Pregnancy test 
o A serum pregnancy test should only be performed at Visit 1 for women of 
childbearing potential 
o A urine pregnancy test should be performed at all designated visits after Visit 1 for 
women of child-bearing potential 
 If urine cannot be obtained in women of childbearing potential, a 
serum pregnancy test should be done in its place 
• Hematology tests 
o Complete blood count (CBC) including: 
 White blood cell (WBC) count 
 Complete differential (relative and absolute) 
 Hematocrit (Hct), hemoglobin, red blood cells (RBC), platelets 


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 Reticulocyte count 
• Urinalysis 
o Blood, RBCs, WBCs, protein, glucose, ketones, specific gravity, pH 
• Urine toxicology (drug) screen 
o Urine toxicology (drug) screen will test for controlled substances. The following 
controlled substances may be tested with a urine toxicology screen: amphetamine, 
barbiturates, benzodiazepines, cocaine, methadone, morphine/opiates, 
methamphetamine, marijuana (tetrahydrocannabinol [THC]), phencyclidine (PCP), 
ecstasy (3,4-methylenedioxymethamphetamine [MDMA]).  
o A urine toxicology dipstick should be used at the Baseline and Week 3 visits. At the 
Baseline visit, the urine toxicology dipstick should be performed before 
randomization. 
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. 
14.2.1 Analysis of Clinical Laboratory Variables 
14.2.1.1 
Observed Values and Change from Baseline 
All laboratory test results will be provided in the listings. The listings will include date and study 
day of collection. All units will be displayed in Système International [SI] units. Out of range 
values will be flagged in the data listings (e.g. ‘L’ or ‘H’). 
Clinical laboratory values for hematology, chemistry and urinalysis will be summarized by 
treatment group using descriptive statistics at Baseline, Week 3 and Week 6. The change from 
Baseline values will also be summarized by treatment group at Week 3 and Week 6. The overall 
minimum and maximum post-baseline observed and change from Baseline values will also be 
summarized. For hemoglobin, hematocrit and uric acid, the above summaries will be presented 
for each gender as well as for both genders combined. For urinalysis with categorical results 
(blood, protein, glucose, and ketones), the number and percentage of subjects will be tabulated 
by category at Baseline, Week 3 and Week 6, with the denominator being the number of subjects 
with non-missing values for the given parameter, visit and treatment group. 
14.2.1.2 
Shift Tables 
Laboratory values (except the ones that were only assessed at screening and urine drug screen) 
will also be summarized in shift tables by treatment group, to determine the number and 


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percentage of subjects with values classified as below (low), within (normal), and above (high) 
normal ranges at Week 3, 6, overall post-baseline minimum and overall post-baseline maximum, 
relative to the same classification at the Baseline visit. For the by-visit shift summary, the 
denominator is the number of subjects with non-missing values at Baseline and the given visit 
for the given parameter and treatment group. For the shift to the overall post-baseline minimum 
or maximum, the denominator is the number of subjects with non-missing Baseline and at least 
one post-baseline value for the given parameter and treatment group. For hemoglobin, hematocrit 
and uric acid, the shift summaries will be presented for each gender as well as for both genders 
combined. 
14.2.1.3 
Potentially Clinically Important (PCI) Laboratory Values 
Number and percentage of subjects with PCI laboratory values at Week 3, 6 and overall 
post-baseline will be summarized by treatment group for selected parameters. PCI criteria are 
listed in Table 2 and Table 3. For the overall post-baseline summaries of PCI values, all 
post-baseline values will be considered, including unscheduled and out of window values. 
Subjects with multiple PCI values for a given parameter will be counted only once for that 
parameter. For the by-visit summary, the numerator for the percentage is the number of subjects 
with a post-baseline PCI value for the given parameter, visit and treatment group, and the 
denominator is the number of subjects with non-missing values for the given parameter, visit and 
treatment group. For the overall post-baseline summary, the numerator for the percentage is the 
number of subjects with at least one post-baseline PCI laboratory value for the given parameter 
and treatment group, and the denominator is the number of subjects with at least one 
post-baseline laboratory value for the given parameter and treatment group. For hemoglobin, 
hematocrit and uric acid, the count and percentage of subjects with PCI values will be presented 
for each gender as well as for both genders combined. A listing of all subjects with any PCI 
values will be provided. 


