Clinical trial NCT03968159
Conditions: Adjunctive Treatment of Major Depressive Disorder
Sponsor: ACADIA Pharmaceuticals Inc.
Start date: 2019-04-25; Completion date: 2020-05-29
Enrollment: 298 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate the efficacy and safety of adjunctive pimavanserin compared to placebo in subjects with major depressive disorder who have an inadequate response to antidepressant therapy

Detailed description:
Two separate studies, idential in design, were planned and initiated under 2 protocol IDs and NCTs, i.e. study ACP-103-54 (NCT03999918) and ACP-103-059 (NCT03968159). In March 2020, recruitment of new patients was paused due to the emerging coronavirus disease 2019 (COVID-19) pandemic. At that point in time, about half of the planned patients had been randomized. The Sponsor decided to combine the 2 identically designed trials, with a prespecified combined statistical analysis plan. As a result, both trials were closed and proceeded with database lock and statistical analysis of the combined data. No further patients were enrolled.

This entry now includes the combined data of studies ACP-103-054 and ACP-103-059.

Arms: arm 1: Pimavanserin 34 mg tablets arm 2: Placebo tablets
Interventions: intervention 1: Pimavanserin intervention 2: Placebo
Intervention descriptions: intervention 1: Pimavanserin 34 mg (provided as 2×17 mg tablets) administered orally as a single dose once daily intervention 2: Placebo (2×placebo tablets \[size- and color-matched to pimavanserin\]) administered orally as a single dose once daily

Protocol documents:
Prot_002.pdf: 
Official Title: A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled 
Study to Evaluate the Efficacy and Safety of Adjunctive Pimavanserin in Subjects 
With Major Depressive Disorder and Inadequate Response to Antidepressant 
Treatment 
NCT Number: NCT03999918 
Document Date: 21 Jun 2020 


 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 1 of 81 
 
 
CLINICAL STUDY PROTOCOL 
 
UNMASKED PROTOCOL  
 
A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled 
Study to Evaluate the Efficacy and Safety of Adjunctive Pimavanserin in 
Subjects With Major Depressive Disorder and Inadequate Response to 
Antidepressant Treatment 
 
Protocol Number: ACP-103-054 
Amendment 4 
EudraCT Number: 2018-003251-37 
 
Original Protocol Date: 30 August 2018 
Protocol Amendment 1 Date: 05 December 2018 
Protocol Amendment 2 Date: 18 March 2019 
Protocol Amendment 3 Date: 29 October 2019 
Protocol Amendment 4 Date: 21 June 2020 
 
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-103-054 
 
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Date: 21 June 2020 
 
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SPONSOR SIGNATURE PAGE 
Title: A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Study to 
Evaluate the Efficacy and Safety of Adjunctive Pimavanserin in Subjects With Major 
Depressive Disorder and Inadequate Response to Antidepressant Treatment 
 
ACADIA President: 
 
President 
ACADIA Pharmaceuticals Inc. 
 
  
 
 
See appended electronic signature page 
 
Signature 
 Date 
 
ACADIA Study Lead: 
 
Executive Director, Clinical Research 
ACADIA Pharmaceuticals Inc. 
 
  
 
 
See appended electronic signature page 
 
Signature 
 Date 


Signature Page for ACP-103-054 Protocol Amendment 4_UNMASKED VERSION
Signature Page for ACP-103-054 Protocol Amendment 4_UNMASKED VERSION
Approve
22-Jun-2020 22:33:33 GMT+0000
Approve
22-Jun-2020 22:37:27 GMT+0000


Study: ACP-103-054 
 
Final Version: 1.0 
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Date: 21 June 2020 
 
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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, and 312, and according to applicable local requirements. 
Confidentiality Statement 
The confidential information in this document is provided to you as a Principal Investigator 
or Consultant for review by you, your staff, and the applicable institutional review 
board/ethics committee. Your acceptance of this document constitutes agreement that you 
will not disclose the information contained herein to others without written authorization 
from the Sponsor. 
Principal Investigator 
 
 
Signature 
 
Date 
 
 
 
Name (printed) 
 
 
 
 


Study: ACP-103-054 
 
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PROTOCOL SYNOPSIS 
Protocol Number 
ACP-103-054 
EudraCT Number 
2018-003251-37 
Protocol Title 
A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled 
Study to Evaluate the Efficacy and Safety of Adjunctive Pimavanserin 
in Subjects With Major Depressive Disorder and Inadequate Response 
to Antidepressant Treatment 
Name of 
Investigational 
Product 
Pimavanserin tablets 
Indication 
Adjunctive treatment of major depressive disorder  
Phase of 
Development 
3 
Sponsor 
ACADIA Pharmaceuticals Inc. 
 
 
Primary Objective 
To evaluate the efficacy of adjunctive 
pimavanserin compared to placebo in subjects 
with major depressive disorder who have an 
inadequate response to antidepressant therapy 
Primary Endpoint 
Change from Baseline to Week 5 in the 
Hamilton Depression Scale (17 items) 
(HAMD-17) total score 
Secondary Objective 
To evaluate the efficacy and benefits of 
adjunctive pimavanserin compared to placebo 
in subjects with major depressive disorder 
who have an inadequate response to 
antidepressant therapy on the following:  
• Functional impairment 
• Clinician’s global impression of 
severity and improvement of depressive 
symptoms 
• Sexual functioning 
• Sleepiness 
• Treatment response and remission 
• Anxiety 
• Impulsiveness 
• Early response to treatment 
Secondary Endpoints 
• Change from Baseline to Week 5 in 
Sheehan Disability Scale (SDS) score 
• Change from Baseline to Week 5 in 
Clinical Global Impression–Severity 
(CGI-S) score for depressive symptoms 
• Clinical Global Impression–
Improvement (CGI-I) score for 
depressive symptoms at Week 5 
• Change from Baseline to Week 5 in the 
Changes in Sexual Functioning 
Questionnaire Short Form (CSFQ-14) 
• Change from Baseline to Week 5 in 
Karolinska Sleepiness Scale (KSS) 
score 
• Treatment responder rates at Week 5. 
Treatment response is defined as a 


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reduction from Baseline in HAMD-17 
total score of 50% or more. 
• Treatment remission rates at Week 5. 
Treatment remission is defined as a 
HAMD-17 total score ≤7. 
• Change from Baseline to Week 5 in the 
Hamilton Depression (HAMD) 
Anxiety/Somatization factor score 
• Change from Baseline to Week 5 in the 
Barratt Impulsiveness Scale (BIS-11) 
• Change from Baseline to Week 1 in the 
HAMD-17 total score 
Safety Objective 
To assess the safety and tolerability of 
pimavanserin compared to placebo in subjects 
with major depressive disorder who have an 
inadequate response to antidepressant therapy  
Safety Assessments 
Safety and tolerability of pimavanserin as 
described by: 
• Treatment-emergent adverse events 
(TEAEs) 
• Potentially clinically important 
laboratory abnormalities, vital signs, 
and electrocardiogram (ECG) results 
• Columbia–Suicide Severity Rating 
Scale (C-SSRS) score 
• Change from Baseline to Week 5 in 
Extrapyramidal Symptom Rating 
Scale–Abbreviated (ESRS-A) score 
• Sexual dysfunction defined as a 
CSFQ-14 total score of ≤47 for men 
and ≤41 for women 
Number of Study 
Sites 
Approximately 40 sites outside the United States (US) will participate 
in this study. 
Number of Subjects 
Planned 
The original planned sample size was 280 subjects randomized in a 
1:1 ratio to either the pimavanserin or the placebo treatment groups 
(i.e., 140 subjects in each treatment group). The study was planned to 
be conducted in non-US countries only. 
In March, 2020, in response to the emerging coronavirus disease 2019 
(COVID-19), ACADIA implemented a temporary pause to new 
enrollment into study ACP-103-054, to decrease potential exposure to 
COVID-19, minimize risks to trial integrity, and to assure the safety of 
already enrolled, ongoing study subjects. The last subject was 
randomized on 17 March 2020, for a total of 150 randomized subjects. 
ACADIA decided to combine its two ongoing, Phase III studies, 
ACP-103-059 (US-based study) and ACP-103-054 (non-US), when 
each were half enrolled, into one study with a pre-specified statistical 


Study: ACP-103-054 
 
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analysis plan. As a result, both studies closed and are proceeding with 
database lock and statistical analysis. No new patients were enrolled 
into these studies. The last subject in Study ACP-103-059 was 
randomized on 17 March 2020, at which time a total of 148 subjects 
had been randomized. 
The combined analysis therefore comprises 298 randomized subjects. 
Test Product, Dose, 
and Administration 
Pimavanserin 34 mg (provided as 2×17 mg tablets) or matching 
placebo (2×placebo tablets [size- and color-matched to pimavanserin]). 
It is recommended that the subject should take the study drug at 
approximately the same time each day. Tablets will be administered 
orally as a single dose once daily. 
Study Design 
This study will be conducted as a multicenter, randomized, 
double-blind, placebo-controlled, parallel-group study in subjects 
experiencing major depressive disorder with inadequate response to a 
selective serotonin reuptake inhibitor (SSRI) or 
serotonin-norepinephrine reuptake inhibitor (SNRI). 
This unmasked protocol version provides details of certain study 
design elements, procedures, and statistical methods that are intended 
for use only by the unmasked Sponsor and restricted Worldwide 
Clinical Trials personnel and their designated agents. 
The study will have three periods (Figure S–1): 
• Screening period (3-28 days) 
• Double-blind treatment period (6 weeks) 
• Safety follow-up period (at least 30 days) 
Screening Period (3-28 Days) 
During the screening period, subjects will be assessed for study 
eligibility and prohibited medications will be discontinued. 
Medications should be discontinued only if it is deemed clinically 
appropriate to do so and in consultation with the treating physician. 
Investigators should not withdraw a subject’s prohibited medication 
for the purpose of enrolling them 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 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 site 
and the Medical Monitor. At Visit 2, subjects will be randomized in a 
1:1 ratio to pimavanserin 34 mg once daily or matching placebo. 
Assessments will be conducted at Week 0 (Baseline), 1, 2, 3, 4, 5, and 
6/EOT or early termination (ET). 


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Safety Follow-up Period (30 Days) 
Eligible subjects who successfully complete the 6-week double-blind 
period will be qualified to enroll in an open-label extension study; 
subjects enrolling in the open-label extension study will not enter the 
30 day safety follow-up period. For subjects who discontinue 
prematurely from the study or who do not enroll in the open-label 
extension study, a safety follow-up telephone call visit will be 
conducted at least 30 days after the last dose of study drug. 
The schedule of assessments is provided in Table S–1. 
Study Duration 
The duration of participation for individual study subjects will be up to 
15 weeks, consisting of a screening period of up to 5 weeks 
(i.e., 4 weeks, with possible extension of up to 7 days), a 6-week 
double-blind treatment period, and a safety follow-up period of at least 
30 days (for those subjects who discontinue prematurely from the 
study or who do not enroll in the open-label extension study) 
(Figure S–1). The study completion date is defined as the date the final 
subject, across all sites, completes their final protocol-defined 
assessment, which includes the safety follow-up visit/contact, if 
applicable. 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: 
1. Is a male or female ≥18 years of age 
2. Can understand the nature of the study and protocol 
requirements and is willing to comply with study drug 
administration requirements and discontinue prohibited 
concomitant medications  
3. Provides written informed consent to participate in the study 
4. Is capable of communicating with the site personnel, able to 
complete subject-reported outcome measures and can be 
reliably rated on assessment scales (in the opinion of the 
Investigator) 
5. Has a clinical diagnosis of major depressive disorder with or 
without anxious distress by Diagnostic and Statistical Manual of 
Mental Disorders, Fifth Edition (DSM-5) criteria and confirmed 
by the Mini-International Neuropsychiatric Interview (MINI) 
during the screening period. Subject may have either recurrent or 
single episode of major depressive disorder. 
6. Is treated during the current major depressive episode with one 
of the following SSRI/SNRI antidepressants at a minimally 
effective dose for at least 8 weeks with at least the same stable 
dose over 4 weeks prior to the SAFER (State versus trait, 
Assessability, Face validity, Ecological validity, and Rule of 


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three Ps [pervasive, persistent, and pathological]) remote 
interview: 
a. Citalopram 
b. Escitalopram 
c. Paroxetine 
d. Fluoxetine 
e. Sertraline 
f. Duloxetine 
g. Venlafaxine 
h. Desvenlafaxine 
i. Venlafaxine XR 
The dose level of the antidepressant is expected to remain stable 
throughout the study.1 Adherence to the antidepressant should 
be reviewed throughout the study. 
7. Must have a detectable blood level of a prescribed SSRI/SNRI 
during Screening. A negative screening test may be repeated as 
assessed by the Medical Monitor when the subject and/or site 
can provide additional evidence of subject adherence to 
antidepressant treatment or evidence of sample or laboratory 
error. 
8. During the screening period, the subject’s inadequate response 
to SSRI/SNRI antidepressant treatment is confirmed by the 
Massachusetts General Hospital Antidepressant Treatment 
Response Questionnaire (MGH ATRQ) through the SAFER 
remote interview and the subject continues to exhibit an 
inadequate response to treatment at the time of the SAFER 
interview. 
9. Subjects who are currently taking a second antidepressant or 
antidepressant augmentation agent at a subtherapeutic dose or 
for inadequate duration at Screening are eligible for inclusion in 
the study if it is clinically appropriate to discontinue the drug 
before the Baseline visit (in the opinion of the Investigator); the 
second antidepressant/augmentation agent must be discontinued 
and washed out at least 5 half-lives prior to Baseline. This 
second antidepressant/augmentation agent should not be 
discontinued solely to make the subject eligible for enrollment 
in the study. 
10. Has a Montgomery-Asberg Depression Rating Scale (MADRS) 
total score >20 at both Screening and Baseline 
                                                 
 
 
1 Please see Appendix C for medication restrictions. 


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11. Has a Clinical Global Impression–Severity (CGI-S) score ≥4 
(moderately ill or worse) for depression at both Screening and 
Baseline 
12. If the subject is female, she must not be pregnant or 
breastfeeding. She must also be of non-childbearing potential 
(defined as either surgically sterilized or at least 1 year 
postmenopausal) OR must agree to use TWO clinically 
acceptable methods of contraception for at least 1 month prior 
to Visit 2 (Baseline), during the study, and 1 month following 
completion of the study. 
Acceptable methods of contraception include the following: 
a. A barrier method (condom, diaphragm, or cervical cap) 
with spermicide 
b. Hormonal contraception, including oral, injectable, 
transdermal, or implantable methods 
c. Intrauterine device (IUD) 
Only one of the two clinically acceptable methods can be a 
hormonal method. 
Exclusion Criteria: 
1. Has a history of schizophrenia or other psychotic disorder, 
major depressive disorder with psychotic features, bipolar I or II 
disorder. Subjects who are currently being treated or require 
treatment for post-traumatic stress disorder, acute stress 
disorder, panic disorder, or obsessive compulsive disorder are 
also not eligible. 
2. Has a current primary diagnosis of borderline, antisocial, 
paranoid, schizoid, schizotypal, or histrionic personality 
disorder, according to DSM-5 criteria 
3. Has met DSM-5 criteria for substance use disorders within the 
last 6 months prior to Screening, except for disorders related to 
the use of caffeine or nicotine 
4. Is suicidal at Visit 1 (Screening) or Visit 2 (Baseline) as defined 
below: 
a. An answer of “yes” to C-SSRS questions 4 or 5 (current 
or over the last 6 months); OR 
b. Has attempted suicide within 1 year prior to Visit 1 
(Screening); OR 
c. Is actively suicidal in the Investigator’s judgment 
5. Has current evidence of delirium or an unstable neurological, 
cardiovascular, respiratory, gastrointestinal, renal, hepatic, 
hematologic, or other medical disorder, including cancer or 
malignancies that, in the judgment of the Investigator or the 
Medical Monitor, would jeopardize the safe participation of the 


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subject in the study or significantly interfere with the conduct or 
interpretation of the study 
6. Has a history of epilepsy 
7. Has atrial fibrillation unless adequately anti-coagulated 
8. Has a history of myocardial infarction, unstable angina, acute 
coronary syndrome, or cerebrovascular accident   
9. Has a history of any of the following: 
a. Greater than New York Heart Association (NYHA) 
Class II congestive heart failure (Appendix A) 
b. Grade II or greater angina pectoris (by Canadian 
Cardiovascular Society Angina Grading Scale) 
(Appendix B) 
c. Sustained ventricular tachycardia 
d. Ventricular fibrillation 
e. Torsade de pointes 
f. Syncope due to an arrhythmia 
g. An implantable cardiac defibrillator 
10. Has laboratory evidence of hypothyroidism 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 enrolled. 
11. Has current unstable diabetes or glycosylated hemoglobin 
(HbA1c) >8% at Screening 
12. Has a known history of a positive hepatitis B virus (HBV), 
hepatitis C virus (HCV), or human immunodeficiency virus 
(HIV) test  
13. Has a history of neuroleptic malignant syndrome or serotonin 
syndrome 
14. Has a known personal or family history of long QT syndrome or 
family history of sudden cardiac death 
15. Has any of the following ECG results at Visit 1 (Screening) or 
Visit 2 (Baseline): 
a. If the subject is not on citalopram, escitalopram, or 
venlafaxine (immediate or extended release): 
i. QTcF >450 ms, if QRS duration <120 ms 
ii. QTcF >470 ms, if QRS duration ≥120 ms 
b. If the subject is on citalopram, escitalopram, or 
venlafaxine (immediate or extended release): 
i. QTcF >425 ms, if QRS duration <120 ms 
ii. QTcF >450 ms, if QRS duration ≥120 ms 
At Screening, if the set of triplicate ECGs has a prolonged QTcF 
due to an identifiable cause, and it is medically appropriate to 
address that cause, a repeat set of triplicate ECGs may be 


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performed during Screening at the discretion of the Medical 
Monitor. 
16. Has a heart rate <50 beats per minute, as measured by 
peripheral pulse rate, not explained by regular exercise or 
medication, in discussion with the Medical Monitor. If 
bradycardia is secondary to iatrogenic or treatable causes and 
these causes are treated, a heart rate assessment can be repeated 
during the screening period. 
17. Requires treatment with a medication or other substance that is 
prohibited by the protocol 
18. At Screening, has a body mass index (BMI) <18.5 kg/m2 or 
>35 kg/m2 or known unintentional clinically significant weight 
loss (i.e., ≥7%) over past 6 months 
19. Has a positive test for an illicit drug or cannabis at Screening or 
Baseline. Subjects who test positive for a controlled substance 
and who have a valid prescription may be retested during 
Screening if they agree to abstain from the medication for the 
length of their participation in the study. The repeat test during 
Screening must be negative for them to participate in the study. 
Additionally, DSM-5 criteria for substance use disorders should 
not be met. 
20. Has received electroconvulsive therapy, transcranial magnetic 
stimulation, or vagal nerve stimulation, or has received deep 
brain stimulation in the current episode of depression 
21. Has received new-onset psychotherapy or had a change in the 
intensity of psychotherapy within 8 weeks prior to Screening 
22. Has participated in or is participating in a noninterventional 
study or clinical trial of any investigational or marketed drug, 
device, or intervention, within 30 days or 5 half-lives, 
whichever is longer, of Visit 2 (Baseline) 
23. Has previously been enrolled in any prior clinical study with 
pimavanserin or is currently taking pimavanserin 
24. Has a significant sensitivity or allergic reaction to pimavanserin 
or its excipients 
25. Is an employee or is a family member of an employee of 
ACADIA Pharmaceuticals Inc. 
26. Is judged by the Investigator or the Medical Monitor to be 
inappropriate for the study for any reason, including if the 
subject is judged to be a danger to self or others 
Sample Size 
Calculations 
A total sample size of 266 evaluable subjects was estimated to provide 
at least 90% power at a two-sided significance level of 0.05 when 
assuming a treatment effect size of 0.4 for pimavanserin compared to 


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placebo on the change from Baseline to Week 5 in the HAMD-17 total 
score. 
Adjusting for a potential non-evaluable rate of up to 5%, 
approximately 280 subjects will be randomized. 
Statistical Methods 
Analysis Sets 
The Full Analysis Set includes all subjects who were randomized, 
received at least one dose of study drug, and have both a Baseline 
(Week 0) value and at least one post-Baseline value for the HAMD-17 
total score in the two studies. The Full Analysis Set will be used for the 
analysis of all efficacy endpoints. 
The Per-protocol Analysis Set includes a subset of subjects in the Full 
Analysis Set without any protocol deviations that could have a 
significant effect on the study conclusions. The Per-protocol Analysis 
Set will be determined prior to unblinding the studies for the final 
analysis and will be used for supportive analysis of selected efficacy 
endpoints. 
The Safety Analysis Set includes all subjects who received at least one 
dose of study drug in the two studies. 
Any other analysis sets, if necessary, will be defined in the statistical 
analysis plan (SAP). 
Efficacy Analyses 
Efficacy analyses will be conducted on the combined database from 
the ACP-103-054 and ACP-103-059 studies for the Full Analysis Set. 
The primary efficacy endpoint, change from Baseline to Week 5 in the 
HAMD-17 total score, will be analyzed using a mixed-effect model 
repeated measures (MMRM). The model will include effects for 
treatment group, visit, treatment-by-visit interaction, baseline 
HAMD-17 total score, the baseline HAMD-17 total score-by-visit 
interaction, and study. An unstructured covariance matrix will be used 
and the Kenward-Roger approximation will be used to adjust the 
denominator degrees of freedom. 
Additional sensitivity analyses will be performed to assess the impact 
of COVID-19. 
Each of the secondary endpoints, other than response and remission, 
will be analyzed using the MMRM method similar to that used for the 
analysis of the primary efficacy endpoint. For CGI-I, the baseline 
CGI-S score will be used as the covariate in the MMRM model. The 
response and remission rates will be compared between the 
pimavanserin and placebo groups using the Cochran-Mantel-Haenszel 
(CMH) test stratified by study. 