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Table 2 
Criteria for Potentially Clinically Important Laboratory Values – Hematology 
and Chemistry 
 
Analyte 
Conventional 
Unit 
Low PCI 
Criteria 
High PCI 
Criteria 
SI Unit 
Low PCI 
Criteria 
High PCI 
Criteria 
Hematology (whole blood) 
Hemoglobin (male) 
g/dL 
<11 
>17 
g/L 
<110 
>170 
Hemoglobin 
(female) 
g/dL 
<10 
>17 
g/L 
<100 
>170 
Hematocrit  
% 
<30 
>50 
L/L 
<0.3 
>0.50 
Leukocyte (White 
Blood Cell Count) 
x 103/uL 
≤2.8 
≥15 
x 109/L 
≤2.8 
≥15 
Neutrophils 
x 103/uL 
≤1.5 
No upper limit 
x 109/L 
≤1.5 
No upper 
limit 
Eosinophils 
% 
No lower 
limit 
≥10 
L/L 
No lower 
limit 
≥.10 
Platelet Count 
x 103/uL 
≤75 
≥700 
109/L 
≤75 
≥700 
Chemistry (serum or plasma) 
ALT (SGPT) 
U/L 
No lower 
limit  
≥3 X ULN 
U/L 
No lower 
limit  
≥3 X ULN 
AST (SGOT) 
U/L 
No lower 
limit  
≥3 X ULN 
U/L 
No lower 
limit  
≥3 X ULN 
Total Bilirubin 
mg/dL 
No lower 
limit 
≥1.5 ULN 
umol/L 
No lower 
limit 
≥1.5 ULN 
BUN 
mg/dL 
No lower 
limit 
≥30.0 
mmol/L 
No lower 
limit 
≥10.71 
Creatine Kinase 
(CPK) 
U/L 
No lower 
limit 
≥3 ULN 
U/L 
No lower 
limit 
≥3 ULN 
Sodium 
mEq/L 
≤125 
≥155 
mmol/L 
≤125 
≥155 
Potassium 
mEq/L 
≤3.0 
≥5.5 
mmol/L 
≤3.0 
≥5.5 
Calcium, total 
mg/dL 
<8.0 
>11.0 
mmol/L 
<2.0 
>2.75 
Lactate 
Dehydrogenase 
(LDH) 
U/L 
No lower 
limit 
≥3 X ULN 
U/L 
No lower 
limit 
≥3 X ULN 
Alkaline 
Phosphatase 
U/L 
No lower 
limit 
≥3 X ULN 
U/L 
No lower 
limit 
≥3 X ULN 
Uric acid  
mg/dL 
No lower 
limit 
≥8.5 
umol/L 
No lower 
limit 
≥505.75 
Albumin 
g/dL 
≤2.6 
≥6.0 
g/L 
≤26 
≥60 
Total Protein 
g/dL 
≤5.0 
≥10.0 
g/L 
≤50 
≥100 
Chloride 
mEq/L 
≤85 
≥120 
mmol/L 
≤85 
≥120 
Glucose (random) 
mg/dL 
≤45.1 
≥115.0 
mmol/L 
≤2.48 
≥6.4 
Serum Creatinine 
mg/dL 
Not 
Applicable 
>1.5 ULN 
umol/L 
Not 
Applicable 
>1.5 ULN 
Triglycerides 
mg/dL 
Not 
Applicable 
>300 
mmol/L 
Not 
Applicable 
>3.39 
Gamma-Glutamyl 
Transferase (GGT) 
U/L 
Not 
Applicable 
≥3 ULN 
U/L 
Not 
Applicable 
≥3 ULN 
Phosphorus, 
inorganic 
mg/dL 
≤1.0 
≥7 
mmol/L 
≤0.32 
≥2.26 


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Table 2 
Criteria for Potentially Clinically Important Laboratory Values – Hematology 
and Chemistry (Continued) 
 
Analyte 
Conventional 
Unit 
Low PCI 
Criteria 
High PCI 
Criteria 
SI Unit 
Low PCI 
Criteria 
High PCI 
Criteria 
Total Cholesterol, 
Fasting 
mg/dL 
No lower 
limit 
≥240 
mmol/L 
No lower 
limit 
≥6,21 
Hb1Ac 
% 
No lower 
limit 
≥7 
L/L 
No lower 
limit 
≥0.07  
 
Table 3 
Criteria for Potentially Clinically Important Laboratory Values - Urinalysis 
Urinalysis  
Low PCI Criteria 
High PCI Criteria 
Blood (occult blood) 
Not Applicable 
≥Moderate or +2 (Q2) 
Protein 
Not Applicable 
≥100 mg/dL (ICON) or +2 (Q2) 
Glucose 
Not Applicable 
≥500 mg/dL (ICON) or +2 (Q2) 
The pregnancy results (positive or negative) for female subjects and the urine drug screen results 
will be presented in a listing. 
14.3 Vital Signs, Height, Weight, and BMI 
Vital signs, height (as measured by a stadiometer) and weight are assessed at Screening and 
Baseline, at all visits from Week 1 through Week 6, and at unscheduled visits. BMI will be 
derived as Weight (kg)/ [Height (m)]2. Height and weight measurements are optional at the 
Week 2 and Week 5 visits if these are conducted remotely. 
Vital signs, height, weight, and BMI will be summarized by treatment group using descriptive 
statistics at Baseline and all post-baseline visits. The change from Baseline values will also be 
summarized by treatment group at the post-baseline visits. 
Vital sign and weight values will be considered PCI if they meet both the observed value criteria 
and the change from baseline criteria listed in Table 4. The number and percentage of subjects 
with post-baseline PCI values will be summarized by treatment group at each post-baseline visit 
and for overall post-baseline. For the overall post-baseline summaries, all post-baseline values 
will be considered, including unscheduled and out of window values. Subjects with multiple PCI 
values for a given parameter will be counted only once for that parameter. For the by-visit 
summary, the numerator for the percentage is the number of subjects with a post-baseline PCI 
value for the given parameter, visit and treatment group, and the denominator is the number of 
subjects with non-missing values for the given parameter, visit and treatment group. For the 
overall post-baseline summary, the numerator for the percentage is the number of subjects with 
at least one post-baseline PCI value for the given parameter and treatment group, and the 


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denominator is the number of subjects with at least one post-baseline value for the given 
parameter and treatment group. A listing of all subjects with any PCI values will be provided. 
Table 4 
Criteria for Potentially Clinically Important Vital Signs 
 
Vital Sign Parameter 
 
Unit 
Criteriaa 
Observed Value 
And/Or 
Change Relative to Baseline 
Systolic blood pressure 
(supine or sitting) 
mmHg 
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% 
a 
A post-baseline value is considered as a PCI value if it meets both criteria for observed value and change from 
baseline. 
14.4 Electrocardiogram (ECG) 
Electrocardiogram is performed at Screening, Baseline, Week 3, and Week 6 visits. 
All tracings will be evaluated by a central reading laboratory. At the Baseline visit, the 
machine-read results will also be recorded. All data, including the machine-read Baseline results, 
will be listed. ECG data summaries will be performed using the centrally evaluated data. 
Observed values of ECG variables (heart rate, PR interval, RR interval, QRS interval, 
QT interval, and QTc intervals) and the changes from baseline at each assessment timepoint will 
be summarized by treatment group. QTc intervals include QTcB (Bazett’s formula) and QTcF 
(Fridericia’s formula). 
QTcF will also be categorized into the following categories (msec) and the number and 
percentage of subjects in each category will be summarized by treatment group at each visit and 
for the overall post-baseline maximum: 
• Observed: ≤450, 451 to 480, 481 to 500, and >500 
• Change from Baseline: ≤10, 11 to 30, 31 to 60, and >60 