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A hierarchical approach will be used to control for multiple endpoints 
(primary and secondary). 
Safety Analyses 
Safety analyses will be conducted on the combined database from the 
ACP-103-054 and ACP-103-059 studies for the Safety Analysis Set. 
Safety results will be summarized by treatment group using descriptive 
statistics. Adverse events (AEs) will be classified into standard 
terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA). All AEs will be listed and TEAEs will be summarized by 
system organ class and preferred term. A TEAE is defined as an AE 
that started after the first administration of study drug and no later than 
the last administration of study drug plus 30 days. Summaries by 
maximum severity and by relationship to study drug will also be 
provided. Serious TEAEs, fatal AEs, and TEAEs leading to 
discontinuation will also be summarized. The relationship of selected 
AEs to COVID-19 will also be assessed and COVID-19 related 
TEAEs will be tabulated. 
Clinical laboratory values for hematology, chemistry and urinalysis 
(specific gravity and pH) will be summarized by treatment group using 
descriptive statistics at Baseline and the end of treatment visit. The 
change from baseline values will also be summarized by treatment 
group. The overall minimum and maximum post-baseline observed 
and change from baseline values will also be summarized. 
The number and percentage of subjects with potentially clinically 
important (PCI) laboratory values at the end of treatment and overall 
post-baseline will be summarized by treatment group for selected 
parameters. The PCI criteria will be specified in the SAP. 
Vital signs including weight, height, and the derived BMI 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. 
Observed values of ECG parameters and the changes from Baseline 
will be summarized by treatment group and visit. Categorical analyses 
will be conducted on the incidence of subjects with prolonged QTc 
intervals and changes in QTc intervals in accordance with ICH 
guidelines. 
For the C-SSRS, the number and percentage of subjects with suicidal 
ideation or suicidal behavior during the study will be tabulated. 
Observed values and change from Baseline in the ESRS-A score will 
be summarized by treatment group and visit. The change from 
Baseline in the ESRS-A score will be analyzed using the MMRM 
method, similar to the MMRM method used to analyze the primary 
endpoint. 


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Number and percentage of subjects with sexual dysfunction (a total 
score of ≤47 for men and ≤41 for women) will be summarized and 
shift tables will be presented. 
Date 
21 June 2020 
 


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Figure S–1 
Schematic of Study Design for ACP-103-054 
 
Abbreviations: QD=once daily; R=randomization 
Note: Subjects who enroll in an open-label extension will not enter the Safety Follow-up Period. 
 
 


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Table S–1 
Schedule of Events and Assessments for ACP-103-054 
Period Screening 
Baseline 
Double-blind Treatment Period 
 
Safety 
Follow-upa 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
(EOT/ET) 
8 
Unscheduled 
Visitk 
9 
Visit Day/Week 
Day -28 
to -3 
Week 
0 
Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
5 
Week 
6 
Week 
10 
Type of Visitb 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Phone call 
Visit window (# days) 
+7 
 
±3 
±3 
±3 
±3 
±3 
±3 
 
+7 
Informed consent and if 
applicable, privacy forms 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Medical history, medication 
history, and demographics 
X 
 
 
 
 
 
 
 
 
 
Psychiatric history 
X 
 
 
 
 
 
 
 
 
 
MGH ATRQc 
X 
 
 
 
 
 
 
 
 
 
SAFER remote interviewd 
X 
 
 
 
 
 
 
 
 
 
MINI 
X 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
 
 
 
 
X 
 
 
Vital signs and weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
12-lead ECGe 
X 
X 
X 
 
 
 
 
X 
 
 
Clinical laboratory testsf 
X 
X 
 
 
 
 
 
X 
 
 
Pregnancy testg 
X 
X 
 
 
 
 
 
X 
 
 
Background antidepressant blood 
levelh 
X 
 
 
 
 
 
 
 
 
 
Urine toxicity (drug) screen 
X 
X 
 
 
 
 
 
X 
 
 
MADRS 
X 
X 
 
 
 
 
 
 
 
 
Table continues on next page 


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Table S–1 
Schedule of Events and Assessments for ACP-103-054 (Continued) 
Period Screening 
Baseline 
Double-blind Treatment Period 
 
Safety 
Follow-upa 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
(EOT/ET) 
8 
Unscheduled 
Visitk 
9 
Visit Day/Week 
Day -28 
to -3 
Week 
0 
Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
5 
Week 
6 
Week 
10 
Type of Visitb 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Phone call 
Visit window (# days) 
+7 
 
±3 
±3 
±3 
±3 
±3 
±3 
 
+7 
HAMD-17i 
 
X 
X 
X 
X 
X 
X 
X 
 
 
SDS 
 
X 
X 
X 
X 
X 
X 
X 
 
 
CGI-S 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
CGI-I 
 
 
X 
X 
X 
X 
X 
X 
 
 
CSFQ-14 
 
X 
X 
X 
X 
X 
X 
X 
 
 
KSS 
 
X 
X 
X 
X 
X 
X 
X 
 
 
BIS-11 
 
X 
X 
 
X 
 
X 
X 
 
 
ESRS-A 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRSj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense study drug 
 
X 
X 
X 
X 
X 
X 
 
Xl 
 
Study drug accountability 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Review of background 
antidepressant adherence  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: BIS-11=Barratt Impulsiveness Scale; CGI-I=Clinical Global Impression–Improvement; CGI-S=Clinical Global Impression–Severity; 
CSFQ-14=Changes in Sexual Functioning Questionnaire Short Form; C-SSRS=Columbia–Suicide Severity Rating Scale; ECG=electrocardiogram; 
eCRF=electronic case report form; EOT=end of treatment; ESRS-A=Extrapyramidal Symptom Rating Scale–Abbreviated; ET=early termination; 
HAMD-17=Hamilton Depression Scale (17 items); KSS=Karolinska Sleepiness Scale; MADRS=Montgomery-Asberg Depression Rating Scale; MGH 
ATRQ=Massachusetts General Hospital Antidepressant Treatment Response Questionnaire; MINI=Mini-International Neuropsychiatric Interview; 
SAFER=State versus trait, Assessability, Face validity, Ecological validity, and Rule of three Ps (pervasive, persistent, and pathological); SDS=Sheehan 
Disability Scale; SNRI=serotonin-norepinephrine reuptake inhibitor; SSRI=selective serotonin reuptake inhibitor.  
Table footnotes on next page 


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a 
This visit is a safety follow-up telephone call visit for subjects who discontinue prematurely from the study or who do not participate in the open-label 
extension study. This visit will occur at least 30 days after the last dose of study drug. 
b 
If visit was performed remotely due to the COVID-19 pandemic, please refer to Sections 3.3.2 (remote clinical assessments), 6.2.7 (efficacy assessments), 
6.3.8 (safety assessments) and 6.5.1 (unscheduled visits) for further information. 
c 
Inadequate response is defined as a response of <50% to a course of treatment of at least 8 weeks at the minimum effective dose (as listed on the ATRQ), 
which has been stable for the 4 weeks prior to the SAFER interview. 
d 
The SAFER remote interview may be conducted via telephone off-site or on-site. If conducted on-site, the site staff should not be present during the 
interview. 
e 
At Visit 1, ECG should be completed in triplicate and collected within a 3-minute period. At all other visits, a single 12-lead ECG should be completed. 
ECGs should be completed with the subject in a supine position after 5 minutes of rest. The ECG should occur before blood sampling or at least 30 minutes 
after blood sampling. 
f 
To include hematology, serum chemistry, prolactin levels, and urinalysis. 
g 
A pregnancy test is only required for women of childbearing potential. Serum pregnancy should only be performed at Visit 1; a urine pregnancy test should 
be performed at Baseline and Week 6 (EOT). If urine cannot be obtained in women of childbearing potential, a serum pregnancy test should be done in its 
place. 
h 
At Screening, blood samples will be collected for the analysis of concomitant SSRI/SNRI concentrations. The presence of SSRI or SNRI must be confirmed 
in order to qualify the subject for further consideration in the study. 
i 
The HAMD-17 is to be the first scale completed at each visit. 
j 
Suicidal assessment is required. The Baseline/Screening version of the C-SSRS will be administered at Screening. The Since Last Visit version of the 
C-SSRS will be administered at all subsequent visits. 
k 
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. 
l 
Study drug may be dispensed to the subject at unscheduled visits if needed. 
 


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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ............................................................................................... 2 
DECLARATION OF INVESTIGATOR ................................................................................... 4 
PROTOCOL SYNOPSIS ........................................................................................................... 5 
TABLE OF CONTENTS ......................................................................................................... 20 
LIST OF TABLES ................................................................................................................... 25 
LIST OF FIGURES ................................................................................................................. 25 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................. 26 
1 
INTRODUCTION ...................................................................................................... 28 
1.1 
Background Information ............................................................................................ 28 
1.2 
Investigational Product ............................................................................................... 30 
1.3 
Previous Clinical Experience ..................................................................................... 30 
1.4 
Study Rationale .......................................................................................................... 32 
1.5 
Benefit/Risk Assessment ............................................................................................ 33 
2 
STUDY OBJECTIVES AND ENDPOINTS .............................................................. 33 
2.1 
Primary Objective....................................................................................................... 33 
2.1.1 
Primary Endpoint ....................................................................................................... 33 
2.2 
Secondary Objective................................................................................................... 34 
2.2.1 
Secondary Endpoints .................................................................................................. 34 
2.3 
Safety Objective ......................................................................................................... 34 
2.3.1 
Safety Assessments..................................................................................................... 35 
3 
STUDY DESCRIPTION ............................................................................................ 35 
3.1 
Overview of Study Design ......................................................................................... 35 
3.1.1 
Screening Period (3-28 Days) .................................................................................... 35 
3.1.2 
Double-Blind Treatment Period (6 Weeks) ................................................................ 36 
3.1.3 
Safety Follow-up Period (30 Days) ............................................................................ 36 
3.2 
Matching Study ACP-103-059 ................................................................................... 36 
3.3 
Impact of COVID-19 Pandemic on Studies -054 and -059........................................ 36 
3.3.1 
Combination of Databases of Studies -054 and -059 ................................................. 36 
3.3.2 
Remote Clinical Assessments ..................................................................................... 37 
3.3.3 
Roll Over Into Open-Label Study ACP-103-055 ....................................................... 37 
4 
SUBJECT ELIGIBILITY AND WITHDRAWAL CRITERIA .................................. 37 


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4.1 
Inclusion Criteria ........................................................................................................ 37 
4.2 
Exclusion Criteria ....................................................................................................... 39 
4.3 
Subject Withdrawal of Consent .................................................................................. 41 
4.4 
Subject or Study Discontinuation ............................................................................... 42 
4.4.1 
Handling of Subject Discontinuation During the Treatment Period .......................... 42 
4.5 
Subject Lost to Follow-up .......................................................................................... 43 
4.6 
Prior and Concomitant Therapy ................................................................................. 43 
4.6.1 
Prior Medication ......................................................................................................... 43 
4.6.2 
Concomitant Medication ............................................................................................ 43 
4.6.2.1 Permitted, Restricted, and Prohibited Medications .................................................... 43 
5 
INVESTIGATIONAL PRODUCT ............................................................................. 44 
5.1 
Investigational Product Description ........................................................................... 44 
5.1.1 
Formulation, Appearance, Packaging, and Labeling .................................................. 44 
5.1.2 
Product Storage and Stability ..................................................................................... 45 
5.1.3 
Dosing and Administration ......................................................................................... 45 
5.1.4 
Method of Assigning Subjects to Treatment Groups.................................................. 45 
5.1.5 
Blinding ...................................................................................................................... 45 
5.1.6 
Study Drug Compliance ............................................................................................. 45 
5.1.7 
Overdose ..................................................................................................................... 45 
5.2 
Investigational Product Accountability Procedures ................................................... 46 
6 
STUDY PROCEDURES ............................................................................................ 46 
6.1 
Screening Assessments ............................................................................................... 46 
6.1.1 
Medical History, Medication History, and Demographics ......................................... 46 
6.1.2 
Psychiatric History ..................................................................................................... 47 
6.1.3 
Background Antidepressant Blood Level ................................................................... 47 
6.1.4 
Massachusetts General Hospital Antidepressant Treatment Response 
Questionnaire.............................................................................................................. 47 
6.1.5 
State versus trait, Assessability, Face validity, Ecological validity, and Rule of 
three Ps (pervasive, persistent, and pathological) (SAFER) Remote Interview ........ 47 
6.1.6 
Mini-International Neuropsychiatric Interview.......................................................... 47 
6.1.7 
Montgomery-Asberg Depression Rating Scale .......................................................... 48 
6.2 
Efficacy Assessments ................................................................................................. 48 
6.2.1 
Hamilton Depression Scale (17 Items) ....................................................................... 48 
6.2.2 
Sheehan Disability Scale ............................................................................................ 48 
6.2.3 
Clinical Global Impression–Severity and Clinical Global Impression–
Improvement Scales ................................................................................................... 48 


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6.2.4 
Changes in Sexual Functioning Questionnaire Short Form ....................................... 49 
6.2.5 
Karolinska Sleepiness Scale ....................................................................................... 49 
6.2.6 
Barratt Impulsiveness Scale ....................................................................................... 49 
6.2.7 
Impact of COVID-19 Pandemic on Efficacy Assessments ........................................ 49 
6.3 
Safety Assessments..................................................................................................... 49 
6.3.1 
Physical Examinations ............................................................................................... 49 
6.3.2 
Vital Signs .................................................................................................................. 49 
6.3.3 
Height, Weight, and Body Mass Index ....................................................................... 50 
6.3.4 
Electrocardiograms ..................................................................................................... 50 
6.3.5 
Columbia–Suicide Severity Rating Scale................................................................... 50 
6.3.6 
Extrapyramidal Symptom Rating Scale–Abbreviated ............................................... 51 
6.3.7 
Laboratory Evaluations .............................................................................................. 51 
6.3.8 
Impact of COVID-19 Pandemic on Safety Assessments ........................................... 53 
6.3.8.1 Priority Medical Assessments in Remote Visits ......................................................... 54 
6.3.8.2 Physical Examinations, Vital Signs, Height, and Weight ........................................... 54 
6.3.8.3 Electrocardiograms ..................................................................................................... 54 
6.3.8.4 Columbia-Suicide Severity Rating Scale ................................................................... 54 
6.3.8.5 Extrapyramidal Symptom Rating Scale-Abbreviated ................................................ 54 
6.3.8.6 Laboratory Evaluations .............................................................................................. 54 
6.4 
Safety Follow-up ........................................................................................................ 54 
6.5 
Unscheduled Visits ..................................................................................................... 55 
6.5.1 
Impact of COVID-19 on Unscheduled Visits ............................................................. 55 
7 
ADVERSE EVENTS ................................................................................................. 55 
7.1 
Specification of Safety Parameters............................................................................. 55 
7.1.1 
Definition of Adverse Event ....................................................................................... 55 
7.1.2 
Definition of Serious Adverse Event .......................................................................... 56 
7.2 
Classification of an Adverse Event ............................................................................ 57 
7.2.1 
Severity of Event ........................................................................................................ 57 
7.2.2 
Relationship to Study Drug ........................................................................................ 57 
7.2.2.1 Duration ...................................................................................................................... 58 
7.2.2.2 Frequency ................................................................................................................... 58 
7.2.2.3 Action Taken with Study Drug ................................................................................... 58 
7.2.2.4 Therapy ....................................................................................................................... 58 
7.2.2.5 Outcome ..................................................................................................................... 58 
7.2.2.6 Seriousness ................................................................................................................. 59 
7.2.3 
Definition of Unexpectedness .................................................................................... 59 
7.3 
Time Period and Frequency for Event Assessment and Follow-up ........................... 59 


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7.4 
Reporting Procedures ................................................................................................. 59 
7.4.1 
Adverse Event Reporting ........................................................................................... 59 
7.4.2 
Serious Adverse Event Reporting............................................................................... 60 
7.4.3 
Reporting of Pregnancy .............................................................................................. 60 
7.4.4 
Reporting of Overdose ............................................................................................... 61 
8 
CLINICAL MONITORING ....................................................................................... 61 
9 
STATISTICAL METHODS AND DATA ANALYSIS .............................................. 61 
9.1 
Statistical and Analytical Plans .................................................................................. 61 
9.2 
Statistical Hypotheses................................................................................................. 61 
9.3 
Sample Size Determination ........................................................................................ 62 
9.4 
Subject Populations for Analysis ................................................................................ 62 
9.5 
Statistical Analyses ..................................................................................................... 62 
9.5.1 
Primary Analyses ........................................................................................................ 62 
9.5.2 
Secondary Analyses .................................................................................................... 63 
9.5.3 
Safety Analyses .......................................................................................................... 63 
9.5.4 
Subgroup Analyses ..................................................................................................... 64 
9.6 
Interim Analyses ......................................................................................................... 64 
9.7 
Measures to Minimize Bias ........................................................................................ 64 
9.7.1 
Masking Procedures ................................................................................................... 64 
9.7.2 
Randomization Procedures ......................................................................................... 64 
9.8 
Breaking the Study Blind/Subject Code ..................................................................... 65 
10 
STUDY MANAGEMENT AND DATA COLLECTION .......................................... 65 
10.1 
Data Collection and Management Responsibilities.................................................... 65 
10.2 
Source Documents ...................................................................................................... 65 
10.3 
Case Report Forms ..................................................................................................... 66 
10.4 
Confidentiality ............................................................................................................ 66 
10.5 
Study Records Retention ............................................................................................ 66 
10.6 
Protocol Exceptions and Deviations........................................................................... 67 
10.7 
Protocol Amendments ................................................................................................ 67 
11 
QUALITY MANAGEMENT .................................................................................... 67 
11.1 
Risk Management ....................................................................................................... 67 
11.2 
Quality Control and Quality Assurance...................................................................... 68 
12 
ETHICAL CONSIDERATIONS ................................................................................ 69 


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12.1 
Ethical Standard ......................................................................................................... 69 
12.2 
Institutional Review Board/Ethics Committee ........................................................... 69 
12.3 
Informed Consent Process .......................................................................................... 69 
12.3.1 Consent and Other Informational Documents Provided to Subjects .......................... 70 
12.3.2 Consent Procedures and Documentation .................................................................... 70 
13 
PUBLICATION PLAN .............................................................................................. 70 
14 
CONFLICT OF INTEREST POLICY ....................................................................... 70 
14.1 
Finance, Insurance, and Indemnity............................................................................. 70 
15 
LITERATURE REFERENCES .................................................................................. 71 
16 
APPENDICES ............................................................................................................ 74 
Appendix A New York Heart Association Classification of Heart Failure ........................... 74 
Appendix B Canadian Cardiovascular Society Angina Grading Scale ................................. 75 
Appendix C Prohibited and Restricted Medications ............................................................. 76 
Appendix D Prohibited and Restricted Concomitant Medications: Inhibitors and 
Inducers of Cytochrome P450 Enzyme 3A4 ................................................... 80 
 


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LIST OF TABLES 
Table S–1 
Schedule of Events and Assessments for ACP-103-054 .................................. 17 
Table 1-1 
Receptor Profiles of Pimavanserin and Compounds With Antidepressant 
Activity ............................................................................................................ 32 
Table 6–1 
Safety Laboratory Evaluations......................................................................... 53 
 
LIST OF FIGURES 
Figure S–1 
Schematic of Study Design for ACP-103-054 ................................................. 16 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Term 
Definition 
5-HT 
5-hydroxytryptamine (serotonin) 
5-HT2A 
5-hydroxytryptamine (serotonin) 2A 
ADP 
Alzheimer’s disease psychosis 
AE 
adverse event 
BIS-11 
Barratt Impulsiveness Scale 
CGI-I 
Clinical Global Impression–Improvement 
CGI-S 
Clinical Global Impression–Severity 
COVID-19 
coronavirus disease 2019 
CSFQ-14 
Changes in Sexual Functioning Questionnaire Short Form 
C-SSRS 
Columbia–Suicide Severity Rating Scale  
DAT 
dopamine transporter 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ESRS-A 
Extrapyramidal Symptom Rating Scale–Abbreviated  
ET 
early termination 
GCP 
Good Clinical Practices 
HAMD-17 
Hamilton Depression Scale (17 items) 
ICF 
informed consent form 
ICH 
International Council for Harmonisation  
IRB 
institutional review board 
IRT 
interactive response technology 
KSS 
Karolinska Sleepiness Scale 
MADRS 
Montgomery-Asberg Depression Rating Scale 
MDD 
major depressive disorder 
MGH ATRQ 
Massachusetts General Hospital Antidepressant Treatment 
Response Questionnaire 
MINI 
Mini-International Neuropsychiatric Interview 
MMRM 
mixed-effect model repeated measures 
NET 
norepinephrine transporter 
PDP 
Parkinson’s disease psychosis 
PR 
PR interval of ECG 
QRS 
QRS interval of ECG 


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Term 
Definition 
QT 
QT interval for heart rate of ECG 
QTcB 
corrected QT interval using Bazett’s correction method 
QTcF 
corrected QT interval using Fridericia’s correction method 
SAE 
serious adverse event 
SAFER 
State versus trait, Assessability, Face validity, Ecological validity, 
and Rule of three Ps (pervasive, persistent, and pathological)  
SAP 
statistical analysis plan 
SDS 
Sheehan Disability Scale 
SERT 
serotonin transporter 
SNRI 
serotonin-norepinephrine reuptake inhibitor 
SSRI 
selective serotonin reuptake inhibitor 
TEAE 
treatment-emergent adverse event 
TSH 
thyroid stimulating hormone 
US 
United States 