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For cardiologist’s interpretations, the number and percentage of subjects with ECG results that 
are determined as normal or abnormal will be summarized at scheduled visits. The overall 
post-baseline worst interpretation will also be summarized (i.e., if a subject has one or more 
post-baseline ECG results that is/are considered as abnormal, this subject will be counted in the 
abnormal category). Cardiologist’s interpretations will also be summarized in a shift table to 
determine the number and percentage of subjects with ECG results classified as normal or 
abnormal at scheduled post-baseline visits relative to the same classification at the Baseline visit. 
The shifts from Baseline to overall post-baseline worst interpretation will also be presented. For 
the by-visit shift summary, the denominator is the number of subjects with non-missing 
cardiologist’s interpretation at Baseline and the given visit for the given treatment group. For the 
summaries of shift from Baseline to the overall post-baseline worst interpretation, the 
denominator is the number of subjects with non-missing Baseline and at least one post-baseline 
cardiologist’s interpretation for the given treatment group. 
Electrocardiogram variable values will be considered as PCI values if they meet or exceed the 
upper limit values listed in Table 5. The number and percentage of subjects with post-baseline 
PCI values will be summarized by treatment group at each post-baseline visit and for overall 
post-baseline. For the by-visit summary, the numerator for the percentage is the number of 
subjects with a post-baseline PCI value for the given parameter, visit and treatment group, and 
the denominator is the number of subjects with non-missing values for the given parameter, visit 
and treatment group. For the overall post-baseline summary, the numerator for the percentage is 
the number of subjects with at least one post-baseline PCI value for the given parameter and 
treatment group, and the denominator is the number of subjects with at least one post-baseline 
value for the given parameter and treatment group. A listing of all subjects with any PCI values 
will be provided. 
Table 5 
Criteria for Potentially Clinically Important ECG Values 
ECG Parameter 
Unit 
High PCI Criteria 
QRS Interval 
msec 
120 
PR Interval 
msec 
220 
QTcB or QTcF 
msec 
>500 
QTcB or QTcF: change from baseline 
>60 msec 
 
14.5 Physical Examination 
Physical examination is performed at Screening, Baseline, Week 3 and Week 6 visits. 


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Physical examination results (normal, abnormal, and not done) at Baseline and all scheduled 
post-baseline visits will be summarized in a frequency table by treatment group, body system 
and visit. 
A listing of physical examination data will be provided.  
14.6 Syncope and somnolence 
Syncope and somnolence are assessed at Screening and Baseline, at all visits from Week 1 
through Week 6, and at unscheduled visits. Occurrences syncope and somnolence should be 
reported as adverse events.  
Subject history of syncope, family history of syncope, subject history of somnolence will be 
summarized as Baseline Disease Characteristics. Incidences of syncope and somnolence during 
the study will be summarized as TEAEs. 
Assessment of syncope and somnolence at each visit will be listed. 
14.7 Other Safety Variables 
14.7.1 Columbia-Suicide Severity Rating Scale (C-SSRS) 
For the C-SSRS, the number and percentage of subjects with suicidal ideation or behavior during 
the study will be tabulated. 
For calculating the percentages, the denominator will be the number of subjects with at least one 
post-baseline C-SSRS. 
14.7.2 Extrapyramidal Symptom Rating Scale–Abbreviated (ESRS-A) 
ESRS-A total scores and the four individual global clinical global impression movement severity 
scores will be summarized by treatment group using descriptive statistics at Baseline and each 
post-baseline visit. The change from Baseline values will also be summarized by treatment group 
at the post-baseline visits. 
15 CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
Plasma concentration data for pimavanserin and its metabolite (AC-279) will be listed and 
summarized using standard summary statistics. 
If data allow, population PK and PK/PD analyses will be performed to further characterize the 
PK profile and exposure response relationship of pimavanserin and its metabolite using measures 
of safety, and efficacy parameters. The results of population PK and PK/PD modeling will be 
presented in a separate report. Pimavanserin plasma concentration data will remain blinded to the 