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1 INTRODUCTION 
This document is a research protocol and the described study will be conducted in 
compliance with the protocol and the International Council for Harmonisation (ICH) 
Good Clinical Practices (GCP) Guideline.  
1.1 
Background Information 
Depression is ranked as the leading cause of disability worldwide by the World Health 
Organization (Murray and Lopez 1996). In particular, major depressive disorder (MDD) is a 
psychiatric illness that is characterized by the occurrence of one or more major depressive 
episodes, along with an absence of any history of manic, mixed, or hypomanic episodes. It is 
a serious, often recurrent medical condition, which is associated with a 15.9% lifetime risk of 
suicide attempt (Chen and Dilsaver 1996). Results of the World Mental Health Survey 
Initiative found that the average lifetime incidence of DSM-4 major depressive episodes was 
14.6%, with a 12-month prevalence of 5.5% in higher income countries (Bromet et al. 2011). 
Despite the availability of numerous pharmacological and psychological treatment options, 
fewer than 50% of all patients with depression show full remission with optimized treatment, 
including courses on numerous medications with and without concurrent psychotherapy 
(Rush et al. 2006). 
Thus, while medications have demonstrated efficacy in the treatment patients with an 
inadequate response to standard antidepressant therapies, there is a clear need for efficacious 
medications with improved tolerability and safety. Current research continues to investigate 
novel molecular and cellular mechanisms of augmentation of antidepressant therapies. 
Pimavanserin was studied in a Phase 2, randomized, double-blind, placebo-controlled, 
two-stage sequential parallel comparison design (SPCD) (Fava et al. 2016) study in adult 
subjects with MDD and an inadequate response to antidepressant therapy with concurrent 
selective serotonin reuptake inhibitor (SSRI)/serotonin-norepinephrine reuptake inhibitor 
(SNRI) (Study ACP-103-042). In the study, 207 adult patients with a confirmed inadequate 
response to existing first-line SSRI or SNRI therapy for MDD received adjunctive treatment 
of either 34 mg pimavanserin or placebo in addition to pre-existing first-line therapy for 
5 weeks (Stage 1). Those patients who did not show a response to placebo in Stage 1 were 
re-randomized to receive either pimavanserin or placebo for a second 5-week treatment 
period (Stage 2). 
Pimavanserin met the overall primary endpoint of the prespecified weighted average results 
of Stage 1 and Stage 2 by significantly reducing the 17-item Hamilton Depression Rating 
Scale (HAMD-17) total score compared to placebo (p=0.039). In addition, in Stage 1 (n=207) 
patients on pimavanserin demonstrated a highly significant improvement over placebo in 


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HAMD-17 (p=0.0003; effect size [Cohen’s d] 0.626). Importantly, this group of patients saw 
a benefit over placebo in the first week of treatment (p=0.0365; effect size [Cohen’s d] 
0.346). Fewer subjects (n=58) than anticipated proceeded to Stage 2, and no treatment benefit 
versus placebo was observed in this small set of placebo non-responders. In summary, 
pimavanserin met the overall primary endpoint of the prespecified weighted average results 
of Stage 1 and Stage 2 and demonstrated a highly significant improvement over placebo in 
HAMD-17 in Stage 1. 
On the key secondary endpoint, pimavanserin demonstrated statistically significant 
reductions compared to placebo in the Sheehan Disability Scale (SDS) score (p=0.004).  
Positive results were also observed for seven of the eleven other secondary endpoints listed 
below with nominal p-values: Clinical Global Impression–Severity (p=0.0084), Clinical 
Global Impression–Improvement (p=0.0289), Short Form-12 Mental Component Summary 
(p<0.0001), Karolinska Sleepiness Scale (p=0.0205), Massachusetts General Hospital Sexual 
Functioning Index (p=0.0003), Barratt Impulsiveness Scale (p=0.0075), as well as response 
rates (p=0.0065), defined as a 50% or greater reduction on the HAMD-17 total score.  
In this Phase 2 study, pimavanserin was generally well-tolerated. The most frequently 
reported treatment-emergent adverse events (TEAEs) included headache in the placebo group 
and headache, dry mouth, and nausea in the pimavanserin group. In Stage 1, for placebo 
subjects, TEAEs leading to discontinuation included depression, swelling face, and 
hypotension; for pimavanserin subjects, a TEAE of vomiting was reported and led to 
discontinuation. In Stage 2, a TEAE of diabetes mellitus was reported in the placebo group 
and led to discontinuation. One subject in each of the pimavanserin and placebo groups 
reported serious adverse events (SAEs). The placebo subject experienced SAEs of prostate 
cancer and calculus bladder; the pimavanserin subject experienced an SAE of acute 
myocardial infarction. These SAEs were deemed not to be related to the study drug by the 
Investigators and both subjects completed the study. No deaths were reported in the study. 
Furthermore, no meaningful differences were observed between the pimavanserin and 
placebo groups in changes in the Barnes Akathisia Scale, the Simpson Angus Scale, and the 
Abnormal Involuntary Movement Scale. Weight changes and ECG changes between the 
pimavanserin and placebo groups were generally similar. In Stage 2, there was a mean 
QTcF interval change of 7.2 ms and -0.8 ms in the pimavanserin and placebo groups, 
respectively, which is consistent with what has been observed with pimavanserin in other 
clinical studies. 
On the basis of the robust preliminary clinical evidence for efficacy and favorable tolerability 
observed in Study ACP-103-042, the present study is being initiated. 


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1.2 
Investigational Product 
Pimavanserin is an atypical antipsychotic that is present in the investigational product as 
pimavanserin tartrate salt with the chemical name, urea, N-[(4-fluorophenyl)methyl]-N-(1-
methyl-4-piperidinyl)-N’-[[4-(2-methylpropoxy)phenyl]methyl]-,(2R,3R)-2,3-
dihydroxybutanedioate (2:1). In April 2016, pimavanserin was approved in the United States 
(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-hydroxytryptamine (5-HT [serotonin]) 2A (5-HT2A) 
receptor. At higher doses, pimavanserin may block 5-HT2C receptors (Vanover et al. 2006). 
Pimavanserin shows no appreciable activity at dopaminergic, adrenergic, histaminergic, or 
muscarinic receptors. Activity at these receptors has been implicated in a range of 
dose-limiting side effects associated with existing antipsychotic drugs including cognitive 
dulling (Saeedi et al. 2006; Mehta et al. 2004; Peretti et al. 1997) and an increased risk of 
mortality in elderly patients with dementia (Wang et al. 2005). On the basis of its novel 
receptor binding profile, pimavanserin may have benefits with regard to overall tolerability 
relative to other antipsychotic agents. 
1.3 
Previous Clinical Experience 
Pimavanserin is an atypical antipsychotic that is approved for the treatment of hallucinations 
and delusions associated with PDP. Studies have also been conducted in Alzheimer’s disease 
psychosis (ADP), dementia-related psychosis and schizophrenia, and studies in Alzheimer’s 
disease agitation and aggression, dementia-related psychosis, and schizophrenia are ongoing. 
A more complete discussion of these studies is available in the current pimavanserin 
Investigator’s brochure. 
Pimavanserin is considered to be generally well tolerated and has an acceptable safety 
profile. In single and multiple dose studies in healthy subjects, the highest doses administered 
were 255 mg and 136 mg/day, respectively. In Phase 1 studies in subjects who received 
pimavanserin without concomitant medication, the most common TEAEs (>3%) were 
postural dizziness (7.7%), headache (6.9%), somnolence (4.6%), nausea (3.8%), and 
dizziness (3.1%) in the single-dose studies (N=130) and headache (15.1%), dizziness (8.6%), 
nausea (7.4%), somnolence (5.1%), and postural dizziness (3.7%) in the multiple-dose 
studies (N=350). Nausea and vomiting were considered dose-limiting. Pimavanserin doses 
≤34 mg generally had a low incidence of TEAEs, with only small differences versus placebo. 
In controlled studies of pimavanserin in subjects with PDP, the most frequent TEAEs 
experienced by subjects in the pimavanserin 34 mg group compared with the placebo group 


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were urinary tract infection (7.4% pimavanserin 34 mg vs. 6.9% placebo), nausea 
(6.9% pimavanserin 34 mg vs. 4.3% placebo), peripheral edema (6.9% pimavanserin 34 mg 
vs. 2.2% placebo), fall (6.4% pimavanserin 34 mg vs. 9.1% placebo), and confusional state 
(5.9% pimavanserin 34 mg vs. 2.6% placebo). In the long-term open-label studies in subjects 
with PDP (as of 28 April 2019), the most frequent TEAEs include fall (31.1%), urinary tract 
infection (19.1%), hallucination (14.5%), decreased weight (13.3%), confusional state 
(11.4%), and constipation (11.2%). It is difficult to interpret these incidence rates in the 
absence of a concurrent control group. The overall incidence of TEAEs appears within what 
would be expected in subjects with the underlying neurodegenerative disease, psychosis, and 
advanced age. 
As of 28 April 2019, 74 subjects have died during participation in the PDP studies, with the 
majority of deaths considered not related or unlikely related to study drug. Five of these deaths 
occurred in 6-week double-blind studies (1 subject received placebo, 1 subject received 8.5 mg 
pimavanserin, and 3 subjects received 34 mg pimavanserin), and 69 deaths occurred in the 
multi-year, long-term open-label extension studies. 
Medical reviews of all deaths occurring in the pimavanserin PDP program, including 
placebo-controlled (6-week) and open-label (long-term) studies, found no common etiology 
or unifying pathology to attribute these deaths to pimavanserin treatment. The causes of death 
(e.g., cardiovascular, respiratory, infection) were consistent with the advanced age, stage of 
illness, and comorbidities of this elderly, medically frail population. Additional information is 
provided in the current pimavanserin Investigator’s brochure. 
In a frail, elderly population of 181 nursing home patients with ADP (90 treated with 
pimavanserin; 91 with placebo), pimavanserin was well tolerated, with no new safety 
observations. There were 8 post-randomization deaths, 4 (4.4%) in each treatment group. 
More subjects had SAEs with pimavanserin (15 subjects, 16.7%) than with placebo 
(10 subjects, 11.0%), but there were fewer discontinuations due to AEs with pimavanserin 
(8 subjects, 8.9%) than with placebo (11 subjects, 12.1%). TEAEs reported in ≥10% of 
subjects in either group were (pimavanserin; placebo) fall (23.3%; 23.1%), urinary tract 
infection (22.2%; 27.5%), agitation (21.1%; 14.3%), lower respiratory tract infection (14.4%; 
13.2%), contusion (12.2%; 15.4%), aggression (10.0%; 4.4%), anemia (10.0%; 8.8%), blood 
lactate dehydrogenase decreased (4.4%; 11.0%), and hyperglycemia (4.4%; 12.1%). Mean 
weight change from Baseline to Day 85 was comparable for the two treatment groups. 
Weight loss ≥7% was more common with pimavanserin (pimavanserin, 14.6%; placebo, 
1.8%). Treatment with pimavanserin had no negative effects on cognition or motor function. 
Pimavanserin increases QT interval. The magnitude of effect in humans has been assessed in 
a thorough QT study with doses of pimavanserin ranging from 17 to 68 mg and in the Phase 3 


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PDP program with a clinical dose of 34 mg. An average prolongation of approximately 5-8 ms 
was observed. No clinically significant patterns have been observed in SAEs and there has 
been no evidence of pimavanserin-related laboratory abnormalities.  
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 drug 
metabolism, pharmacokinetics (PK), efficacy, and safety. 
1.4 
Study Rationale 
5-HT2A serotonin receptors represent important targets for depression. A variety of studies 
have shown antidepressant activity from compounds with potent antagonist or inverse agonist 
activity at 5-HT2A receptors, and to varying degrees 5-HT2C receptors, but low affinity to 
SERT, NET, and DAT, either alone or when coadministered with SSRIs (Table 1-1). These 
compounds include volinanserin, pruvanserin, ketanserin, ritanserin, mirtazapine, mianserin, 
and trazodone (Table 1-1). Pimavanserin, with its potent activity as a 5-HT2A 
antagonist/inverse agonist and lesser activity as a 5-HT2C antagonist/inverse agonist, has a 
similar receptor profile to many compounds with antidepressant activity. Therefore, although 
there are no preclinical data on pimavanserin in animal models of depression, it would also 
be expected to have antidepressant activity. 
Table 1-1 
Receptor Profiles of Pimavanserin and Compounds With 
Antidepressant Activity 
Target 
PIM 
RIT 
VOL 
PRUV 
PIP 
KET 
MIRT 
MIAN 
TRAZ 
SERT 
Low 
Low 
Low 
Low 
N/A 
Low 
Low 
Low 
350 
NET 
Low 
Low 
Low 
Low 
N/A 
Low 
Low 
70 
Low 
DAT 
Low 
Low 
Low 
Low 
N/A 
Low 
Low 
Low 
Low 
5-HT2A 
0.4 
0.1 
0.2 
0.7 
5 
2 
70 
3 
35 
5-HT2C 
16 
3 
125 
Low 
120 
125 
40 
3 
200 
Other 
noteworthy 
targets 
None 
None 
None 
None 
D4 (5) 
α2 (35) 
α1 (15-20) α2 (15-20) 
H1 (1) 
α2 (4-20) 
H1 (1) 
5-HT1A 
(100) 
Sources: Data on file, except for pipamperone (Schotte et al. 1996); trazodone and mianserin (PDSP Ki 
database, see Roth et al. 2000); and mirtazepine (Brayfield 2014 and Wikström et al. 2002) 
Abbreviations: α1=alpha1 adrenergic receptor; α2=alpha2 adrenergic receptor; DAT=dopamine transporter; 
H1=histamine 1 receptor; KET=ketanserin; MIAN=mianserin; MIRT=mirtazepine; N/A=not available; 
NET=norepinephrine transporter; PIM=pimavanserin; PIP=pipamperone; PRUV=pruvanserin; 
RIT=ritanserin; SERT=serotonin transporter; TRAZ=trazodone; VOL=volinanserin 
Note: Values represent the affinity (Ki) in nM of the indicated ligands and transporters/receptors. For 
“Other noteworthy targets,” Ki values are provided in parentheses. “Low” denotes a Ki >1000 nM. 
Clinical data with pimavanserin have been consistent with these preclinical data, 
demonstrating efficacy in PDP and ADP with an acceptable tolerability and safety profile. 
Furthermore, the robustness of the clinical evidence for efficacy and favorable tolerability 


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observed in Study ACP-103-042 supports further investigation of pimavanserin in the 
treatment of subjects with major depressive disorder who have had an inadequate response to 
antidepressant therapy. 
1.5 
Benefit/Risk Assessment 
This study will examine a range of symptoms to explore the efficacy and safety of adjunctive 
pimavanserin in the treatment of patients with MDD.  
Pimavanserin, with its potent activity as a 5-HT2A antagonist/inverse agonist and lesser 
activity as a 5-HT2C antagonist/inverse agonist, has a receptor profile similar to that of many 
compounds with antidepressant activity. In a randomized, double-blind, placebo-controlled 
Phase 2 study (ACP-103-042) exploring adjunctive pimavanserin, adult MDD patients with 
inadequate response to antidepressant therapy showed improvements in measures of 
depression, disability, clinical global impression, sleepiness, and sexual functioning, as 
summarized in Section 1.1.  
Clinical studies conducted in a range of patient populations (approximately 2720 exposed 
subjects, including patients with PDP, ADP, Alzheimer’s disease agitation and aggression, 
schizophrenia, and MDD, as well as healthy subjects) have shown that pimavanserin is 
generally well tolerated and has an acceptable safety profile. In the Phase 2 study 
(ACP-103-042) no new safety signals were observed in the MDD patient population that 
were not already described in the approved NUPLAZID® prescribing information 
(ACADIA Pharmaceuticals Inc. 2019).  
On the basis of nonclinical and clinical data, it is therefore believed that pimavanserin has 
potential for benefit in the adjunctive treatment of MDD, with an acceptable safety profile. 
A more complete assessment of the overall benefit/risk profile of pimavanserin is provided in 
the current Investigator’s Brochure. 
2 STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objective 
The primary objective of this study is to evaluate the efficacy of adjunctive pimavanserin 
compared to placebo in subjects with major depressive disorder who have an inadequate 
response to antidepressant therapy. 
2.1.1 
Primary Endpoint 
The primary endpoint of this study is the change from Baseline to Week 5 in the Hamilton 
Depression Scale (17 items) (HAMD-17) total score. 


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2.2 
Secondary Objective 
The secondary objective of this study is to evaluate the efficacy and benefits of adjunctive 
pimavanserin compared to placebo in subjects with major depressive disorder who have an 
inadequate response to antidepressant therapy on the following: 
• Functional impairment 
• Clinician’s global impression of severity and improvement of depressive symptoms 
• Sexual functioning 
• Sleepiness 
• Treatment response and remission 
• Anxiety 
• Impulsiveness 
• Early response to treatment 
2.2.1 
Secondary Endpoints 
The secondary endpoints of this study are the following: 
• Change from Baseline to Week 5 in Sheehan Disability Scale (SDS) score 
• Change from Baseline to Week 5 in Clinical Global Impression–Severity (CGI-S) 
score for depressive symptoms 
• Clinical Global Impression–Improvement (CGI-I) score for depressive symptoms at 
Week 5 
• Change from Baseline to Week 5 in the Changes in Sexual Functioning Questionnaire 
Short Form (CSFQ-14) 
• Change from Baseline to Week 5 in Karolinska Sleepiness Scale (KSS) score 
• Treatment responder rates at Week 5. Treatment response is defined as a reduction 
from Baseline in HAMD-17 total score of 50% or more. 
• Treatment remission rates at Week 5. Treatment remission is defined as a HAMD-17 
total score ≤7. 
• Change from Baseline to Week 5 in the Hamilton Depression (HAMD) 
Anxiety/Somatization factor score 
• Change from Baseline to Week 5 in the Barratt Impulsiveness Scale (BIS-11) 
• Change from Baseline to Week 1 in the HAMD-17 total score 
2.3 
Safety Objective 
The safety objective of this study is to assess the safety and tolerability of pimavanserin 
compared to placebo in subjects with major depressive disorder who have an inadequate 
response to antidepressant therapy.  


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2.3.1 
Safety Assessments 
The safety assessments in this study include the following: 
• Treatment-emergent adverse events (TEAEs) 
• Potentially clinically important laboratory abnormalities, vital signs, and 
electrocardiogram (ECG) results 
• Columbia–Suicide Severity Rating Scale (C-SSRS) score 
• Change from Baseline in Extrapyramidal Symptom Rating Scale–Abbreviated 
(ESRS-A) score 
• Sexual dysfunction defined as a CSFQ-14 total score of ≤47 for men and ≤41 for 
women 
3 STUDY DESCRIPTION 
3.1 
Overview of Study Design 
This study will be conducted as a multicenter, randomized, double-blind, placebo-controlled, 
parallel-group study in subjects with MDD and inadequate response to antidepressant 
treatment. Approximately 40 sites outside of the US will participate in this study. The 
duration of participation for individual study subjects will be up to 15 weeks.  
The study will have three periods (Figure S–1): 
• Screening period (3-28 days) 
• Double-blind treatment period (6 weeks) 
• Safety follow-up period (at least 30 days) 
The study completion date (or when a subject is considered to have completed the study) is 
defined as the date the final subject, across all sites, completes their final protocol-defined 
assessment. Please note that this includes the safety follow-up visit/contact, whichever is 
later. Procedures for when a subject is lost to follow-up are provided in Section 4.5. 
If the study is terminated for any reason, subjects remaining in the study will return to 
standard of care. 
3.1.1 
Screening Period (3-28 Days) 
During the screening period, subjects will be assessed for study eligibility and prohibited 
medications will be discontinued if medically appropriate. Subject eligibility will be assessed 
by the site and the Sponsor through an eligibility review process. The screening period may 
be extended up to 7 days to confirm subject eligibility when discussed with and approved by 
the Medical Monitor in advance. 


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Investigators should not withdraw a subject’s prohibited medication for the purpose of 
enrolling them into the study. Medications should only be discontinued if it is deemed 
clinically appropriate to do so and in consultation with the treating physician. 
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 site and the Medical Monitor. At Visit 2, 
subjects will be randomized in a 1:1 ratio to pimavanserin 34 mg once daily or matching 
placebo. It is recommended that the subject should take the study drug at approximately the 
same time each day. Assessments will be conducted at Weeks 0 (Baseline), 1, 2, 3, 4, 5, and 
6/EOT or early termination (ET). 
3.1.3 
Safety Follow-up Period (30 Days) 
Eligible subjects who successfully complete the 6-week double-blind period will be qualified 
to enroll in an open-label extension study. For subjects who discontinue prematurely from the 
study or who do not enroll in the open-label extension study, a safety follow-up telephone 
call visit will be conducted at least 30 days after the last dose of study drug. 
3.2 
Matching Study ACP-103-059 
Study ACP-103-059, conducted only in the US, is identical in design with Study ACP-103-
054, conducted in parallel outside of the US. 
3.3 
Impact of COVID-19 Pandemic on Studies -054 and -059 
In March, 2020, the emerging coronavirus disease 2019 (COVID-19) pandemic resulted in 
the implementation of measures designed to ensure subject safety in both studies. Screening 
and randomization of new subjects into studies ACP-103-054 and ACP-103-059 were 
temporarily paused. All randomized subjects that were ongoing in the studies at the time 
screening was paused were allowed to complete as per protocol and enroll in the OLE 
provided that the subject, investigator and medical monitor agreed that it was in the best 
interest of the subject to do so, and the investigator could assure the site’s ability to properly 
monitor the safety and well-being of the study subject, in accordance to study protocol. 
3.3.1 
Combination of Databases of Studies -054 and -059 
At the time screening was paused, approximately half of the planned subjects had been 
randomized in each study. ACADIA decided to combine the two studies, ACP-103-059 and 
ACP-103-054, into one study with a pre-specified statistical analysis plan. As a result, both 
studies closed and are proceeding with database lock and statistical analysis. No new patients 
were enrolled into these studies. The modifications to the statistical handling of the study are 
described briefly in Section 9 and in detail in the Statistical Analysis Plan. 


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3.3.2 
Remote Clinical Assessments 
In the interim between the pause in screening and the termination of the studies, several 
subjects remained in the study who could not attend clinic visits. These subjects were allowed 
to conduct remote visits via telephone or video, or site personnel could conduct the visit in a 
subject’s home. Remote visits were not recommended for the Week 1 and Week 6 visits as 
these visits required ECGs. Subjects were not allowed to roll over into the open-label 
extension study unless they came to the research site to conduct an in-person Week 6 visit.   
Sites were required to document details of all visits that were administered remotely.  
Further details about accommodations and modifications to assessments, relating to the 
COVID-19 pandemic, can be found in Sections 6.2.7 (efficacy assessments), 6.3.8 (safety 
assessments) and 6.5.1 (unscheduled visits) and Section 9 (additional sensitivity analyses).    
3.3.3 
Roll Over Into Open-Label Study ACP-103-055  
Subjects may have rolled over into the ACP-103-055 study (open-label extension) provided 
that the subject, Investigator and medical monitor agreed that it was in the best interest of the 
patient, and the study site could assure its ability to properly monitor the safety and well-
being of the patient in accordance with the study protocol.  
Additionally, all inclusion/exclusion criteria must have been verified prior to rollover and the 
subject must have presented to the clinic in person to sign the ACP-103-055 informed 
consent form (ICF) and have all ACP-103-054 end of treatment procedures. 
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 to be eligible for participation in 
the study: 
1. Is a male or female ≥18 years of age 
2. Can understand the nature of the study and protocol requirements and is willing to 
comply with study drug administration requirements and discontinue prohibited 
concomitant medications  
3. Provides written informed consent to participate in the study 
4. Is capable of communicating with the site personnel, able to complete subject-reported 
outcome measures and can be reliably rated on assessment scales (in the opinion of the 
Investigator) 


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5. Has a clinical diagnosis of major depressive disorder with or without anxious distress by 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria 
and confirmed by the Mini-International Neuropsychiatric Interview (MINI) during the 
screening period. Subject may have either recurrent or single episode of major 
depressive disorder. 
6. Is treated during the current major depressive episode with one of the following 
SSRI/SNRI antidepressants at a minimally effective dose for at least 8 weeks with at 
least the same stable dose over 4 weeks prior to the SAFER (State versus trait, 
Assessability, Face validity, Ecological validity, and Rule of three Ps [pervasive, 
persistent, and pathological]) remote interview: 
a. Citalopram 
b. Escitalopram 
c. Paroxetine 
d. Fluoxetine 
e. Sertraline 
f. Duloxetine 
g. Venlafaxine 
h. Desvenlafaxine 
i. Venlafaxine XR 
The dose level of the antidepressant is expected to remain stable throughout the study.2 
Adherence to the antidepressant should be reviewed throughout the study. 
7. Must have a detectable blood level of a prescribed SSRI/SNRI during Screening. A 
negative screening test may be repeated as assessed by the Medical Monitor when the 
subject and/or site can provide additional evidence of subject adherence to 
antidepressant treatment or evidence of sample or laboratory error. 
8. During the screening period, the subject’s inadequate response to SSRI/SNRI 
antidepressant treatment is confirmed by the Massachusetts General Hospital 
Antidepressant Treatment Response Questionnaire (MGH ATRQ) through the SAFER 
remote interview and the subject continues to exhibit an inadequate response to 
treatment at the time of the SAFER interview. 
9. Subjects who are currently taking a second antidepressant or antidepressant 
augmentation agent at a subtherapeutic dose or for inadequate duration at Screening 
are eligible for inclusion in the study if it is clinically appropriate to discontinue the 
                                                 
 
 
2 Please see Appendix C for medication restrictions. 


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drug before the Baseline visit (in the opinion of the Investigator); the second 
antidepressant/augmentation agent must be discontinued and washed out at least 
5 half-lives prior to Baseline. This second antidepressant/augmentation agent should 
not be discontinued solely to make the subject eligible for enrollment in the study. 
10. Has a Montgomery-Asberg Depression Rating Scale (MADRS) total score >20 at both 
Screening and Baseline 
11. Has a Clinical Global Impression–Severity (CGI-S) score ≥4 (moderately ill or worse) 
for depression at both Screening and Baseline 
12. If the subject is female, she must not be pregnant or breastfeeding. She must also be of 
non-childbearing potential (defined as either surgically sterilized or at least 1 year 
postmenopausal) OR must agree to use TWO clinically acceptable methods of 
contraception for at least 1 month prior to Visit 2 (Baseline), during the study, and 
1 month following completion of the study. 
Acceptable methods of contraception include the following: 
a. A barrier method (condom, diaphragm, or cervical cap) with spermicide 
b. Hormonal contraception, including oral, injectable, transdermal, or 
implantable methods 
c. Intrauterine device (IUD) 
Only one of the two clinically acceptable methods can be a hormonal method. 
4.2 
Exclusion Criteria 
A subject must meet none of the following exclusion criteria to be eligible for the study: 
1. Has a history of schizophrenia or other psychotic disorder, major depressive disorder 
with psychotic features, bipolar I or II disorder. Subjects who are currently being 
treated or require treatment for post-traumatic stress disorder, acute stress disorder, 
panic disorder, or obsessive compulsive disorder are also not eligible. 
2. Has a current primary diagnosis of borderline, antisocial, paranoid, schizoid, 
schizotypal, or histrionic personality disorder, according to DSM-5 criteria 
3. Has met DSM-5 criteria for substance use disorders within the last 6 months prior to 
Screening, except for disorders related to the use of caffeine or nicotine 
4. Is suicidal at Visit 1 (Screening) or Visit 2 (Baseline) as defined below: 
a. An answer of “yes” to C-SSRS questions 4 or 5 (current or over the last 
6 months); OR 
b. Has attempted suicide within 1 year prior to Visit 1 (Screening); OR 
c. Is actively suicidal in the Investigator’s judgment 
5. Has current evidence of delirium or an unstable neurological, cardiovascular, 
respiratory, gastrointestinal, renal, hepatic, hematologic, or other medical disorder, 


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including cancer or malignancies that, in the judgment of the Investigator or the 
Medical Monitor, would jeopardize the safe participation of the subject in the study or 
significantly interfere with the conduct or interpretation of the study 
6. Has a history of epilepsy 
7. Has atrial fibrillation unless adequately anti-coagulated 
8. Has a history of myocardial infarction, unstable angina, acute coronary syndrome, or 
cerebrovascular accident   
9. Has a history of any of the following: 
a. Greater than New York Heart Association (NYHA) Class II congestive heart 
failure (Appendix A) 
b. Grade II or greater angina pectoris (by Canadian Cardiovascular Society 
Angina Grading Scale) (Appendix B) 
c. Sustained ventricular tachycardia 
d. Ventricular fibrillation 
e. Torsade de pointes 
f. Syncope due to an arrhythmia 
g. An implantable cardiac defibrillator 
10. Has laboratory evidence of hypothyroidism 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 enrolled 
11. Has current unstable diabetes or glycosylated hemoglobin (HbA1c) >8% at Screening 
12. Has a known history of a positive hepatitis B virus (HBV), hepatitis C virus (HCV), or 
human immunodeficiency virus (HIV) test  
13. Has a history of neuroleptic malignant syndrome or serotonin syndrome 
14. Has a known personal or family history of long QT syndrome or family history of 
sudden cardiac death 
15. Has any of the following ECG results at Visit 1 (Screening) or Visit 2 (Baseline): 
a. If the subject is not on citalopram, escitalopram, or venlafaxine (immediate or 
extended release): 
i. QTcF >450 ms, if QRS duration <120 ms 
ii. QTcF >470 ms, if QRS duration ≥120 ms 
b. If the subject is on citalopram, escitalopram, or venlafaxine (immediate or 
extended release): 
i. QTcF >425 ms, if QRS duration <120 ms 
ii. QTcF >450 ms, if QRS duration ≥120 ms 


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At Screening, if the set of triplicate ECGs has a prolonged QTcF due to an identifiable 
cause, and it is medically appropriate to address that cause, a repeat set of triplicate 
ECGs may be performed during Screening at the discretion of the Medical Monitor. 
16. Has a heart rate <50 beats per minute, as measured by peripheral pulse rate, not 
explained by regular exercise or medication, in discussion with the Medical Monitor. 
If bradycardia is secondary to iatrogenic or treatable causes and these causes are 
treated, a heart rate assessment can be repeated during the screening period. 
17. Requires treatment with a medication or other substance that is prohibited by the 
protocol 
18. At Screening, has a body mass index (BMI) <18.5 kg/m2 or >35 kg/m2 or known 
unintentional clinically significant weight loss (i.e., ≥7%) over past 6 months 
19. Has a positive test for an illicit drug or cannabis at Screening or Baseline. Subjects 
who test positive for a controlled substance and who have a valid prescription may be 
retested during Screening if they agree to abstain from the medication for the length of 
their participation in the study. The repeat test during Screening must be negative for 
them to participate in the study. Additionally, DSM-5 criteria for substance use 
disorders should not be met. 
20. Has received electroconvulsive therapy, transcranial magnetic stimulation, or vagal 
nerve stimulation, or has received deep brain stimulation in the current episode of 
depression 
21. Has received new-onset psychotherapy or had a change in the intensity of 
psychotherapy within 8 weeks prior to Screening 
22. Has participated in or is participating in a noninterventional study or clinical trial of 
any investigational or marketed drug, device, or intervention, within 30 days or 
5 half-lives, whichever is longer, of Visit 2 (Baseline) 
23. Has previously been enrolled in any prior clinical study with pimavanserin or is 
currently taking pimavanserin 
24. Has a significant sensitivity or allergic reaction to pimavanserin or its excipients 
25. Is an employee or is a family member of an employee of ACADIA Pharmaceuticals 
Inc. 
26. Is judged by the Investigator or the Medical Monitor to be inappropriate for the study 
for any reason, including if the subject is judged to be a danger to self or others 
4.3 
Subject Withdrawal of Consent 
In accordance with the Declaration of Helsinki and other applicable regulations, a subject has 
the right to withdraw from the study at any time, and for any reason, without prejudice to his 
or her future medical care. 


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Should a subject request or decide to withdraw consent, every reasonable effort should be 
made to complete and report observations as thoroughly as possible up to the date of 
withdrawal, including the evaluations specified at the ET or safety follow-up visit (whichever 
visit is applicable), as outlined in Table S–1. 
4.4 
Subject or Study Discontinuation 
Subjects may be discontinued from the study for a number of reasons, including, but not 
limited to, those listed below: 
• Adverse event 
• Death 
• Lack of efficacy 
• Lost to follow-up (Section 4.5) 
• Non-compliance with study drug 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Study terminated by Sponsor 
• Use of prohibited medication 
• Other 
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. 
4.4.1 
Handling of Subject Discontinuation During the Treatment Period 
Unless the subject has withdrawn consent to be contacted for this 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 for 
any reason. All information will be reported on the applicable pages of the electronic case 
report form (eCRF). 


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If a subject is discontinued from the study because of an AE, every reasonable attempt should 
be made to follow the subject until the AE resolves or until the Investigator deems the AE to 
be chronic or stable. For subjects who continue to be followed for safety, SAEs should 
continue to be reported as described in Section 7.4.2. All SAEs will continue to be followed 
until such events have resolved or the Investigator deems them to be chronic or stable. 
4.5 
Subject Lost to Follow-up 
A subject will be considered lost to follow-up if they fail to attend a scheduled visit 
(including the safety follow-up visit) and is unable to be contacted by the study site. 
Every reasonable effort should be made to contact the subject and will include a minimum of 
three documented phone calls (each performed at different times of the day) and, if necessary, 
a certified letter to the subject’s last known mailing address or local equivalent methods. All 
contact attempts are to be documented in the source documents. 
4.6 
Prior and Concomitant Therapy 
All medications used from study screening until completion of the safety follow-up visit are 
to be recorded. 
4.6.1 
Prior Medication 
Prior medication is defined as any medication taken before the date of the first dose of study 
drug. 
4.6.2 
Concomitant Medication 
Concomitant medication is defined as any medication taken on or after the date of the first 
dose of study drug. 
In order to ensure that appropriate concomitant therapy is administered, it is essential that 
subjects be instructed not to take any medication without prior consultation with the 
Investigator (unless the subject is receiving treatment for a medical emergency). 
The Investigator may prescribe appropriate medication to treat AEs. Relationship to 
COVID-19 will be assessed for selected medications. The Sponsor and Investigator or 
designee will confer to determine whether it is appropriate to continue such a subject in the 
trial if a prohibited medication is prescribed. 
4.6.2.1 
Permitted, Restricted, and Prohibited Medications 
Prohibitions and restrictions for concomitant medications should be followed between the 
initial screening visit and Visit 8/ET as specified in Appendix C and Appendix D. 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. 


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Use of medications that could interfere with study conduct or any questions regarding 
prohibited and restricted concomitant medications should be reviewed and/or discussed with 
the Medical Monitor or designee. 
Medications that can prolong QT interval are prohibited (or restricted if approved by the 
Medical Monitor) as specified in Appendix C. 
Permitted concomitant medications should remain at a stable dose throughout the study.  
If a subject is on a medication restricted by the protocol, the medication should be adjusted if 
it is determined by the Investigator to be clinically appropriate (e.g., if the subject’s 
symptoms are not well-controlled or if the subject cannot tolerate the current medication) in 
consultation with the treating physician. 
Subjects who require current treatment with a prohibited medication will be withdrawn from 
the study. 
Subjects who have 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 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. 
5 INVESTIGATIONAL PRODUCT 
5.1 
Investigational Product Description 
The investigational product will be pimavanserin 34 mg (provided as 2×17 mg tablets) or 
matching placebo (2×placebo tablets). Placebo tablets will be size- and color-matched to the 
pimavanserin tablets. Tablets will be administered orally as a single dose once daily. 
5.1.1 
Formulation, Appearance, Packaging, and Labeling 
The Sponsor will supply pimavanserin 17 mg tablets and matching placebo tablets. 
Pimavanserin tartrate is a white to off-white powder. Pimavanserin 17 mg tablets include the 
active compound (pimavanserin tartrate) and the following excipients: pregelatinized starch, 
magnesium stearate, and microcrystalline cellulose, and the tablet coating is 
 
 
. The drug product is formulated with standard pharmaceutical excipients at 
17 mg strength (20 mg of pimavanserin tartrate). 


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Placebo tablets contain all of the same excipients as pimavanserin 17 mg tablets but do not 
contain any pimavanserin tartrate. 
Pimavanserin and placebo tablets are manufactured under current Good Manufacturing 
Practices. 
During the treatment period, study drug will be distributed in a quantity sufficient to ensure 
the subject has an adequate supply of study drug between study visits. 
5.1.2 
Product Storage and Stability 
Investigational product must be stored between 15°C and 30°C (59°F and 86°F) in a secure 
area with restricted access and according to local and national regulations. 
5.1.3 
Dosing and Administration 
The first dose of study drug will be administered at the site. Study drug kits will then be 
dispensed to the subject to take home. Each daily dose consists of two individual tablets that 
should be taken together. Subjects should be instructed to take two whole tablets, orally, once 
daily. Subjects should be instructed to not crush the tablets. The tablets may be taken with or 
without food. 
5.1.4 
Method of Assigning Subjects to Treatment Groups 
At Week 0 (Visit 2), eligible subjects who meet inclusion and do not meet exclusion criteria 
will be randomized in a 1:1 ratio to receive either 34 mg pimavanserin once daily or placebo. 
5.1.5 
Blinding 
Treatment assignments will be blinded to all study subjects, Investigators, raters, site 
personnel, and Sponsor personnel. In the event of a potential suspected unexpected serious 
adverse reaction (SUSAR), in accordance with current health authority guidance, treatment 
assignments for the affected subject may be unblinded to a controlled group of the Sponsor’s 
Safety and/or Regulatory personnel for reporting purposes.  
Details regarding medical emergency unblinding procedures are provided in Section 9.8. 
5.1.6 
Study Drug Compliance 
If a subject misses one dose of study drug, he or she should not take an extra dose the next 
day. Subjects who are less than 80% compliant with study drug as assessed at more than one 
study visit should be discussed with the Medical Monitor or designee. 
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, irrespective of outcome, 


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even if toxic effects were not observed (Section 7.4.4). All events of overdose are to be 
captured as protocol deviations. 
5.2 
Investigational Product Accountability Procedures 
The Investigator or designee will keep current and accurate records of the study drug product 
dispensed, used, and returned for each subject to assure the regulatory authority and the 
Sponsor that the study drug is being handled appropriately. Subjects should be instructed to 
return all packaging and unused study drug to the Investigator at regularly scheduled clinic 
visits and ET visits. Any study drug supplied is for use in this study only and should not be 
used for any other purpose. 
At appropriate intervals during the study, study drug reconciliation will be performed by the 
Sponsor (or designee) who may return appropriate unused study drug and used and unused 
packaging to the Sponsor’s designee for destruction. 
At the conclusion of the study, final study drug reconciliation will be conducted at the site. 
Final study drug accountability documentation will be maintained at both the site and at the 
Sponsor. Any remaining unused study drug and all used and unused packaging will be sent 
back to the Sponsor’s designee for destruction, as allowed by country specific regulations. 
Documentation of study drug destruction will be recorded and maintained by both the 
Sponsor and the Sponsor’s designee. 
6 STUDY PROCEDURES 
Study specific procedures 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. 
6.1 
Screening Assessments 
Subject eligibility will be assessed during the Screening period by the site and the Sponsor 
through an eligibility review process. The Screening period (between the Screening and 
Baseline visit) may be extended by up to 7 days when awaiting results to confirm subject 
eligibility when discussed with the Medical Monitor in advance. 
6.1.1 
Medical History, Medication History, and Demographics 
A complete medical history and medication history will be obtained from each potential 
subject. Demographic information, including date of birth, gender, race, and ethnicity 
(if allowed by local regulations) will be recorded as well. Any new medical condition 
beginning after the ICF has been signed will be captured as an AE. In addition, a history of 
the medications that the subject has taken for the current depressive episode should be 


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obtained. Subjects may be asked to provide pharmacy or medical records to substantiate the 
medication history. 
6.1.2 
Psychiatric History 
Details of the subject’s psychiatric history and treatment will be collected. 
6.1.3 
Background Antidepressant Blood Level 
At Screening, blood samples for the analysis of the concomitant selective serotonin reuptake 
inhibitor (SSRI)/serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressants will be 
collected. At Screening, the presence of SSRI or SNRI must be confirmed in order to qualify 
the subject for further consideration in the study. Review of subject adherence with 
background antidepressant therapy should be conducted at screening visit and all visits.  
6.1.4 
Massachusetts General Hospital Antidepressant Treatment Response 
Questionnaire 
The MGH ATRQ (Fava and Davidson 1996; Fava 2003) is a clinician-assisted questionnaire 
that examines a patient’s antidepressant treatment history using specific anchor points to 
define the adequacy of both the dose and duration of each antidepressant course, as well as 
the degree of symptomatic improvement obtained with each course. This validated 
questionnaire allows for the determination of inadequate response to antidepressant therapy 
in MDD (Chandler et al. 2010). Inadequate response is defined as a response of <50% to a 
course of treatment of at least 8 weeks at the minimum effective dose (as listed on the 
ATRQ), which has been stable for the 4 weeks prior to the SAFER interview.  
6.1.5 
State versus trait, Assessability, Face validity, Ecological validity, and Rule of 
three Ps (pervasive, persistent, and pathological) (SAFER) Remote Interview 
To ensure that appropriate subjects are entered into the study, an interview will be conducted 
. 
The interview may be conducted via telephone off-site or on-site, during Screening. If 
conducted on-site, the site staff should not be present during the interview. The assessments 
administered will be the SAFER Interview, which will include the MADRS, the CGI-S, and 
the MGH ATRQ. Sites will be notified of the results within 24 hours of the interview. 
6.1.6 
Mini-International Neuropsychiatric Interview 
The MINI is a brief, structured, diagnostic interview covering a broad range of major 
psychiatric disorders in DSM-5 and ICD-10 (Sheehan et al. 1998). The MINI is divided into 
modules, with each module corresponding to a diagnostic category. After completing the 
questions in each module, the interviewer (i.e., the Investigator or designee) assesses whether 
the diagnostic criteria are met. 


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In addition, one module for depressive disorders from the MINI-Plus will be used in 
conjunction with the MINI. The MINI-Plus is a more extensive version of the MINI, 
including additional disorders and disorder subtyping (Sheehan et al. 1998). 
MINI Version 7.0.2 for DSM-5 will be used in this study and will be conducted during 
Screening. 
6.1.7 
Montgomery-Asberg Depression Rating Scale 
The MADRS (Montgomery and Asberg 1979) is a 10-item, clinician-rated instrument 
measuring depression severity. It will be administered during Screening and at Baseline by 
the Investigator or designee with a Structured Interview Guide for the Montgomery-Asberg 
Depression Rating Scale (SIGMA) (Williams and Kobak 2008). The timeframe for this scale 
is the past 7 days. 
6.2 
Efficacy Assessments 
6.2.1 
Hamilton Depression Scale (17 Items) 
The HAMD-17 (Hamilton 1960) is completed with the Structured Interview Guide for the 
Hamilton Depression Rating Scale (SIGH-D) (Williams 1988) by the Investigator or designee 
based on an assessment of a patient’s symptoms. The timeframe for this scale is the past 
7 days. The HAMD-17 is to be the first scale completed at each visit. The HAMD-17 will be 
used as the primary efficacy analysis. 
The anxiety/somatization factor of the HAMD-17 (Cleary and Guy 1977) includes six items: 
psychic anxiety, somatic anxiety, gastrointestinal somatic symptoms, general somatic 
symptoms, hypochondriasis, and insight, and will be used for secondary efficacy analyses. 
6.2.2 
Sheehan Disability Scale 
The SDS (Sheehan et al. 1996) is a three-item patient-facing questionnaire used to evaluate 
impairments in the domains of work, social life/leisure, and family life/home responsibility. 
All items are rated on an 11-point continuum (0=no impairment to 10=most severe). The 
timeframe for this scale is the past week. The SDS will be used for secondary efficacy 
analyses. 
6.2.3 
Clinical Global Impression–Severity and Clinical Global Impression–
Improvement Scales 
The CGI-S and CGI-I (Guy 1976) are scales used by the Investigator or designee to rate the 
severity of the disorder and the global improvement since beginning of the study. The CGI-S 
rates the severity of a patient’s depression over the past 7 days and will be completed with a 
structured interview guide for global impressions (SIGGI) (Targum et al. 2013). The CGI-S 
will be used for secondary efficacy analyses. The CGI-I rates the change in a patient’s 


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depression over the past 7 days relative to the patient’s symptoms at Baseline and will be 
used for secondary efficacy analyses. 
6.2.4 
Changes in Sexual Functioning Questionnaire Short Form 
Sexual functioning will be assessed using the CSFQ-14 (Keller et al. 2006), a 14-item version 
of the CSFQ (Clayton et al. 1997). This is a patient-facing questionnaire, with a male version 
and a female version, that provides scores for three scales corresponding to the phases of the 
sexual response cycle (i.e., desire, arousal, and orgasm) and the five scales of the original 
CSFQ (sexual desire, sexual frequency, sexual satisfaction, sexual arousal, and sexual 
completion). The CSFQ-14 will be used for secondary efficacy analyses. 
6.2.5 
Karolinska Sleepiness Scale 
The KSS (Akerstedt and Gillberg 1990) is a patient-facing scale that measures the patient’s 
drowsiness and is frequently used in studies measuring subjective sleepiness. Scoring is 
based on a 9-point verbally anchored scale ranging from “extremely alert” to “very sleepy, 
great effort to keep awake, fighting sleep.” The timeframe for this scale is the past 7 days. 
The KSS will be used for secondary efficacy analyses. 
6.2.6 
Barratt Impulsiveness Scale 
The BIS-11 (Patton et al. 1995) is a questionnaire designed to assess the 
personality/behavioral construct of impulsiveness. It is composed of 30 items describing 
common impulsive or non-impulsive (for reverse scored items) behaviors and preferences. 
Items are scored on the following 4-point scale: Rarely/Never=1; Occasionally=2; Often=3; 
Almost Always/Always=4. The BIS-11 will be used for secondary efficacy analyses. 
6.2.7 
Impact of COVID-19 Pandemic on Efficacy Assessments 
In the interim between the pause in screening and the termination of the studies due to the 
COVID-19 pandemic, several subjects remained in the study who could not attend clinic 
visits. These subjects were allowed to participate in remote visits via telephone or video, or 
site staff could have visited subjects in their homes.  
6.3 
Safety Assessments 
6.3.1 
Physical Examinations 
A general physical examination will be conducted at Screening, Baseline, and Week 6/ET. 
6.3.2 
Vital Signs 
Vital signs will include body temperature, resting respiration rate, sitting systolic and 
diastolic blood pressure, and pulse rate. The sitting blood pressure should be measured after 
the subject has been sitting for ≥3 minutes. 
Vital signs will be measured at all scheduled and unscheduled visits. 