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Investigators and Sponsor study team until the unblinding of the clinical database at the end of 
the study. 
16 INTERIM ANALYSIS 
No interim analyses are planned for this study. 
17 DATA MONITORING/REVIEW COMMITTEE 
An independent Data and Safety Monitoring Board (DSMB) will review interim safety data 
including data on AEs, 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 roles and responsibilities of DSMB members and planned frequency of 
meetings will be detailed in the DSMB Charter. 
An independent statistical group not affiliated with the Sponsor will produce unblinded statistical 
outputs and provide these outputs to DSMB members using a secure method. The Sponsor and 
the Investigators will remain blinded until the official unblinding of the database at the end of the 
study. 
18 COMPUTER METHODS  
Statistical analyses will be performed using Version 9.4 (or newer) of SAS on a suitably 
qualified and validated environment. 
Validation and quality control of the tables, listings and figures containing the results of the 
statistical analyses will follow appropriate standard operating procedures. 
19 CHANGES TO ANALYSES SPECIFIED IN PROTOCOL 
No changes are made to the analyses specified in the protocol. 


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20 REFERENCES 
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. 
Diggle, P.J., K.-Y. Liang, and S.L. Zeger. 1994. Analysis of Longitudinal Data. New York: 
Oxford University Press. 
EMA (2009). Guideline on Missing Data in Confirmatory Clinical Trials, European Medicines 
Agency, London, UK. 
FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic | 
Guidance for Industry, Investigators, and Institutional Review Boards (March 2020). 
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.  
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. 
Ratitch, B. and O’Kelly, M. (2011). Implementation of Pattern-Mixture Models Using 
Standard SAS/STAT Procedures, in Proceedings of PharmaSUG 2011 (Pharmaceutical 
Industry SAS Users Group), SP04, Nashville. 
 
Sparrow SS, Cicchetti DV, Saulnier CA. Vineland Adaptive Behavior Scales, Third Edition: 
Vineland-3. Pearson; 2016. 
Yuan, Y. Sensitivity analysis in multiple imputation for missing data, in Proceedings of SAS 
Global Forum 2014.


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21 APPENDICES 
21.1 Schedule of Events and Assessments 
Period 
Screening 
 
Double-blind treatment period 
Follow-up 
 
 
Baseline 
 
 
 
 
 
EOT/ETr Unscheduleda 
Safety  
follow-upb 
Visit Week 
-4 to 0 
0 
1 
2 
3 
4 
5 
6 
 
10 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
 
9 
Visit window (days) 
+7c 
 
3d 
3d 
3d 
3d 
3d 
3d 
 
+3d 
Type of visite  
Clinic 
Clinic 
Clinic 
Clinic/ 
Remote 
Clinic 
Clinic  
Clinic/ 
Remote 
Clinic 
Clinic 
Telephone 
Informed consent/assent  
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
Xf 
 
 
 
 
 
 
 
 
Medical history and demographics 
X 
 
 
 
 
 
 
 
 
 
Autism disease history 
X 
 
 
 
 
 
 
 
 
 
HBV, HCV and HIV history 
X 
 
 
 
 
 
 
 
 
 
COVID-19 historyt 
X 
 
 
 
 
 
 
 
 
 
ADI-Ru, bb 
X 
 
 
 
 
 
 
 
 
 
MINI-KIDu 
X 
 
 
 
 
 
 
 
 
 
Capsule swallowing testg 
X 
X 
 
 
 
 
 
 
 
 
Medication history 
X 
X 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
 
X 
 
 
X 
 
 
Vital signs  
X 
X 
X 
Xv 
X 
X 
Xv 
X 
X 
 
Height w, weight, and BMI 
X 
X 
X 
Xv 
X 
X 
Xv 
X 
X 
 
12-lead ECGh, i, q 
X 
X 
 
 
X 
 
 
X 
 
 
Pharmacokinetic sample collectioni, j, q 
 
Xk 
X 
 
X 
 
 
X 
Xl 
 
Clinical laboratory tests i, q, s, aa, cc 
X 
X 
 
 
X 
 
 
X 
 
 
Thyroid function tests i 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test i, m 
X 
X 
 
 
X 
 
 
X 
 
 
 
 


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21.1 
Schedule of Events and Assessments (Continued) 
Period 
Screening 
 
Double-blind treatment Period 
Follow-up 
 
 
Baseline 
 
 
 
 
 
EOT/ETr Unscheduleda 
Safety  
follow-upb 
Visit Week 
-4 to 0 
0 
1 
2 
3 
4 
5 
6 
 