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6.3.3 
Height, Weight, and Body Mass Index 
Height will be measured at Screening. 
Weight will be measured at all scheduled and unscheduled visits. 
Body mass index will be calculated using the following formula: 
Weight (kg) / [height (m)]2. 
6.3.4 
Electrocardiograms 
All 12-lead ECGs will be complete, standardized recordings. At Visit 1 (Screening), the ECG 
should be completed in triplicate and collected within a 3-minute period. At all other visits, a 
single 12-lead ECG should be completed. All ECGs will be centrally read; the interpretation 
by the central cardiologist is considered the official result. 
At Visit 1 (Screening) the mean QTcF/QRS values of all the tracings of adequate quality will 
be used to determine eligibility. If a site performs additional ECGs beyond the set of triplicate 
ECGs prescribed at Screening or the single ECG prescribed at Baseline, the mean QTcF/QRS 
values of all the tracings of adequate quality will be used to determine eligibility. 
• At Screening, if the set of triplicate ECGs has a prolonged QTcF due to an identifiable 
cause, and it is medically appropriate to address that cause, a repeat set of triplicate 
ECGs may be performed during Screening at the discretion of the Medical Monitor if 
time permits during the Screening period. 
• At Baseline, a subject who met the eligibility criteria during the central read of the 
screening ECGs may be enrolled based on the machine read of the locally completed 
ECG. If the interpretation of the ECG by the central cardiologist returned after 
randomization indicates QTcF outside of the allowable range, the subject will be 
discontinued from the study, but this will not be considered a protocol deviation. 
Electrocardiograms should be performed before blood sampling or at least 30 minutes after 
blood sampling. The subject must rest in a supine position for 5 minutes before the ECG is 
obtained. ECG tracings (paper or electronic) will be reviewed and interpreted by a qualified 
clinician. ECG tracings and results (ventricular rate, PR, QRS, QT, QTcF, and QTcB 
intervals) will be included and summarized in the subject’s study records. 
6.3.5 
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 Baseline/Screening version will be administered at Visit 1 (Screening), and the Since 
Last Visit version will be administered at all subsequent visits, including unscheduled visits. 


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The C-SSRS results for each subject should be reviewed by the Investigator at each visit. If at 
any time the C-SSRS results for a given subject reveal potential suicidality, then the 
Investigator should assess the clinical significance of such results. If a clinically significant 
risk of suicidality is identified for a subject, then the Investigator should discontinue the 
subject and implement appropriate treatment (Section 4.4). 
6.3.6 
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.  
6.3.7 
Laboratory Evaluations 
Clinical laboratory sample collection (including HbA1c at Screening only) is encouraged, but 
not required to be completed under fasting conditions. The laboratory evaluations will 
include, but are not limited to, the following: 
• Clinical chemistry serum tests 
o Sodium (Na), potassium (K), chloride (Cl), phosphorus (P), calcium (Ca), 
magnesium (Mg), carbon dioxide (CO2), blood urea nitrogen (BUN), 
creatinine (CR), uric acid 
 Mg should only be performed at Visit 1 (Screening) 
o Alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), 
total bilirubin (TBIL), lactate dehydrogenase (LDH) 
o HbA1c 
 HbA1c should only be performed at Visit 1 (Screening) 
o Glucose 
o Albumin (ALB), total protein 
o Prolactin 
o Creatine kinase (CK)/creatine phosphokinase (CPK) 
o Lipid panel 
 Total cholesterol, HDL-cholesterol, triglycerides, LDL-cholesterol, 
cholesterol/HDL ratio, non-HDL cholesterol 


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• Thyroid stimulating hormone (TSH) and free thyroxine (free T4), if TSH is out of 
range 
o TSH/free T4 should only be performed at Visit 1 (Screening) 
• 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 
• Urine toxicity (drug) screen 
o Urine toxicity (drug) screen will test for controlled substances according to the 
schedule presented in Table 6-1. Negative drug screens are required for study 
eligibility. 
o Sites will be supplied with instant-read dipstick urine toxicity (drug) screen 
tests to utilize as a tool at the Baseline and Week 6 visit in order to determine 
if the subject continues to meet eligibility. This test will not take the place of 
the urine toxicity (drug) screening performed by the central laboratory. 


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o Subjects who test positive for a controlled substance in the urine toxicity 
(drug) screen performed by the central laboratory and who have a valid 
prescription may be retested during Screening if they agree to abstain from the 
medication for the length of their participation in the study and if abstinence 
from medication usage is achieved at least 7 days prior to Visit 2 (Baseline). 
The repeat test during Screening must be negative for them to participate in 
the study. Additionally, DSM-5 criteria for substance use disorders should not 
be met.  
o Subjects who test positive in the urine toxicity (drug) screen performed by the 
central laboratory for benzodiazepines, tetrahydrocannabinol (THC), or 
opiates will be withdrawn from the study unless any prohibited medication or 
substance has been discontinued and withdrawal from the study presents an 
unacceptable medical risk for 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 a subject is 
allowed to remain in the trial, this will be reported as a major protocol 
deviation, not a waiver. In addition, restrictions listed in Appendix C should be 
followed. 
o Reasonable efforts should be made to collect a urine sample at applicable 
scheduled visits as described in “Urinalysis” above 
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 
Testsa,b 
Visit 1 (Screening) 
CHEM, TSH/free T4, CBC, UA, urine toxicity (drug) screen, and serum 
pregnancy test 
Visit 2 (Baseline) 
CHEM, CBC, UA, urine toxicity (drug) screen, and urine pregnancy test 
Visit 8 (ET/EOT) 
CHEM, CBC, UA, urine toxicity (drug) screen, and urine pregnancy test 
Abbreviations: CBC=complete blood count; CHEM=clinical chemistry serum tests; EOT=end of treatment; ET=early 
termination; HbA1c=glycosylated hemoglobin; TSH=thyroid stimulating hormone; UA=urinalysis 
a 
A pregnancy test is only required for women of childbearing potential. If urine cannot be obtained in women of 
childbearing potential, a serum pregnancy test should be done in its place. 
b 
An Mg level, HbA1c test, and TSH/free T4 test are only required at Visit 1 (Screening). 
6.3.8 
Impact of COVID-19 Pandemic on Safety Assessments 
In the interim between the pause in screening and the termination of the studies due to the 
COVID-19 pandemic, several subjects remained in the study who could not attend clinic 


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visits. These subjects were allowed to conduct remote visits via telephone or video, or site 
staff could have visited subjects in their homes.  
Some safety assessments may not have been performed, or may have been performed under 
different circumstances, due to the subject not being able to come to the clinic. Modifications 
and accommodations for safety assessments in the context of remote visits are described 
briefly below:  
6.3.8.1 
Priority Medical Assessments in Remote Visits 
The C-SSRS was to be performed as a priority, along with an assessment of AEs and 
COVID-19 symptoms. Additionally, subjects were to be queried about concomitant 
medications, and their background antidepressant and IP compliance. 
6.3.8.2 
Physical Examinations, Vital Signs, Height, and Weight 
Physical examinations, vitals, height, and weight may not have been performed because the 
visit had to be conducted remotely. If the visit was remote, subject may have reported vitals 
obtained on home devices.   
6.3.8.3 
Electrocardiograms 
ECGs may have been performed by site staff during a home visit.  
6.3.8.4 
Columbia-Suicide Severity Rating Scale 
See Section 6.3.8.1 above.  
6.3.8.5 
Extrapyramidal Symptom Rating Scale-Abbreviated 
When the ESRS-A motor examination could not be performed (e.g., when the visit was 
performed via telephone with no video component) then no scoring of symptoms was to be 
completed. The clinical interview questions were to be asked for all symptom areas in order 
to obtain information about the presence and severity of involuntary movements experienced 
by the patient and this was to be documented in the source record. The clinical significance of 
any symptoms was to be evaluated by the investigator and the adverse event page updated 
when new or worsening symptoms were reported. 
6.3.8.6 
Laboratory Evaluations 
If subjects could not attend clinic visits for laboratory evaluations, they were allowed to use 
local laboratories, or to have site staff visit them at their homes for blood draws. 
6.4 
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 


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not eligible for the open-label study, as well as those who discontinue prematurely from the 
study. Subjects should have the following completed at least 30 days after last dose of study 
drug: 
• Assessment of concomitant medications/treatments 
• Assessment of AEs 
6.5 
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 concomitant medications/treatments, measurement of vital signs and weight, 
ESRS-A, and completion of the C-SSRS (Since Last Visit version). The Investigator may 
perform any additional safety evaluations deemed by the Investigator to be clinically 
indicated. Study drug may be dispensed to the subject at unscheduled visits if needed. 
6.5.1 
Impact of COVID-19 on Unscheduled Visits 
If subjects were not able to attend the clinic for an unscheduled visit, this may have occurred 
remotely or by site staff visit to the subject’s home. 
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). The condition that leads to the procedure is an AE if not present at 
Baseline. 
• Overdose of concomitant medication without any signs or symptoms unless the subject 
is hospitalized for observation 
• Hospitalization for elective surgery planned prior to study (situation where an 
untoward medical occurrence has not occurred) 
• Pregnancy will not be considered an AE, but if it occurs, it will be reported on a 
pregnancy form 
7.1.2 
Definition of Serious Adverse Event 
In addition to the severity rating, each AE will be classified by the Investigator as “serious” 
or “not serious.” The seriousness of an event will be defined according to the applicable 
regulations and generally refers to the outcome of an event. An SAE is one that meets one or 
more of the following: 
• Is fatal 
• Is immediately life threatening 
• Results in disability or permanent damage 
• Requires hospitalization 
• Prolongs existing hospitalization 
• Is a congenital anomaly or birth defect (in an offspring) 
• Is medically significant 
Definition of Life Threatening 
A life-threatening event places the subject at immediate risk of death from the event as it 
occurred. This does not include an AE, which, had it occurred in a more severe form, might 
have caused death. 
Definition of Hospitalization 
Hospitalization is defined by 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 


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• 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, or convulsions that do not result in hospitalization or 
development of drug dependency or drug abuse. 
An SAE may also include any other event that the Investigator or Medical Monitor judges to 
be serious or that suggests a significant hazard, contraindication, side effect, or precaution. 
7.2 
Classification of an Adverse Event 
7.2.1 
Severity of Event 
The severity of each AE will be graded on a 3-point scale and reported in detail as indicated 
on the eCRF: 
• Mild: awareness of sign or symptom but easily tolerated, causing minimal discomfort, 
and not interfering with normal everyday activities 
• Moderate: sufficiently discomforting to interfere with normal everyday activities 
• Severe: incapacitating and/or preventing normal everyday activities 
7.2.2 
Relationship to Study Drug 
The causality of each AE should be assessed and classified by the Investigator as “related” or 
“not related.” An event is considered related if there is a reasonable possibility that the event 
may have been caused by the product under investigation (i.e., there are facts, evidence, or 
arguments to suggest possible causation). 
Consider the following when assessing causality: 
• Temporal associations between the agent and the event 


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• Response to 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 
7.2.2.1 
Duration 
The start and stop dates for AEs will be recorded using the following criteria: 
• Start: Date of the first episode of the AE or date of significant sustained worsening in 
severity 
• Stop: Date when AE either ceased permanently or changed in severity 
7.2.2.2 
Frequency 
The frequency of the AE should be indicated according to the following definitions: 
• Single: Experienced once, without recurrence 
• Recurrent: More than one discrete episode with the same severity 
7.2.2.3 
Action Taken with Study Drug 
• Dose not changed: No change in study drug 
• Drug interrupted: Study drug temporarily stopped 
• Drug withdrawn: Study drug discontinued permanently 
7.2.2.4 
Therapy 
• None: No new treatment instituted 
• Medication: New treatment initiated as a direct result of AE 
• Other: Other action required 
7.2.2.5 
Outcome 
• Recovered/resolved: Recovered or resolved 
• Recovered/resolved with sequelae: Recovered or resolved with sequelae 
• Not recovered/not resolved: Not recovered or not resolved 
• Fatal: Death due to an AE 
• Unknown: Unknown 


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7.2.2.6 
Seriousness 
• Not serious 
• Serious 
7.2.3 
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. All AEs must be either resolved or stable at the end of the 
study safety follow-up period. If ongoing at the end of the study safety follow-up period, the 
subject should be referred for appropriate treatment. 
In the event that a subject discontinues and has an ongoing AE at the time of discontinuation 
(Section 4.4.1) or is withdrawn from the study because of an AE, the subject should be 
followed and treated by the Investigator until the AE has resolved, stabilized, or a new 
chronic baseline has been established. 
7.4 
Reporting Procedures 
7.4.1 
Adverse Event Reporting 
The Investigator must record all observed AEs and all reported AEs. At each visit, the 
Investigator should ask the subject a nonspecific question (e.g., “Have you noticed anything 
different since your last visit?”) to assess whether any AEs have been experienced since the 
last report or visit. 
Note that any use of medication (and specifically any newly prescribed medication) during 
the course of a study may indicate the occurrence of an AE that may need to be recorded on 
both the AE and the concomitant medication page. 
All AEs, 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. 


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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; 
use the appropriate form for initial and/or follow-up reporting.  
At a minimum, events identified by the Sponsor to require expedited reporting as serious, 
unexpected, and related to study drug must be brought to the attention of the responsible 
institutional review board/ethics committee (IRB/EC), as per applicable regulations. These 
will be provided by the Sponsor after their assessment. For European Union member states, 
the Sponsor or its designee will provide reports of suspected unexpected serious adverse 
reactions (SUSARs) directly to the ECs, as required by local legislation. In all other 
countries, it is the Investigator’s responsibility to provide these expedited reports to the 
responsible IRB/EC. It is also the Investigator’s responsibility to notify the responsible 
IRB/EC regarding any new and significant safety information. 
When an SAE occurs, Investigators will review all documentation related to the event and 
will complete the paper SAE form (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 for 30 days after last dose of 
study drug for any SAEs and/or other reportable information until such events have resolved 
or the Investigator, in conjunction with the Sponsor, 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 study follow-up period of 30 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 
withdrawn 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. 


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Any AEs that are the consequence of pregnancy and which meet the criteria for serious 
should also be reported via the SAE form. 
7.4.3.1 Reporting Paternal Drug Exposure 
Paternal drug exposure is defined as a father’s exposure to a medicinal product before or 
during his partner’s pregnancy. Any paternal drug exposure cases must be reported to the 
Sponsor within 24 hours of discovery via the Pregnancy form. Any AEs that are the 
consequence of paternal drug exposure and which meet the criteria for serious must also be 
reported to the Sponsor within 24 hours of discovery via the SAE form. 
7.4.4 
Reporting of Overdose 
An overdose is a deliberate or inadvertent administration of a treatment at a dose higher than 
the maximum recommended dose per protocol. It must be reported to the Sponsor or 
designee on the Overdose form within 24 hours of discovery. In addition, all events of 
overdose are to be captured as protocol deviations. 
8 CLINICAL 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. 
9.2 
Statistical Hypotheses 
The hypotheses for the primary endpoint are the following: 
• The null hypothesis: There is no difference in the mean change from Baseline to 
Week 5 in the HAMD-17 total score between the pimavanserin and the placebo 
treatment groups. 
• The alternative hypothesis: There is a difference in the mean change from Baseline to 
Week 5 in the HAMD-17 total score between the pimavanserin and the placebo 
treatment groups. 


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9.3 
Sample Size Determination 
This study plans to screen approximately 560 adult subjects to randomize approximately 
280 subjects, allowing for a 50% screen failure rate. These approximately 280 subjects will 
be randomized in a 1:1 ratio to either the pimavanserin or the placebo treatment groups 
(i.e., 140 subjects in each treatment group). 
A total sample size of 266 evaluable subjects was estimated to provide at least 90% power at 
a two-sided significance level of 0.05 when assuming a treatment effect size of 0.4 for 
pimavanserin compared to placebo on the change from Baseline to Week 5 in the HAMD-17 
total score. Adjusting for a potential non-evaluable rate of up to 5%, approximately 
280 subjects will be randomized. 
9.4 
Subject Populations for Analysis 
The Full Analysis Set includes all subjects who were randomized, received at least one dose 
of study drug, and have both a Baseline (Week 0) value and at least one post-Baseline value 
for the HAMD-17 total score in the two studies. The Full Analysis Set will be used for the 
analysis of all efficacy endpoints. 
The Per-protocol Analysis Set includes a subset of subjects in the Full Analysis Set without 
any protocol deviations that could have a significant effect on the study conclusions. The 
Per-protocol Analysis Set will be determined prior to unblinding the studies for the final 
analysis and will be used for supportive analysis of selected efficacy endpoints. 
The Safety Analysis Set includes all subjects who received at least one dose of study drug in 
the two studies. 
Any other analysis sets, if necessary, will be defined in the SAP. 
9.5 
Statistical Analyses 
9.5.1 
Primary Analyses 
The primary efficacy endpoint, change from Baseline to Week 5 in the HAMD-17 total score, 
will be evaluated using a mixed-effect model repeated measures (MMRM). The model will 
include effects for treatment group, visit, treatment-by-visit interaction, baseline HAMD-17 
total score, the baseline HAMD-17 total score-by-visit interaction, and study. An unstructured 
covariance matrix will be used and the Kenward-Roger approximation will be used to adjust 
the denominator degrees of freedom. 
A hierarchical approach will be used to control for multiple endpoints (primary and 
secondary). Details will be provided in the SAP. 


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Sensitivity analyses will be performed to assess the impact of missing data, including 
analyses based on a missing not at random assumption. Additional sensitivity analyses will be 
performed to assess the impact of COVID-19.  
9.5.2 
Secondary Analyses 
Each of the secondary endpoints, other than response and remission, will be analyzed using 
the MMRM method similar to that used for the analysis of the primary efficacy endpoint. For 
CGI-I, the baseline CGI-S score will be used as the covariate in the MMRM model. The 
response and remission rates will be compared between the pimavanserin and placebo groups 
using the Cochran-Mantel-Haenszel (CMH) test stratified by study. 
9.5.3 
Safety Analyses 
Safety results will be summarized by treatment group using descriptive statistics. Adverse 
events will be classified into standard terminology using the Medical Dictionary for 
Regulatory Activities (MedDRA). 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 the first administration of study drug and no later than the 
last administration of study drug plus 30 days. Summaries by maximum severity and by 
relationship to study drug will also be provided. Serious TEAEs, fatal AEs, and TEAEs 
leading to discontinuation will also be summarized. The relationship of selected AEs to 
COVID-19 will also be assessed and COVID-19 related TEAEs will be tabulated. 
Clinical laboratory values for hematology, chemistry, and urinalysis (specific gravity and pH) 
will be summarized by treatment group using descriptive statistics at Baseline and the end of 
the treatment period visits. The change from baseline values will also be summarized by 
treatment group. The overall minimum and maximum post-baseline observed and change 
from baseline values will also be summarized. 
The number and percentage of subjects with potentially clinically important (PCI) laboratory 
values at the end of the treatment period and overall post-baseline will be summarized by 
treatment group for selected parameters. The PCI criteria will be specified in the SAP. 
Vital signs including weight, height, and the derived BMI 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. 
Observed values of electrocardiogram parameters and the changes from Baseline will be 
summarized by treatment group and visit. 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 Food and Drug Administration (FDA) E14 guidance 
document. 