10 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
 
9 
Visit window (days) 
+7c 
 
3d 
3d 
3d 
3d 
3d 
3d 
 
+3d 
Type of visite 
Clinic 
Clinic 
Clinic 
Clinic/ 
Remote 
Clinic 
Clinic  
Clinic/ 
Remote 
Clinic 
Clinic 
Telephone 
Urine toxicology (drug) screen 
(UDS)n 
X 
X 
 
 
X  
 
 
X 
 
 
ABCu 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
CGI-S of irritability 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
CGI-I of irritability 
 
 
X 
X 
X 
X 
X 
X 
 
 
RBS-Ru 
X 
X 
 
 
X 
 
 
X 
 
 
VABS-Socializationu 
 
X 
 
 
X 
 
 
X 
 
 
CGSQu 
X 
X 
 
X 
 
X 
 
X 
 
 
C-SSRSu 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ESRS-Au, x 
X 
X 
X 
Xx 
X 
X 
Xx 
X 
X 
 
Accurate Symptom Reporting (ASR) 
Trainingu 
X 
 
 
 
 
 
 
 
 
 
Assessment of concomitant 
medicationst 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of syncope occurrencey 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of somnolence 
occurrencez 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Study drug dispensation 
 
X 
X 
 
X 
X 
 
 
Xo 
 
Study drug return and accountabilityp 
 
 
X 
X 
X 
X 
X 
X 
X 
 


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Abbreviations: ABC=Aberrant Behavior Checklist; ADI-R=Autism Diagnostic Interview–Revised; AE=adverse event; BMI=body mass index; CGI-I=Clinical 
Global Impression–Improvement; CGI-S=Clinical Global Impression–Severity; CGSQ=Caregiver Strain Questionnaire; COVID-19=coronavirus disease 2019; 
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; MINI-KID=Mini International Neuropsychiatric Interview for Children and 
Adolescents; PK=pharmacokinetic; RBS-R=Repetitive Behavior Scale–Revised; SAE=serious adverse event; 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 discontinue treatment prematurely from the study or who do not participate in the long-
term extension 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 
The Screening Period can be extended up to an additional 7 days (i.e., for a total of 5 weeks) before the Baseline visit, after discussion with the Medical 
Monitor. Discussion between the Investigator and Medical Monitor about eligibility is encouraged, to ensure that scientifically informed eligibility decisions 
are being made with all the necessary information, and in an objective and homogenous manner consistent with the protocol. Following the discussion, the 
Principal Investigator will document and sign off on the final eligibility decision. 
d 
Visit timing and windows are relative to the Baseline visit, not relative to the previous visit. 
e 
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. Remote visits are permitted for Week 2 (Visit 4), Week 4 (Visit 6), and Week 5 (Visit 7). For all other 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. 
f 
All assessments must be completed and subject must meet required eligibility criteria before being randomized or enrolled. 
g 
Subjects will be assessed for their ability to swallow a test capsule (i.e., placebo). If the subject is unable to swallow a test capsule at the Screening visit, they 
may take some capsules home to practice, and will be re-assessed at the Baseline visit. 
h 
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 that can 
occur either at Screening or Baseline. 
i 
Mild sedation is allowed exceptionally for ECGs and blood draws during the study (e.g., alprazolam at appropriate doses according to age) 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. 
j 
For all PK samples (scheduled and unscheduled, and except at the Baseline visit) the dates and times of administration of the last three doses of the study drug 
should be recorded. 
k 
At the Baseline visit, a PK sample is drawn predose. 
l 
Every effort should be made to collect a PK sample at an unscheduled visit because of an SAE, or an AE leading to discontinuation. 
m 
For female subjects of childbearing potential, a serum pregnancy test will be completed at the Screening visit; urine pregnancy dipstick tests will be completed 
at all other scheduled timepoints. 