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For the C-SSRS, the number and percentage of subjects with suicidal ideation or suicidal 
behavior during the study will be tabulated. 
Observed values and change from Baseline in the ESRS-A score will be summarized by 
treatment group and visit. The change from Baseline in the ESRS-A score will be analyzed 
using the MMRM method, similar to the MMRM method used to analyze the primary 
endpoint. 
Number and percentage of subjects with sexual dysfunction (a total score of <47 for men and 
<41 for women) will be summarized and shift tables will be presented.   
9.5.4 
Subgroup Analyses 
Selected analyses may be performed in subgroups. Details will be provided in the SAP. 
9.6 
Interim Analyses 
No interim analyses are planned.  
9.7 
Measures to Minimize Bias 
9.7.1 
Masking Procedures 
This unmasked protocol version provides details of certain study design elements, 
procedures, and statistical methods that are not available in the masked version of the 
protocol. 
This document is intended for use only by the unmasked Sponsor and restricted Worldwide 
Clinical Trials personnel and their designated agents for purposes of regulatory document 
preparation in conjunction with review by IRBs, IECs and regulatory authorities. Access to 
this document by other entities may be considered on a case-by-case basis by the Sponsor. 
The information contained herein is UNMASKED and CONFIDENTIAL. Therefore, it must 
NOT be shared with or communicated to any individual at an investigational site or from site 
facing members of the clinical operations team of the contract research organization except 
with explicit and fully documented authorization from the Sponsor. 
The key element revealed but that is masked in the masked protocol is that the key timepoint 
for analysis of the efficacy endpoints is Week 5. 
Investigators will receive the masked version of the clinical study protocol. 
9.7.2 
Randomization Procedures 
Eligible subjects will be randomized into one of two treatment groups (pimavanserin or 
placebo) in a 1:1 ratio using an interactive response technology (IRT) system. The 
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 


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designee to the treatment codes, and providing identical tablets and packaging for the 
pimavanserin and placebo treatments. 
9.8 
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. 
Unblinding of individual treatment assignment during the study is discouraged. The 
Investigator may break the blind in the event of a medical emergency if it is considered 
necessary for the care of the subject. The Investigator should attempt whenever possible to 
contact the Medical Monitor before unblinding a subject’s treatment to discuss the event. 
Lack of Medical Monitor contact does not preclude the Investigator from unblinding the 
subject. In an emergency situation, the subject’s treatment assignment may be obtained by the 
Investigator from the IRT system. Details of the process to be followed are provided in a 
separate IRT manual. In the event that the IRT system is used to perform a code break, the 
Sponsor or designee will be notified immediately via an automated notification from the 
IRT system that an unblinding has occurred. The notification only alerts the Sponsor or 
designee that the unblinding occurred, and does not include any information about the 
unblinded subject’s treatment assignment. 
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). Direct 
access includes permission to examine, analyze, verify, and reproduce any records and 
reports that are needed for the evaluation of the study. The Investigator must ensure the 
reliability and availability of source documents from which the information on the eCRF was 
derived. 
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 electronic data capture 
(EDC) database by trained site personnel. The source documentation may consist of source 


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notes captured by site personnel as well as laboratory reports, ECG reports, and electronic 
source data. 
10.3 Case Report Forms 
Subject data required by this protocol are to be recorded in an EDC system on eCRFs. 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 at 
the site. 
10.4 Confidentiality 
The Investigator must ensure that each subject’s anonymity is maintained as described below. 
On the eCRFs 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, medical records submitted 
with SAE reporting) 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), where applicable. The Sponsor 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, 
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. 


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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-randomization 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 6.4). 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. 
Protocol deviations will be reviewed periodically over the course of the study. The review 
process, definition of the deviation categories, and the classification of a deviation as major 
or minor are detailed in the Protocol Deviation Management Plan. Protocol deviations will 
also be assessed with respect to relationship to COVID-19, and COVID-19 related protocol 
deviations will be tabulated. 
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 
activities with a focus on critical processes and critical study data:  


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• 
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 reduced (e.g., mitigating) or can be 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 to be 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 are 
ongoing during trial execution and risk outcomes are reported 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. Some remote monitoring of study sites was also 
performed as a result of the travel and visiting restrictions caused by the COVID-19 
pandemic. 
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, a certain percentage 
of sites participating in this study will be audited. These audits may include a review of site 
facilities (e.g., pharmacy, drug storage areas, and laboratories) and review of study-related 
records may occur in order to evaluate the trial conduct and compliance with the protocol, 
ICH guidance on GCP, and applicable regulatory requirements. 


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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, and any subject information or advertising materials. 
The study will not be initiated until the IRB/EC provides written approval of the protocol and 
the informed consent and until approved documents have been obtained by the Investigator 
and copies received by the Sponsor. All amendments will be sent to the IRB/EC for 
information (minor amendment) or for submission (major amendment) before 
implementation. The Investigator will supply the IRB/EC and the Sponsor with appropriate 
reports on the progress of this study, including any necessary safety updates, in accordance 
with the applicable government regulations and in agreement with policy established by the 
Sponsor. 
12.3 Informed Consent Process 
Properly executed, written informed consent must be obtained from each subject prior to any 
screening procedures. 
The informed consent must, at a minimum, include the elements of consent described in the 
ICH guidance on GCP and the US CFR 21 part 50.25. A copy of the ICF planned for use will 
be reviewed by the Sponsor or designee for acceptability and must be submitted by the 
Investigator or designee together with the protocol, to the appropriate IRB/EC for review and 


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approval prior to the start of the study at that investigational site. Consent forms must be in a 
language fully comprehensible to the prospective subject. The Investigator must provide the 
Sponsor or designee with a copy of the IRB/EC letter approving the protocol and the ICF 
before the study drug supplies will be shipped and the study can be initiated. 
The consent form must be revised if new information becomes available during the study that 
may be relevant to the subject's willingness to continue participation. Any revision must be 
submitted to the appropriate IRB/EC for review and approval in advance of use. 
12.3.1 
Consent and Other Informational Documents Provided to Subjects 
The subject must be given a copy of the signed informed consent and the original maintained 
in the designated location at the site. 
12.3.2 
Consent Procedures and Documentation 
It is the Investigator or designee’s responsibility to obtain written informed consent from the 
subject after adequate explanation of the aims, methods, anticipated benefits, and potential 
hazards of the study. The subject must be given ample time to decide about study participation 
and opportunity to inquire about details of the study. The IRB/EC-approved consent form must 
be personally signed and dated by the subject and by the person who conducted the informed-
consent discussion. The Investigator or appropriate site personnel must document the details of 
obtaining informed consent in the subject’s study documents. 
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. 
13 PUBLICATION PLAN 
All publication rights are delineated in the Clinical Study Agreement and/or other separate 
agreements with the Investigator and/or Institution, as applicable. 
14 CONFLICT OF INTEREST POLICY 
14.1 Finance, Insurance, and Indemnity 
Arrangements for finance, insurance, and indemnity are delineated in the Clinical Study 
Agreement and/or other separate agreements with the Investigator and/or Institution, as 
applicable. 
 
 


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15 LITERATURE REFERENCES 
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Fava M. Diagnosis and definition of treatment-resistant depression. Biol Psychiatry. 
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Fava M, Davidson KG. Definition and epidemiology of treatment-resistant depression. 
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as adjunctive treatment for inadequate response to antidepressants: a randomized 
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Guy W. ECDEU Assessment Manual for Psychopharmacology—Revised (DHEW Publ No. 
ADM 76-338). Rockville, MD, US Department of Health, Education, and Welfare Public 
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Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56-62. 
Keller A, McGarvey EL, Clayton AH. Reliability and construct validity of the Changes in 
Sexual Functioning Questionnaire short-form (CSFQ-14). J Sex Marital Ther. 
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Mehta MA, Manes FF, Magnolfi G, Sahakian BJ, Robbins TW. Impaired set-shifting and 
dissociable effects on tests of spatial working memory following the dopamine D2 receptor 
antagonist sulpiride in human volunteers. Psychopharmacology. 2004;176(3-4):331-342. 
Montgomery SA, Asberg M. A new depression rating scale designed to be sensitive to 
change. Br J Psychiatry. 1979;134:382-389. 
Murray CJ, Lopez AD. Evidence-based health policy: lessons from the Global Burden of 
Disease Study. Science. 1996;274(5288):740-743. 
Patton JH, Stanford MS, Barratt ES. Factor structure of the Barratt impulsiveness scale. 
J Clin Psychol. 1995;51(6):768-774. 
Peretti CS, Danion JM, Kauffmann-Muller F, Grange D, Patat A, Rosenzweig P. Effects of 
haloperidol and amisulpride on motor and cognitive skill learning in healthy volunteers. 
Psychopharmacology. 1997;131(4):329-338. 
Posner K, Brown GK, Stanley B, et al. The Columbia–Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry. 2011;168(12):1266-1277. 
Roth BL, Lopez E, Patel S, Kroeze WK. The multiplicity of serotonin receptors: uselessly 
diverse molecules or an embarrassment of riches? Neuroscientist. 2000;6(4):252-262. 
Rush AJ, Kraemer HC, Sackeim HA, et al. Report by the ACNP Task Force on Response and 
Remission in Major Depressive Disorder. Neuropsychopharmacology. 2006;31:1841-1853. 


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Saeedi H, Remington G, Christensen BK. Impact of haloperidol, a dopamine D2 antagonist, 
on cognition and mood. Schizophr Res. 2006;85(1-3):222-231. 
Schotte A, Janssen PF, Gommeren W, et al. Risperidone compared with new and reference 
antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology. 
1996;124(1-2):57-73. 
Sheehan DV, Harnett-Sheehan K, Raj BA. The measurement of disability. Int Clin 
Psychopharmacol. 1996;11(suppl 3):89-95. 
Sheehan DV, Lecrubier Y, Sheehan KH, et al. The Mini-International Neuropsychiatric 
Interview (M.I.N.I.): the development and validation of a structured diagnostic interview for 
DSM-IV and ICD-10. J Clin Psychiatry. 1998;59(suppl 20):22-33. 
Targum SD, Houser C, Northcutt J, Little JA, Cutler AJ, Walling DP. A structured interview 
guide for global impressions: increasing reliability and scoring accuracy for CNS trials. Ann 
Gen Psychiatry. 2013;12(1):2. 
Vanover KE, Weiner DM, Makhay M, et al. Pharmacological and behavioral profile of N-(4-
fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl) 
carbamide (2R,3R)-dihydroxybutanedioate (2:1) (ACP-103), a novel 5-
hydroxytryptamine(2A) receptor inverse agonist. J Pharmacol Exp Ther. 
2006;317(2):910-918. 
Wang PS, Schneeweiss S, Avorn J, et al. Risk of death in elderly users of conventional vs. 
atypical antipsychotic medications. N Engl J Med. 2005;353(22):2335-2341. 
Wikström HV, Mensonides-Harsema MM, Cremers TI, Moltzen EK, Arnt J. Synthesis and 
pharmacological testing of 1,2,3,4,10,14b-hexahydro-6-methoxy-2-
methyldibenzo[c,f]pyrazino[1,2-a]azepin and its enantiomers in comparison with the two 
antidepressants mianserin and mirtazapine. J Med Chem. 2002;45(15):3280–3285. 
Williams JB. A structured interview guide for the Hamilton Depression Rating Scale. Arch 
Gen Psychiatry. 1988;45(8):742-747. 
Williams JB, Kobak KA. Development and reliability of a structured interview guide for the 
Montgomery-Asberg Depression Rating Scale (SIGMA). Br J Psychiatry. 
2008;192(1):52-58. 


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Appendix C Prohibited and Restricted Medications 
Subjects taking prohibited medications at study entry will not be eligible for the study.  
Subjects who require current treatment with a prohibited medication will be withdrawn from 
the study. 
Subjects who have previously taken a prohibited medication during the study will be 
withdrawn from the study unless:  
• the prohibited medication has been discontinued AND  
• withdrawal from the study presents an unacceptable medical risk to the subject 
The justification to allow the subject to continue in the trial will be made by the 
Sponsor/Medical Monitor with medical input from the Investigator, and will be documented. 
If allowed to remain in the trial, this will be reported as a major protocol deviation and not a 
waiver. 
The table below lists prohibitions and restrictions by medication class, including 
representative medications within class. A prohibited medication is not allowed. A restricted 
medication is allowed only under certain conditions. 
Medication Class 
Medicationa 
Prohibition/restrictions 
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 study 
Anticholinergics 
PROHIBITED 
• 
Centrally acting 
anticholinergics 
o 
benztropine 
o 
biperiden 
o 
trihexiphenidyl 
• 
Anticholinergic medications whose 
primary mechanism of action is 
centrally acting are prohibited and 
should be washed out and discontinued 
at least 2 weeks or 5 half-lives 
(whichever is longer) prior to Baseline 
UNRESTRICTED 
• 
Peripherally acting 
anticholinergics 
• 
Peripherally acting anticholinergic 
medications are allowed without 
restriction 
Anticonvulsant and 
mood stabilizers 
PROHIBITED 
• 
carbamazepine 
• 
lamotrigine 
• 
lithium 
• 
phenytoin 
• 
valproate 
• 
Must be washed out 5 half-lives prior to 
Baseline 
• 
Prohibited throughout the study 
Antidepressants 
other than 
PROHIBITED 
• 
mirtazapine 
• 
Prohibited throughout the study 


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Medication Class 
Medicationa 
Prohibition/restrictions 
background therapy 
(see Inclusion 
Criterion #6) 
• 
nefazadone 
• 
fluvoxamine 
• 
mianserin 
• 
trazodone 
• 
amitriptyline 
• 
nortriptyline 
• 
imipramine 
• 
trimipramine 
• 
desipramine 
• 
clomipramine 
• 
bupropion 
• 
levomilnacipran 
• 
vilazodone 
• 
vortioxetine 
• 
ketamine 
• 
esketamine 
• 
Must be discontinued at least 2 weeks 
or 5 half-lives (whichever is longer) 
prior to the Baseline visit 
RESTRICTED 
• 
citalopram 
• 
escitalopram 
• 
venlafaxine 
• 
If subject is remaining on these 
medications, the dose of the permitted 
antidepressants on the left must be 
unchanged for at least 4 weeks prior to 
the SAFER Remote Interview and 
should be expected to remain 
unchanged until the subject’s final visit. 
If the medication is being discontinued, 
it must be discontinued at least 2 weeks 
or 5 half-lives (whichever is longer) 
prior to the Baseline visit. 
o 
Citalopram is restricted to a 
maximum dose of 20 mg/day  
o 
Escitalopram is restricted to a 
maximum dose of 10 mg/day  
o 
Venlafaxine is restricted to a 
maximum dose of 225 mg/day 
Antihistamines 
RESTRICTED 
• 
diphenhydramine 
• 
brompheniramine 
• 
chlorpheniramine  
 
• 
Prohibited at Baseline 
• 
First generation antihistamines are not 
allowed during the study to treat 
insomnia 
• 
Limited short-term use of first 
generation antihistamines for a few days 
is allowed during the study for 
treatment of allergies and as 
antihistamine-decongestant for colds 
only 
• 
First generation antihistamines should 
not be used within 12 hours of an 
efficacy assessment 


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Medication Class 
Medicationa 
Prohibition/restrictions 
UNRESTRICTED 
• 
cetirizine 
• 
loratadine 
• 
fexofenadine  
• 
Second and third generation 
antihistamines are allowed without 
restriction 
Anxiolytics 
PROHIBITED 
• 
chlordiazepoxide 
• 
diazepam 
• 
flurazepam 
• 
alprazolam 
• 
clonazepam 
• 
lorazepam 
• 
oxazepam 
• 
temazepam 
• 
midazolam 
• 
triazolam 
• 
Prohibited at study entry and throughout 
the study 
Hypnotics and 
sleeping agents 
PROHIBITED 
• 
zolpidem 
• 
zopiclone 
• 
eszopiclone 
• 
zaleplon 
• 
ramelteon 
• 
Prohibited at study entry and throughout 
the study 
Stimulants and 
wake-promoting 
agents 
PROHIBITED 
• 
methylphenidate 
• 
modafinil 
• 
armodafinil 
• 
amphetamine 
• 
Prohibited at study entry and throughout 
the study (see Section 6.3.7 for 
procedures related to a positive 
amphetamine test at study entry) 
Non-stimulant 
ADHD medications 
PROHIBITED 
• 
atomoxetine 
• 
Prohibited at study entry and throughout 
the study 
Serotonin 
antagonists  
PROHIBITED 
• 
cyproheptadine 
• 
Prohibited throughout the study 
• 
Must be discontinued at least 3 weeks 
prior to the Baseline visit 
Antiarrhythmic 
drugs 
PROHIBITED 
• 
ajmaline 
• 
amakalant, semantilide 
• 
amiodarone 
• 
bretylium 
• 
disopyramide 
• 
dofetilide 
• 
dronedarone 
• 
flecainide 
• 
Prohibited at study entry and throughout 
the study 


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Medication Class 
Medicationa 
Prohibition/restrictions 
• 
ibutilide 
• 
procainamide 
• 
propafenone 
• 
quinidine 
• 
sotalol, d-sotalol 
Opioids 
PROHIBITED 
• 
methadone 
• 
hydrocodone 
• 
oxycodone 
• 
codeine 
• 
morphine 
• 
Prohibited at Baseline 
• 
Subjects who require chronic treatment 
with opioid medication or who have a 
substance use disorder are not eligible 
for this study 
• 
Limited short term use of opioids for a 
few days only is allowed during the 
study for treatment of acute pain 
following trauma or surgical procedure 
• 
Opioids should not be used within 
12 hours of an efficacy assessment 
Antimicrobials, 
antifungals, and 
antimalarials 
PROHIBITED 
• 
clarithromycin 
• 
erythromycin 
• 
levofloxacin 
• 
moxifloxacin 
• 
pentamidine 
• 
roxithromycin 
• 
Prohibited at study entry and throughout 
the study 
RESTRICTED 
• 
artenimol/piperaquine 
• 
azithromycin 
• 
bedaquiline 
• 
ciprofloxacin 
• 
gemifloxacin 
• 
norfloxacin 
• 
ofloxacin 
• 
fluconazole 
• 
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 
Principal Investigator. 
• 
The medications on the left 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 
a 
Medications within each class include but are not limited to the examples listed in this table. 


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Appendix D 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 (peak) observed drug concentration (Cmax) of approximately 1.5-fold 
and area under the plasma concentration-time curve (AUC) of approximately 3-fold.  
Strong inhibitors of CYP3A4 are to be stopped at least 7 days or 5 half-lives prior to 
investigational product administration, whichever is longer. Strong inducers of CYP3A4 are 
to be stopped 30 days or 5 half-lives prior to investigational product administration, 
whichever is longer. Moderate inhibitors and inducers of CYP3A4 are allowed but should be 
used with caution. 


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STRONG 
INHIBITORS 
grapefruit juice
a 
boceprevir (Victrelis®) 
clarithromycin (Biaxin®) 
cobicistat (part of Stribild®) 
conivaptan (Vaprisol®) 
fluvoxamine (Luvox®) 
indinavir (Crixivan®) 
itraconazole (Sporanox®) 
ketoconazole (Nizoral®) 
lopinavir and ritonavir (Kaletra®) 
mibefradil (Posicor®) 
nefazodone (Serzone®) 
nelfinavir (Viracept®) 
posaconazole (Noxafil®) 
quinupristin (Synercid®) 
ritonavir (Norvir®, part of Viekira 
Pak™) 
saquinavir (Invirase®) 
telaprevir (Incivek®) 
telithromycin (Ketek®) 
voriconazole (Vfend®) 
MODERATE 
INHIBITORS 
grapefruit juice
a 
amprenavir (Agenerase®) 
aprepitant (Emend®) 
atazanavir (Reyataz®) 
ciprofloxacin (Cipro®) 
darunavir/ritonavir 
(Prezista®/Ritonavir) 
diltiazem 
erythromycin (Erythrocin® 
Lactobionate) 
fluconazole (Diflucan®) 
fosamprenavir (Lexiva®) 
imatinib (Gleevec®) 
verapamil (Calan®) 
STRONG 
INDUCERS 
avasimibe 
carbamazepine (Tegretol®) 
phenobarbital (Luminal®, Solfoton®) 
phenytoin (Dilantin®)  
rifampin (Rifadin®, Rifadin® IV, 
Rimactane®) 
St. John’s Wort 
MODERATE 
INDUCERS 
bosentan (Tracleer®) 
efavirenz (Sustiva®) 
etravirine (Intelence®) 
modafinil (Provigil®) 
nafcillin (Unipen®, Nallpen®) 
a 
The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-
dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain 
preparation was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when another 
preparation was used (e.g., low dose, single strength). (FDA Drug Development and Drug Interactions 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabelin
g/ucm093664.htm#classInhibit). 
 

Prot_000.pdf: 
Official Title: A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled 
Study to Evaluate the Efficacy and Safety of Adjunctive Pimavanserin in Subjects 
With Major Depressive Disorder and Inadequate Response to Antidepressant 
Treatment 
NCT Number: NCT03968159 
Document Date: 21 Jun 2020 


 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 1 of 81 
 
 
CLINICAL STUDY PROTOCOL 
 
UNMASKED PROTOCOL  
 
A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled 
Study to Evaluate the Efficacy and Safety of Adjunctive Pimavanserin in 
Subjects With Major Depressive Disorder and Inadequate Response to 
Antidepressant Treatment 
 
Protocol Number: ACP-103-059 
Amendment 3 
 
Original Protocol Date: 05 December 2018 
Protocol Amendment 1 Date: 18 March 2019 
Protocol Amendment 2 Date: 29 October 2019 
Protocol Amendment 3 Date: 21 June 2020 
 
Confidentiality Statement 
This protocol is the confidential information of ACADIA Pharmaceuticals Inc. and is 
intended solely for the guidance of the clinical investigation. This protocol may not be 
disclosed to parties not associated with the clinical investigation or used for any purpose 
without the prior written consent of ACADIA Pharmaceuticals Inc. 


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SPONSOR SIGNATURE PAGE 
Title: A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Study to 
Evaluate the Efficacy and Safety of Adjunctive Pimavanserin in Subjects With Major 
Depressive Disorder and Inadequate Response to Antidepressant Treatment      
 
ACADIA President: 
 
President 
ACADIA Pharmaceuticals Inc. 
 
  
 
 
See appended electronic signature page 
 
Signature 
 Date 
 
ACADIA Study Lead: 
 
Executive Director, Clinical Research 
ACADIA Pharmaceuticals Inc. 
 
  
 
 
See appended electronic signature page 
 
Signature 
 Date 


Signature Page for ACP-103-059 Protocol Amendment 3_UNMASKED VERSION
Signature Page for ACP-103-059 Protocol Amendment 3_UNMASKED VERSION
Approve
22-Jun-2020 16:48:30 GMT+0000
Approve
22-Jun-2020 22:39:11 GMT+0000


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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, and 312, and according to applicable local requirements. 
Confidentiality Statement 
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will not disclose the information contained herein to others without written authorization 
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Study: ACP-103-059 
 
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PROTOCOL SYNOPSIS 
Protocol Number 
ACP-103-059 
EudraCT Number 
Not applicable 
Protocol Title 
A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled 
Study to Evaluate the Efficacy and Safety of Adjunctive Pimavanserin 
in Subjects With Major Depressive Disorder and Inadequate Response 
to Antidepressant Treatment 
Name of 
Investigational 
Product 
Pimavanserin tablets 
Indication 
Adjunctive treatment of major depressive disorder  
Phase of 
Development 
3 
Sponsor 
ACADIA Pharmaceuticals Inc. 
 