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n 
A urine toxicology dipstick should be used in addition to the urine toxicology screen at both the Baseline visit and visit 8 (to confirm eligibility in Study 
ACP-103-070). A rapid UDS dipstick will be used at Visit 3.  
o 
Study drug may be dispensed to the subject at unscheduled visits if needed. 
p 
If visit is remote, accountability will be assessed verbally with the caregiver, and verified at the next clinic visit. 
q     The involvement of experienced personnel in the conduction of routine procedures such as blood drawing and ECG recording in this population is strongly 
recommended. 
r 
The ET visit will not be done if the subject withdraws consent to participate in all parts of the study and withdrawal of consent happens before that 
timepoint. 
s 
Prolactin results should be blinded to the Investigator and the Sponsor after Baseline. Results will be monitored by an independent Medical Monitor from the 
Clinical Research Organization (CRO). 
t 
Including COVID-19 vaccination. 
u 
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, that 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. The ASR training should be done at Screening before the caregiver completes any scales, and 
repeated whenever there is a change in caregiver or if the site feels a caregiver requires retraining. 
v 
If visit is conducted remotely, vital signs, height, weight, and BMI are optional. 
w 
As measured by stadiometer. 
x 
The ESRS-A will only be conducted at clinic visits and not at remote visits. 
y 
If the caregiver reports an occurrence of  syncope, the investigator should ask the “syncope adverse event questions”, as a tool to guide diagnosis, in 
Appendix G of protocol. 
z 
If the caregiver reports an occurrence of  somnolence, the investigator should ask the “somnolence adverse event questions”, as a tool to guide diagnosis, in 
Appendix H of protocol.  
aa 
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. 
bb 
If an ADI-R has been completed for the subject by a certified rater (certified by Dr. Olsen and approved by the Sponsor) within 6 months prior to the 
Screening visit and if the original complete ADI-R response booklet with the patients’ answers is available as source data, then there is no need to conduct 
the ADI-R at Screening. The ADI-R can be administered remotely. 
cc 
The creatinine value should also be used to calculate estimated glomerular filtration rate (eGFR) according to the bedside Schwartz equation eGFR=0.413 × 
(height/serum creatinine), where height is in cm, and creatinine is in mg/dL. Subjects are excluded if eGFR is <30 mL/min. 


Protocol ACP-103-069 
Version 3.0 
Statistical Analysis Plan 
29 July 2024 
 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc. 
Page 50 of 52 
21.2 SAS Programming Code for MMRM Model 
The following sample SAS® code can be implemented for the MMRM analysis (modify as 
needed): 
 
        
 
        
 
 
        
 
        
 
 
 
 
 


Protocol ACP-103-069 
Version 3.0 
Statistical Analysis Plan 
29 July 2024 
 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc. 
Page 51 of 52 
21.3 SAS Programming Code for Multiple Imputation under MNAR 
The following sample SAS® code can be implemented to generate multiple imputed datasets 
(modify as needed): 
  
        
        
           
        
 
 
  
 
 
 
 
 
  
 
 
 
run; 
 
 
 
    
    
    
 
 
 
 
run; 
 
%end; 
 
%mend; 
 
 
  


Protocol ACP-103-069 
Version 3.0 
Statistical Analysis Plan 
29 July 2024 
 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc. 
Page 52 of 52 
21.4 Summary of Version Changes 
Version 
No: 
Document History 
Description of Update 
Author(s) 
Version Date 
1.0 
Original version 
Di An 
30 APR 2021 
1.1 
Updated due to protocol amendments 1 and 2 
Bruce Coate  
10 DEC 2021 
2.0 
Updated due to protocol amendment 3 and FDA 
request to include SAS code for tipping point analysis 
Bruce Coate 
12 APR 2022 
2.1 
Reference Protocol Amendment 4 
Bruce Coate 
22 DEC 2022 
3.0 
Updated for changes in protocol amendment 4-IT; 
Removed the upper limit of Week 6 analysis visit 
window; Removed subgroup analysis by ADI-R and 
added subgroup analysis by stimulant use; Added 
details for some scales; Updated example SAS codes 
for sensitivity analysis and PCI cutoff for phosphate 
and urinalysis; Updated responder analysis to set 
missing score as non-responder; Updated hierarchical 
testing by adding the CGI-S; Added a section of 
Syncope and somnolence; Fixed minor typographical 
errors 
I-Yuan Liu 
29 JUL 2024