 
Primary Objective 
To evaluate the efficacy of adjunctive 
pimavanserin compared to placebo in subjects 
with major depressive disorder who have an 
inadequate response to antidepressant therapy 
Primary Endpoint 
Change from Baseline to Week 5 in the 
Hamilton Depression Scale (17 items) 
(HAMD-17) total score 
Secondary Objective 
To evaluate the efficacy and benefits of 
adjunctive pimavanserin compared to placebo 
in subjects with major depressive disorder 
who have an inadequate response to 
antidepressant therapy on the following:  
• Functional impairment 
• Clinician’s global impression of 
severity and improvement of depressive 
symptoms 
• Sexual functioning 
• Sleepiness 
• Treatment response and remission 
• Anxiety 
• Impulsiveness 
• Early response to treatment 
Secondary Endpoints 
• Change from Baseline to Week 5 in 
Sheehan Disability Scale (SDS) score 
• Change from Baseline to Week 5 in 
Clinical Global Impression–Severity 
(CGI-S) score for depressive symptoms 
• Clinical Global Impression–
Improvement (CGI-I) score for 
depressive symptoms at Week 5 
• Change from Baseline to Week 5 in the 
Changes in Sexual Functioning 
Questionnaire Short Form (CSFQ-14) 
• Change from Baseline to Week 5 in 
Karolinska Sleepiness Scale (KSS) 
score 
• Treatment responder rates at Week 5. 
Treatment response is defined as a 


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reduction from Baseline in HAMD-17 
total score of 50% or more. 
• Treatment remission rates at Week 5. 
Treatment remission is defined as a 
HAMD-17 total score ≤7. 
• Change from Baseline to Week 5 in the 
Hamilton Depression (HAMD) 
Anxiety/Somatization factor score 
• Change from Baseline to Week 5 in the 
Barratt Impulsiveness Scale (BIS-11) 
• Change from Baseline to Week 1 in the 
HAMD-17 total score 
Safety Objective 
To assess the safety and tolerability of 
pimavanserin compared to placebo in subjects 
with major depressive disorder who have an 
inadequate response to antidepressant therapy  
Safety Assessments 
Safety and tolerability of pimavanserin as 
described by: 
• Treatment-emergent adverse events 
(TEAEs) 
• Potentially clinically important 
laboratory abnormalities, vital signs, 
and electrocardiogram (ECG) results 
• Columbia–Suicide Severity Rating 
Scale (C-SSRS) score 
• Change from Baseline to Week 5 in 
Extrapyramidal Symptom Rating 
Scale–Abbreviated (ESRS-A) score 
• Sexual dysfunction defined as a 
CSFQ-14 total score of ≤47 for men 
and ≤41 for women 
Number of Study 
Sites 
Approximately 40 sites in the United States (US) will participate in 
this study. 
Number of Subjects 
Planned 
The original planned sample size was 280 subjects randomized in a 
1:1 ratio to either the pimavanserin or the placebo treatment groups 
(i.e., 140 subjects in each treatment group). The study was planned to 
be conducted in the US only. 
In March, 2020, in response to the emerging coronavirus disease 2019 
(COVID-19), ACADIA implemented a temporary pause to new 
enrollment into study ACP-103-059, to decrease potential exposure to 
COVID-19, minimize risks to trial integrity, and to assure the safety of 
already enrolled, ongoing study subjects. The last subject was 
randomized on 17 March 2020, for a total of 148 randomized subjects. 
ACADIA decided to combine its two ongoing, Phase III studies, 
ACP-103-059 (US-based study) and ACP-103-054 (non-US), when 
each were half enrolled, into one study with a pre-specified statistical 


Study: ACP-103-059 
 
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analysis plan. As a result, both studies closed and are proceeding with 
database lock and statistical analysis. No new patients were enrolled 
into these studies. The last subject in Study ACP-103-054 was 
randomized on 17 March 2020, at which time a total of 150 subjects 
had been randomized. 
The combined analysis therefore comprises 298 randomized subjects. 
Test Product, Dose, 
and Administration 
Pimavanserin 34 mg (provided as 2×17 mg tablets) or matching 
placebo (2×placebo tablets [size- and color-matched to pimavanserin]). 
It is recommended that the subject should take the study drug at 
approximately the same time each day. Tablets will be administered 
orally as a single dose once daily. 
Study Design 
This study will be conducted as a multicenter, randomized, 
double-blind, placebo-controlled, parallel-group study in subjects 
experiencing major depressive disorder with inadequate response to a 
selective serotonin reuptake inhibitor (SSRI) or 
serotonin-norepinephrine reuptake inhibitor (SNRI). 
This unmasked protocol version provides details of certain study 
design elements, procedures, and statistical methods that are intended 
for use only by the unmasked Sponsor and restricted Worldwide 
Clinical Trials personnel and their designated agents. 
The study will have three periods (Figure S–1): 
• Screening period (3-28 days) 
• Double-blind treatment period (6 weeks) 
• Safety follow-up period (at least 30 days) 
Screening Period (3-28 Days) 
During the screening period, subjects will be assessed for study 
eligibility and prohibited medications will be discontinued. 
Medications should be discontinued only if it is deemed clinically 
appropriate to do so and in consultation with the treating physician. 
Investigators should not withdraw a subject’s prohibited medication 
for the purpose of enrolling them 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 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 site 
and the Medical Monitor. At Visit 2, subjects will be randomized in a 
1:1 ratio to pimavanserin 34 mg once daily or matching placebo. 
Assessments will be conducted at Week 0 (Baseline), 1, 2, 3, 4, 5, and 
6/EOT or early termination (ET). 


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Safety Follow-up Period (30 Days) 
Eligible subjects who successfully complete the 6-week double-blind 
period will be qualified to enroll in an open-label extension study; 
subjects enrolling in the open-label extension study will not enter the 
30 day safety follow-up period. For subjects who discontinue 
prematurely from the study or who do not enroll in the open-label 
extension study, a safety follow-up telephone call visit will be 
conducted at least 30 days after the last dose of study drug. 
The schedule of assessments is provided in Table S–1. 
Study Duration 
The duration of participation for individual study subjects will be up to 
15 weeks, consisting of a screening period of up to 5 weeks 
(i.e., 4 weeks, with possible extension of up to 7 days), a 6-week 
double-blind treatment period, and a safety follow-up period of at least 
30 days (for those subjects who discontinue prematurely from the 
study or who do not enroll in the open-label extension study) 
(Figure S–1). The study completion date is defined as the date the final 
subject, across all sites, completes their final protocol-defined 
assessment, which includes the safety follow-up visit/contact, if 
applicable. 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: 
1. Is a male or female ≥18 years of age 
2. Can understand the nature of the study and protocol 
requirements and is willing to comply with study drug 
administration requirements and discontinue prohibited 
concomitant medications  
3. Provides written informed consent to participate in the study 
4. Is capable of communicating with the site personnel, able to 
complete subject-reported outcome measures and can be 
reliably rated on assessment scales (in the opinion of the 
Investigator) 
5. Has a clinical diagnosis of major depressive disorder with or 
without anxious distress by Diagnostic and Statistical Manual of 
Mental Disorders, Fifth Edition (DSM-5) criteria and confirmed 
by the Mini-International Neuropsychiatric Interview (MINI) 
during the screening period. Subject may have either recurrent or 
single episode of major depressive disorder. 
6. Is treated during the current major depressive episode with one 
of the following SSRI/SNRI antidepressants at a minimally 
effective dose for at least 8 weeks with at least the same stable 
dose over 4 weeks prior to the SAFER (State versus trait, 
Assessability, Face validity, Ecological validity, and Rule of 


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three Ps [pervasive, persistent, and pathological]) remote 
interview: 
a. Citalopram 
b. Escitalopram 
c. Paroxetine 
d. Fluoxetine 
e. Sertraline 
f. Duloxetine 
g. Venlafaxine 
h. Desvenlafaxine 
i. Venlafaxine XR 
The dose level of the antidepressant is expected to remain stable 
throughout the study.1 Adherence to the antidepressant should 
be reviewed throughout the study. 
7. Must have a detectable blood level of a prescribed SSRI/SNRI 
during Screening. A negative screening test may be repeated as 
assessed by the Medical Monitor when the subject and/or site 
can provide additional evidence of subject adherence to 
antidepressant treatment or evidence of sample or laboratory 
error. 
8. During the screening period, the subject’s inadequate response 
to SSRI/SNRI antidepressant treatment is confirmed by the 
Massachusetts General Hospital Antidepressant Treatment 
Response Questionnaire (MGH ATRQ) through the SAFER 
remote interview and the subject continues to exhibit an 
inadequate response to treatment at the time of the SAFER 
interview. 
9. Subjects who are currently taking a second antidepressant or 
antidepressant augmentation agent at a subtherapeutic dose or 
for inadequate duration at Screening are eligible for inclusion in 
the study if it is clinically appropriate to discontinue the drug 
before the Baseline visit (in the opinion of the Investigator); the 
second antidepressant/augmentation agent must be discontinued 
and washed out at least 5 half-lives prior to Baseline. This 
second antidepressant/augmentation agent should not be 
discontinued solely to make the subject eligible for enrollment 
in the study. 
10. Has a Montgomery-Asberg Depression Rating Scale (MADRS) 
total score >20 at both Screening and Baseline 
                                                 
 
 
1 Please see Appendix C for medication restrictions. 


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11. Has a Clinical Global Impression–Severity (CGI-S) score ≥4 
(moderately ill or worse) for depression at both Screening and 
Baseline 
12. If the subject is female, she must not be pregnant or 
breastfeeding. She must also be of non-childbearing potential 
(defined as either surgically sterilized or at least 1 year 
postmenopausal) OR must agree to use TWO clinically 
acceptable methods of contraception for at least 1 month prior 
to Visit 2 (Baseline), during the study, and 1 month following 
completion of the study. 
Acceptable methods of contraception include the following: 
a. A barrier method (condom, diaphragm, or cervical cap) 
with spermicide 
b. Hormonal contraception, including oral, injectable, 
transdermal, or implantable methods 
c. Intrauterine device (IUD) 
Only one of the two clinically acceptable methods can be a 
hormonal method. 
Exclusion Criteria: 
1. Has a history of schizophrenia or other psychotic disorder, 
major depressive disorder with psychotic features, bipolar I or II 
disorder. Subjects who are currently being treated or require 
treatment for post-traumatic stress disorder, acute stress 
disorder, panic disorder, or obsessive compulsive disorder are 
also not eligible. 
2. Has a current primary diagnosis of borderline, antisocial, 
paranoid, schizoid, schizotypal, or histrionic personality 
disorder, according to DSM-5 criteria 
3. Has met DSM-5 criteria for substance use disorders within the 
last 6 months prior to Screening, except for disorders related to 
the use of caffeine or nicotine 
4. Is suicidal at Visit 1 (Screening) or Visit 2 (Baseline) as defined 
below: 
a. An answer of “yes” to C-SSRS questions 4 or 5 (current 
or over the last 6 months); OR 
b. Has attempted suicide within 1 year prior to Visit 1 
(Screening); OR 
c. Is actively suicidal in the Investigator’s judgment 
5. Has current evidence of delirium or an unstable neurological, 
cardiovascular, respiratory, gastrointestinal, renal, hepatic, 
hematologic, or other medical disorder, including cancer or 
malignancies that, in the judgment of the Investigator or the 
Medical Monitor, would jeopardize the safe participation of the 


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subject in the study or significantly interfere with the conduct or 
interpretation of the study 
6. Has a history of epilepsy 
7. Has atrial fibrillation unless adequately anti-coagulated 
8. Has a history of myocardial infarction, unstable angina, acute 
coronary syndrome, or cerebrovascular accident   
9. Has a history of any of the following: 
a. Greater than New York Heart Association (NYHA) 
Class II congestive heart failure (Appendix A) 
b. Grade II or greater angina pectoris (by Canadian 
Cardiovascular Society Angina Grading Scale) 
(Appendix B) 
c. Sustained ventricular tachycardia 
d. Ventricular fibrillation 
e. Torsade de pointes 
f. Syncope due to an arrhythmia 
g. An implantable cardiac defibrillator 
10. Has laboratory evidence of hypothyroidism 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 enrolled. 
11. Has current unstable diabetes or glycosylated hemoglobin 
(HbA1c) >8% at Screening 
12. Has a known history of a positive hepatitis B virus (HBV), 
hepatitis C virus (HCV), or human immunodeficiency virus 
(HIV) test  
13. Has a history of neuroleptic malignant syndrome or serotonin 
syndrome 
14. Has a known personal or family history of long QT syndrome or 
family history of sudden cardiac death 
15. Has any of the following ECG results at Visit 1 (Screening) or 
Visit 2 (Baseline): 
a. If the subject is not on citalopram, escitalopram, or 
venlafaxine (immediate or extended release): 
i. QTcF >450 ms, if QRS duration <120 ms 
ii. QTcF >470 ms, if QRS duration ≥120 ms 
b. If the subject is on citalopram, escitalopram, or 
venlafaxine (immediate or extended release): 
i. QTcF >425 ms, if QRS duration <120 ms 
ii. QTcF >450 ms, if QRS duration ≥120 ms 
At Screening, if the set of triplicate ECGs has a prolonged QTcF 
due to an identifiable cause, and it is medically appropriate to 
address that cause, a repeat set of triplicate ECGs may be 


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performed during Screening at the discretion of the Medical 
Monitor. 
16. Has a heart rate <50 beats per minute, as measured by 
peripheral pulse rate, not explained by regular exercise or 
medication, in discussion with the Medical Monitor. If 
bradycardia is secondary to iatrogenic or treatable causes and 
these causes are treated, a heart rate assessment can be repeated 
during the screening period. 
17. Requires treatment with a medication or other substance that is 
prohibited by the protocol 
18. At Screening, has a body mass index (BMI) <18.5 kg/m2 or 
>35 kg/m2 or known unintentional clinically significant weight 
loss (i.e., ≥7%) over past 6 months 
19. Has a positive test for an illicit drug or cannabis at Screening or 
Baseline. Subjects who test positive for a controlled substance 
and who have a valid prescription may be retested during 
Screening if they agree to abstain from the medication for the 
length of their participation in the study. The repeat test during 
Screening must be negative for them to participate in the study. 
Additionally, DSM-5 criteria for substance use disorders should 
not be met. 
20. Has received electroconvulsive therapy, transcranial magnetic 
stimulation, or vagal nerve stimulation, or has received deep 
brain stimulation in the current episode of depression 
21. Has received new-onset psychotherapy or had a change in the 
intensity of psychotherapy within 8 weeks prior to Screening 
22. Has participated in or is participating in a noninterventional 
study or clinical trial of any investigational or marketed drug, 
device, or intervention, within 30 days or 5 half-lives, 
whichever is longer, of Visit 2 (Baseline) 
23. Has previously been enrolled in any prior clinical study with 
pimavanserin or is currently taking pimavanserin 
24. Has a significant sensitivity or allergic reaction to pimavanserin 
or its excipients 
25. Is an employee or is a family member of an employee of 
ACADIA Pharmaceuticals Inc. 
26. Is judged by the Investigator or the Medical Monitor to be 
inappropriate for the study for any reason, including if the 
subject is judged to be a danger to self or others 
Sample Size 
Calculations 
A total sample size of 266 evaluable subjects was estimated to provide 
at least 90% power at a two-sided significance level of 0.05 when 
assuming a treatment effect size of 0.4 for pimavanserin compared to 


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placebo on the change from Baseline to Week 5 in the HAMD-17 total 
score. 
Adjusting for a potential non-evaluable rate of up to 5%, 
approximately 280 subjects will be randomized. 
Statistical Methods 
Analysis Sets 
The Full Analysis Set includes all subjects who were randomized, 
received at least one dose of study drug, and have both a Baseline 
(Week 0) value and at least one post-Baseline value for the HAMD-17 
total score in the two studies. The Full Analysis Set will be used for the 
analysis of all efficacy endpoints. 
The Per-protocol Analysis Set includes a subset of subjects in the Full 
Analysis Set without any protocol deviations that could have a 
significant effect on the study conclusions. The Per-protocol Analysis 
Set will be determined prior to unblinding the studies for the final 
analysis and will be used for supportive analysis of selected efficacy 
endpoints. 
The Safety Analysis Set includes all subjects who received at least one 
dose of study drug in the two studies.  
Any other analysis sets, if necessary, will be defined in the statistical 
analysis plan (SAP). 
Efficacy Analyses 
Efficacy analyses will be conducted on the combined database from 
the ACP-103-054 and ACP-103-059 studies for the Full Analysis Set. 
The primary efficacy endpoint, change from Baseline to Week 5 in the 
HAMD-17 total score, will be analyzed using a mixed-effect model 
repeated measures (MMRM). The model will include effects for 
treatment group, visit, treatment-by-visit interaction, baseline 
HAMD-17 total score, the baseline HAMD-17 total score-by-visit 
interaction, and study. An unstructured covariance matrix will be used 
and the Kenward-Roger approximation will be used to adjust the 
denominator degrees of freedom. 
Additional sensitivity analyses will be performed to assess the impact 
of COVID-19. 
Each of the secondary endpoints, other than response and remission, 
will be analyzed using the MMRM method similar to that used for the 
analysis of the primary efficacy endpoint. For CGI-I, the baseline 
CGI-S score will be used as the covariate in the MMRM model. The 
response and remission rates will be compared between the 
pimavanserin and placebo groups using the Cochran-Mantel-Haenszel 
(CMH) test stratified by study. 


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A hierarchical approach will be used to control for multiple endpoints 
(primary and secondary).  
Safety Analyses 
Safety analyses will be conducted on the combined database from the 
ACP-103-054 and ACP-103-059 studies for the Safety Analysis Set. 
Safety results will be summarized by treatment group using descriptive 
statistics. Adverse events (AEs) will be classified into standard 
terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA). All AEs will be listed and TEAEs will be summarized by 
system organ class and preferred term. A TEAE is defined as an AE 
that started after the first administration of study drug and no later than 
the last administration of study drug plus 30 days. Summaries by 
maximum severity and by relationship to study drug will also be 
provided. Serious TEAEs, fatal AEs, and TEAEs leading to 
discontinuation will also be summarized. The relationship of selected 
AEs to COVID-19 will also be assessed and COVID-19 related 
TEAEs will be tabulated. 
Clinical laboratory values for hematology, chemistry and urinalysis 
(specific gravity and pH) will be summarized by treatment group using 
descriptive statistics at Baseline and the end of treatment visit. The 
change from baseline values will also be summarized by treatment 
group. The overall minimum and maximum post-baseline observed 
and change from baseline values will also be summarized. 
The number and percentage of subjects with potentially clinically 
important (PCI) laboratory values at the end of treatment and overall 
post-baseline will be summarized by treatment group for selected 
parameters. The PCI criteria will be specified in the SAP. 
Vital signs including weight, height, and the derived BMI 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. 
Observed values of ECG parameters and the changes from Baseline 
will be summarized by treatment group and visit. Categorical analyses 
will be conducted on the incidence of subjects with prolonged QTc 
intervals and changes in QTc intervals in accordance with ICH 
guidelines. 
For the C-SSRS, the number and percentage of subjects with suicidal 
ideation or suicidal behavior during the study will be tabulated. 
Observed values and change from Baseline in the ESRS-A score will 
be summarized by treatment group and visit. The change from 
Baseline in the ESRS-A score will be analyzed using the MMRM 
method, similar to the MMRM method used to analyze the primary 
endpoint. 


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Number and percentage of subjects with sexual dysfunction (a total 
score of ≤47 for men and ≤41 for women) will be summarized and 
shift tables will be presented. 
Date 
21 June 2020 
 


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Figure S–1 
Schematic of Study Design for ACP-103-059 
 
Abbreviations: QD=once daily; R=randomization 
Note: Subjects who enroll in an open-label extension will not enter the Safety Follow-up Period. 
 
 


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Table S–1 
Schedule of Events and Assessments for ACP-103-059 
Period Screening 
Baseline 
Double-blind Treatment Period 
 
Safety 
Follow-upa 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
(EOT/ET) 
8 
Unscheduled 
Visitk 
9 
Visit Day/Week 
Day -28 
to -3 
Week 
0 
Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
5 
Week 
6 
Week 
10 
Type of Visitb 
Clinic 
Clinic 
Clinic 
Clinic  
Clinic  
Clinic  
Clinic  
Clinic 
Clinic  
Phone call 
Visit window (# days) 
+7 
 
±3 
±3 
±3 
±3 
±3 
±3 
 
+7 
Informed consent and if 
applicable, privacy forms 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Medical history, medication 
history, and demographics 
X 
 
 
 
 
 
 
 
 
 
Psychiatric history 
X 
 
 
 
 
 
 
 
 
 
MGH ATRQc 
X 
 
 
 
 
 
 
 
 
 
SAFER remote interviewd 
X 
 
 
 
 
 
 
 
 
 
MINI 
X 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
 
 
 
 
X 
 
 
Vital signs and weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
12-lead ECGe 
X 
X 
X 
 
 
 
 
X 
 
 
Clinical laboratory testsf 
X 
X 
 
 
 
 
 
X 
 
 
Pregnancy testg 
X 
X 
 
 
 
 
 
X 
 
 
Background antidepressant blood 
levelh 
X 
 
 
 
 
 
 
 
 
 
Urine toxicity (drug) screen 
X 
X 
 
 
 
 
 
X 
 
 
MADRS 
X 
X 
 
 
 
 
 
 
 
 
Table continues on next page 


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Table S–1 
Schedule of Events and Assessments for ACP-103-059 (Continued) 
Period Screening 
Baseline 
Double-blind Treatment Period 
 
Safety 
Follow-upa 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
(EOT/ET) 
8 
Unscheduled 
Visitk 
9 
Visit Day/Week 
Day -28 
to -3 
Week 
0 
Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
5 
Week 
6 
Week 
10 
Type of Visitb 
Clinic 
Clinic 
Clinic 
Clinic  
Clinic  
Clinic  
Clinic  
Clinic 
Clinic  
Phone call 
Visit window (# days) 
+7 
 
±3 
±3 
±3 
±3 
±3 
±3 
 
+7 
HAMD-17i 
 
X 
X 
X 
X 
X 
X 
X 
 
 
SDS 
 
X 
X 
X 
X 
X 
X 
X 
 
 
CGI-S 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
CGI-I 
 
 
X 
X 
X 
X 
X 
X 
 
 
CSFQ-14 
 
X 
X 
X 
X 
X 
X 
X 
 
 
KSS 
 
X 
X 
X 
X 
X 
X 
X 
 
 
BIS-11 
 
X 
X 
 
X 
 
X 
X 
 
 
ESRS-A 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRSj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense study drug 
 
X 
X 
X 
X 
X 
X 
 
Xl 
 
Study drug accountability 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Review of background 
antidepressant adherence  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: BIS-11=Barratt Impulsiveness Scale; CGI-I=Clinical Global Impression–Improvement; CGI-S=Clinical Global Impression–Severity; 
CSFQ-14=Changes in Sexual Functioning Questionnaire Short Form; C-SSRS=Columbia–Suicide Severity Rating Scale; ECG=electrocardiogram; 
eCRF=electronic case report form; EOT=end of treatment; ESRS-A=Extrapyramidal Symptom Rating Scale–Abbreviated; ET=early termination; 
HAMD-17=Hamilton Depression Scale (17 items); KSS=Karolinska Sleepiness Scale; MADRS=Montgomery-Asberg Depression Rating Scale; MGH 
ATRQ=Massachusetts General Hospital Antidepressant Treatment Response Questionnaire; MINI=Mini-International Neuropsychiatric Interview; 
SAFER=State versus trait, Assessability, Face validity, Ecological validity, and Rule of three Ps (pervasive, persistent, and pathological); SDS=Sheehan 
Disability Scale; SNRI=serotonin-norepinephrine reuptake inhibitor; SSRI=selective serotonin reuptake inhibitor. 
Table footnotes on next page 


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a 
This visit is a safety follow-up telephone call visit for subjects who discontinue prematurely from the study or who do not participate in the open-label 
extension study. This visit will occur at least 30 days after the last dose of study drug. 
b 
If visit was performed remotely due to the COVID-19 pandemic, please refer to Sections 3.3.2 (remote clinical assessments), 6.2.7 (efficacy assessments), 
6.3.8 (safety assessments) and 6.5.1 (unscheduled visits) for further information. 
c 
Inadequate response is defined as a response of <50% to a course of treatment of at least 8 weeks at the minimum effective dose (as listed on the ATRQ), 
which has been stable for the 4 weeks prior to the SAFER interview. 
d 
The SAFER remote interview may be conducted via telephone off-site or on-site. If conducted on-site, the site staff should not be present during the 
interview. 
e 
At Visit 1, ECG should be completed in triplicate and collected within a 3-minute period. At all other visits, a single 12-lead ECG should be completed. 
ECGs should be completed with the subject in a supine position after 5 minutes of rest. The ECG should occur before blood sampling or at least 30 minutes 
after blood sampling.  
f 
To include hematology, serum chemistry, prolactin levels, and urinalysis. 
g 
A pregnancy test is only required for women of childbearing potential. Serum pregnancy should only be performed at Visit 1; a urine pregnancy test should 
be performed at Baseline and Week 6 (EOT). If urine cannot be obtained in women of childbearing potential, a serum pregnancy test should be done in its 
place. 
h 
At Screening, blood samples will be collected for the analysis of concomitant SSRI/SNRI concentrations. The presence of SSRI or SNRI must be confirmed 
in order to qualify the subject for further consideration in the study. 
i 
The HAMD-17 is to be the first scale completed at each visit. 
j 
Suicidal assessment is required. The Baseline/Screening version of the C-SSRS will be administered at Screening. The Since Last Visit version of the 
C-SSRS will be administered at all subsequent visits. 
k 
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. 
l 
Study drug may be dispensed to the subject at unscheduled visits if needed. 
 


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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ............................................................................................... 2 
DECLARATION OF INVESTIGATOR ................................................................................... 4 
PROTOCOL SYNOPSIS ........................................................................................................... 5 
TABLE OF CONTENTS ......................................................................................................... 20 
LIST OF TABLES ................................................................................................................... 25 
LIST OF FIGURES ................................................................................................................. 25 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................. 26 
1 
INTRODUCTION ...................................................................................................... 28 
1.1 
Background Information ............................................................................................ 28 
1.2 
Investigational Product ............................................................................................... 30 
1.3 
Previous Clinical Experience ..................................................................................... 30 
1.4 
Study Rationale .......................................................................................................... 32 
1.5 
Benefit/Risk Assessment ............................................................................................ 33 
2 
STUDY OBJECTIVES AND ENDPOINTS .............................................................. 33 
2.1 
Primary Objective....................................................................................................... 33 
2.1.1 
Primary Endpoint ....................................................................................................... 33 
2.2 
Secondary Objective................................................................................................... 34 
2.2.1 
Secondary Endpoints .................................................................................................. 34 
2.3 
Safety Objective ......................................................................................................... 34 
2.3.1 
Safety Assessments..................................................................................................... 35 
3 
STUDY DESCRIPTION ............................................................................................ 35 
3.1 
Overview of Study Design ......................................................................................... 35 
3.1.1 
Screening Period (3-28 Days) .................................................................................... 35 
3.1.2 
Double-Blind Treatment Period (6 Weeks) ................................................................ 36 
3.1.3 
Safety Follow-up Period (30 Days) ............................................................................ 36 
3.2 
Matching Study ACP-103-054 ................................................................................... 36 
3.3 
Impact of COVID-19 Pandemic on Studies -059 and -054........................................ 36 
3.3.1 
Combination of Databases of Studies -059 and -054 ................................................. 36 
3.3.2 
Remote Clinical Assessments ..................................................................................... 37 
3.3.3 
Roll Over Into Open-Label Study ACP-103-055 ....................................................... 37 
4 
SUBJECT ELIGIBILITY AND WITHDRAWAL CRITERIA .................................. 37 


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4.1 
Inclusion Criteria ........................................................................................................ 37 
4.2 
Exclusion Criteria ....................................................................................................... 39 
4.3 
Subject Withdrawal of Consent .................................................................................. 41 
4.4 
Subject or Study Discontinuation ............................................................................... 42 
4.4.1 
Handling of Subject Discontinuation During the Treatment Period .......................... 42 
4.5 
Subject Lost to Follow-up .......................................................................................... 43 
4.6 
Prior and Concomitant Therapy ................................................................................. 43 
4.6.1 
Prior Medication ......................................................................................................... 43 
4.6.2 
Concomitant Medication ............................................................................................ 43 
4.6.2.1 Permitted, Restricted, and Prohibited Medications .................................................... 43 
5 
INVESTIGATIONAL PRODUCT ............................................................................. 44 
5.1 
Investigational Product Description ........................................................................... 44 
5.1.1 
Formulation, Appearance, Packaging, and Labeling .................................................. 44 
5.1.2 
Product Storage and Stability ..................................................................................... 45 
5.1.3 
Dosing and Administration ......................................................................................... 45 
5.1.4 
Method of Assigning Subjects to Treatment Groups.................................................. 45 
5.1.5 
Blinding ...................................................................................................................... 45 
5.1.6 
Study Drug Compliance ............................................................................................. 45 
5.1.7 
Overdose ..................................................................................................................... 45 
5.2 
Investigational Product Accountability Procedures ................................................... 46 
6 
STUDY PROCEDURES ............................................................................................ 46 
6.1 
Screening Assessments ............................................................................................... 46 
6.1.1 
Medical History, Medication History, and Demographics ......................................... 46 
6.1.2 
Psychiatric History ..................................................................................................... 47 
6.1.3 
Background Antidepressant Blood Level ................................................................... 47 
6.1.4 
Massachusetts General Hospital Antidepressant Treatment Response 
Questionnaire.............................................................................................................. 47 
6.1.5 
State versus trait, Assessability, Face validity, Ecological validity, and Rule of 
three Ps (pervasive, persistent, and pathological) (SAFER) Remote Interview ........ 47 
6.1.6 
Mini-International Neuropsychiatric Interview.......................................................... 47 
6.1.7 
Montgomery-Asberg Depression Rating Scale .......................................................... 48 
6.2 
Efficacy Assessments ................................................................................................. 48 
6.2.1 
Hamilton Depression Scale (17 Items) ....................................................................... 48 
6.2.2 
Sheehan Disability Scale ............................................................................................ 48 
6.2.3 
Clinical Global Impression–Severity and Clinical Global Impression–
Improvement Scales ................................................................................................... 48 


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6.2.4 
Changes in Sexual Functioning Questionnaire Short Form ....................................... 49 
6.2.5 
Karolinska Sleepiness Scale ....................................................................................... 49 
6.2.6 
Barratt Impulsiveness Scale ....................................................................................... 49 
6.2.7 
Impact of COVID-19 Pandemic on Efficacy Assessments ........................................ 49 
6.3 
Safety Assessments..................................................................................................... 49 
6.3.1 
Physical Examinations ............................................................................................... 49 
6.3.2 
Vital Signs .................................................................................................................. 49 
6.3.3 
Height, Weight, and Body Mass Index ....................................................................... 50 
6.3.4 
Electrocardiograms ..................................................................................................... 50 
6.3.5 
Columbia–Suicide Severity Rating Scale................................................................... 50 
6.3.6 
Extrapyramidal Symptom Rating Scale–Abbreviated ............................................... 51 
6.3.7 
Laboratory Evaluations .............................................................................................. 51 
6.3.8 
Impact of COVID-19 Pandemic on Safety Assessments ........................................... 53 
6.3.8.1 Priority Medical Assessments in Remote Visits ......................................................... 54 
6.3.8.2 Physical Examinations, Vital Signs, Height, and Weight ........................................... 54 
6.3.8.3 Electrocardiograms ..................................................................................................... 54 
6.3.8.4 Columbia-Suicide Severity Rating Scale ................................................................... 54 
6.3.8.5 Extrapyramidal Symptom Rating Scale-Abbreviated ................................................ 54 
6.3.8.6 Laboratory Evaluations .............................................................................................. 54 
6.4 
Safety Follow-up ........................................................................................................ 54 
6.5 
Unscheduled Visits ..................................................................................................... 55 
6.5.1 
Impact of COVID-19 on Unscheduled Visits ............................................................. 55 
7 
ADVERSE EVENTS ................................................................................................. 55 
7.1 
Specification of Safety Parameters............................................................................. 55 
7.1.1 
Definition of Adverse Event ....................................................................................... 55 
7.1.2 
Definition of Serious Adverse Event .......................................................................... 56 
7.2 
Classification of an Adverse Event ............................................................................ 57 
7.2.1 
Severity of Event ........................................................................................................ 57 
7.2.2 
Relationship to Study Drug ........................................................................................ 57 
7.2.2.1 Duration ...................................................................................................................... 58 
7.2.2.2 Frequency ................................................................................................................... 58 
7.2.2.3 Action Taken with Study Drug ................................................................................... 58 
7.2.2.4 Therapy ....................................................................................................................... 58 
7.2.2.5 Outcome ..................................................................................................................... 58 
7.2.2.6 Seriousness ................................................................................................................. 59 
7.2.3 
Definition of Unexpectedness .................................................................................... 59 
7.3 
Time Period and Frequency for Event Assessment and Follow-up ........................... 59 


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7.4 
Reporting Procedures ................................................................................................. 59 
7.4.1 
Adverse Event Reporting ........................................................................................... 59 
7.4.2 
Serious Adverse Event Reporting............................................................................... 60 
7.4.3 
Reporting of Pregnancy .............................................................................................. 60 
7.4.4 
Reporting of Overdose ............................................................................................... 61 
8 
CLINICAL MONITORING ....................................................................................... 61 
9 
STATISTICAL METHODS AND DATA ANALYSIS .............................................. 61 
9.1 
Statistical and Analytical Plans .................................................................................. 61 
9.2 
Statistical Hypotheses................................................................................................. 61 
9.3 
Sample Size Determination ........................................................................................ 62 
9.4 
Subject Populations for Analysis ................................................................................ 62 
9.5 
Statistical Analyses ..................................................................................................... 62 
9.5.1 
Primary Analyses ........................................................................................................ 62 
9.5.2 
Secondary Analyses .................................................................................................... 63 
9.5.3 
Safety Analyses .......................................................................................................... 63 
9.5.4 
Subgroup Analyses ..................................................................................................... 64 
9.6 
Interim Analyses ......................................................................................................... 64 
9.7 
Measures to Minimize Bias ........................................................................................ 64 
9.7.1 
Masking Procedures ................................................................................................... 64 
9.7.2 
Randomization Procedures ......................................................................................... 64 
9.8 
Breaking the Study Blind/Subject Code ..................................................................... 65 
10 
STUDY MANAGEMENT AND DATA COLLECTION .......................................... 65 
10.1 
Data Collection and Management Responsibilities.................................................... 65 
10.2 
Source Documents ...................................................................................................... 65 
10.3 
Case Report Forms ..................................................................................................... 66 
10.4 
Confidentiality ............................................................................................................ 66 
10.5 
Study Records Retention ............................................................................................ 66 
10.6 
Protocol Exceptions and Deviations........................................................................... 67 
10.7 
Protocol Amendments ................................................................................................ 67 
11 
QUALITY MANAGEMENT .................................................................................... 67 
11.1 
Risk Management ....................................................................................................... 67 
11.2 
Quality Control and Quality Assurance...................................................................... 68 
12 
ETHICAL CONSIDERATIONS ................................................................................ 69 


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12.1 
Ethical Standard ......................................................................................................... 69 
12.2 
Institutional Review Board/Ethics Committee ........................................................... 69 
12.3 
Informed Consent Process .......................................................................................... 69 
12.3.1 Consent and Other Informational Documents Provided to Subjects .......................... 70 
12.3.2 Consent Procedures and Documentation .................................................................... 70 
13 
PUBLICATION PLAN .............................................................................................. 70 
14 
CONFLICT OF INTEREST POLICY ....................................................................... 70 
14.1 
Finance, Insurance, and Indemnity............................................................................. 70 
15 
LITERATURE REFERENCES .................................................................................. 71 
16 
APPENDICES ............................................................................................................ 74 
Appendix A New York Heart Association Classification of Heart Failure ........................... 74 
Appendix B Canadian Cardiovascular Society Angina Grading Scale ................................. 75 
Appendix C Prohibited and Restricted Medications ............................................................. 76 
Appendix D Prohibited and Restricted Concomitant Medications: Inhibitors and 
Inducers of Cytochrome P450 Enzyme 3A4 .................................................... 80 
 


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LIST OF TABLES 
Table S–1 
Schedule of Events and Assessments for ACP-103-059 .................................. 17 
Table 1-1 
Receptor Profiles of Pimavanserin and Compounds With Antidepressant 
Activity ............................................................................................................ 32 
Table 6–1 
Safety Laboratory Evaluations......................................................................... 53 
 
LIST OF FIGURES 
Figure S–1 
Schematic of Study Design for ACP-103-059 ................................................. 16 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Term 
Definition 
5-HT 
5-hydroxytryptamine (serotonin) 
5-HT2A 
5-hydroxytryptamine (serotonin) 2A 
ADP 
Alzheimer’s disease psychosis 
AE 
adverse event 
BIS-11 
Barratt Impulsiveness Scale 
CGI-I 
Clinical Global Impression–Improvement 
CGI-S 
Clinical Global Impression–Severity 
COVID-19 
coronavirus disease 2019 
CSFQ-14 
Changes in Sexual Functioning Questionnaire Short Form 
C-SSRS 
Columbia–Suicide Severity Rating Scale  
DAT 
dopamine transporter 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ESRS-A 
Extrapyramidal Symptom Rating Scale–Abbreviated  
ET 
early termination 
GCP 
Good Clinical Practices 
HAMD-17 
Hamilton Depression Scale (17 items) 
ICF 
informed consent form 
ICH 
International Council for Harmonisation  
IRB 
institutional review board 
IRT 
interactive response technology 
KSS 
Karolinska Sleepiness Scale 
MADRS 
Montgomery-Asberg Depression Rating Scale 
MDD 
major depressive disorder 
MGH ATRQ 
Massachusetts General Hospital Antidepressant Treatment 
Response Questionnaire 
MINI 
Mini-International Neuropsychiatric Interview 
MMRM 
mixed-effect model repeated measures 
NET 
norepinephrine transporter 
PDP 
Parkinson’s disease psychosis 
PR 
PR interval of ECG 
QRS 
QRS interval of ECG 


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Term 
Definition 
QT 
QT interval for heart rate of ECG 
QTcB 
corrected QT interval using Bazett’s correction method 
QTcF 
corrected QT interval using Fridericia’s correction method 
SAE 
serious adverse event 
SAFER 
State versus trait, Assessability, Face validity, Ecological validity, 
and Rule of three Ps (pervasive, persistent, and pathological)  
SAP 
statistical analysis plan 
SDS 
Sheehan Disability Scale 
SERT 
serotonin transporter 
SNRI 
serotonin-norepinephrine reuptake inhibitor 
SSRI 
selective serotonin reuptake inhibitor 
TEAE 
treatment-emergent adverse event 
TSH 
thyroid stimulating hormone 
US 
United States 


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1 INTRODUCTION 
This document is a research protocol and the described study will be conducted in 
compliance with the protocol and the International Council for Harmonisation (ICH) Good 
Clinical Practices (GCP) Guideline.  
1.1 
Background Information 
Depression is ranked as the leading cause of disability worldwide by the World Health 
Organization (Murray and Lopez 1996). In particular, major depressive disorder (MDD) is a 
psychiatric illness that is characterized by the occurrence of one or more major depressive 
episodes, along with an absence of any history of manic, mixed, or hypomanic episodes. It is 
a serious, often recurrent medical condition, which is associated with a 15.9% lifetime risk of 
suicide attempt (Chen and Dilsaver 1996). Results of the World Mental Health Survey 
Initiative found that the average lifetime incidence of DSM-4 major depressive episodes was 
14.6%, with a 12-month prevalence of 5.5% in higher income countries (Bromet et al. 2011). 
Despite the availability of numerous pharmacological and psychological treatment options, 
fewer than 50% of all patients with depression show full remission with optimized treatment, 
including courses on numerous medications with and without concurrent psychotherapy 
(Rush et al. 2006). 
Thus, while medications have demonstrated efficacy in the treatment patients with an 
inadequate response to standard antidepressant therapies, there is a clear need for efficacious 
medications with improved tolerability and safety. Current research continues to investigate 
novel molecular and cellular mechanisms of augmentation of antidepressant therapies. 
Pimavanserin was studied in a Phase 2, randomized, double-blind, placebo-controlled, 
two-stage sequential parallel comparison design (SPCD) (Fava et al. 2016) study in adult 
subjects with MDD and an inadequate response to antidepressant therapy with concurrent 
selective serotonin reuptake inhibitor (SSRI)/serotonin-norepinephrine reuptake inhibitor 
(SNRI) (Study ACP-103-042). In the study, 207 adult patients with a confirmed inadequate 
response to existing first-line SSRI or SNRI therapy for MDD received adjunctive treatment 
of either 34 mg pimavanserin or placebo in addition to pre-existing first-line therapy for 
5 weeks (Stage 1). Those patients who did not show a response to placebo in Stage 1 were 
re-randomized to receive either pimavanserin or placebo for a second 5-week treatment 
period (Stage 2). 
Pimavanserin met the overall primary endpoint of the prespecified weighted average results 
of Stage 1 and Stage 2 by significantly reducing the 17-item Hamilton Depression Rating 
Scale (HAMD-17) total score compared to placebo (p=0.039). In addition, in Stage 1 (n=207) 
patients on pimavanserin demonstrated a highly significant improvement over placebo in 


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HAMD-17 (p=0.0003; effect size [Cohen’s d] 0.626). Importantly, this group of patients saw 
a benefit over placebo in the first week of treatment (p=0.0365; effect size [Cohen’s d] 
0.346). Fewer subjects (n=58) than anticipated proceeded to Stage 2, and no treatment benefit 
versus placebo was observed in this small set of placebo non-responders. In summary, 
pimavanserin met the overall primary endpoint of the prespecified weighted average results 
of Stage 1 and Stage 2 and demonstrated a highly significant improvement over placebo in 
HAMD-17 in Stage 1. 
On the key secondary endpoint, pimavanserin demonstrated statistically significant 
reductions compared to placebo in the Sheehan Disability Scale (SDS) score (p=0.004).  
Positive results were also observed for seven of the eleven other secondary endpoints listed 
below with nominal p-values: Clinical Global Impression–Severity (p=0.0084), Clinical 
Global Impression–Improvement (p=0.0289), Short Form-12 Mental Component Summary 
(p<0.0001), Karolinska Sleepiness Scale (p=0.0205), Massachusetts General Hospital Sexual 
Functioning Index (p=0.0003), Barratt Impulsiveness Scale (p=0.0075), as well as response 
rates (p=0.0065), defined as a 50% or greater reduction on the HAMD-17 total score.  
In this Phase 2 study, pimavanserin was generally well-tolerated. The most frequently 
reported treatment-emergent adverse events (TEAEs) included headache in the placebo group 
and headache, dry mouth, and nausea in the pimavanserin group. In Stage 1, for placebo 
subjects, TEAEs leading to discontinuation included depression, swelling face, and 
hypotension; for pimavanserin subjects, a TEAE of vomiting was reported and led to 
discontinuation. In Stage 2, a TEAE of diabetes mellitus was reported in the placebo group 
and led to discontinuation. One subject in each of the pimavanserin and placebo groups 
reported serious adverse events (SAEs). The placebo subject experienced SAEs of prostate 
cancer and calculus bladder; the pimavanserin subject experienced an SAE of acute 
myocardial infarction. These SAEs were deemed not to be related to the study drug by the 
Investigators and both subjects completed the study. No deaths were reported in the study. 
Furthermore, no meaningful differences were observed between the pimavanserin and 
placebo groups in changes in the Barnes Akathisia Scale, the Simpson Angus Scale, and the 
Abnormal Involuntary Movement Scale. Weight changes and ECG changes between the 
pimavanserin and placebo groups were generally similar. In Stage 2, there was a mean QTcF 
interval change of 7.2 ms and -0.8 ms in the pimavanserin and placebo groups, respectively, 
which is consistent with what has been observed with pimavanserin in other clinical studies. 
On the basis of the robust preliminary clinical evidence for efficacy and favorable tolerability 
observed in Study ACP-103-042, the present study is being initiated. 


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1.2 
Investigational Product 
Pimavanserin is an atypical antipsychotic that is present in the investigational product as 
pimavanserin tartrate salt with the chemical name, urea, N-[(4-fluorophenyl)methyl]-N-(1-
methyl-4-piperidinyl)-N’-[[4-(2-methylpropoxy)phenyl]methyl]-,(2R,3R)-2,3-
dihydroxybutanedioate (2:1). In April 2016, pimavanserin was approved in the United States 
(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-hydroxytryptamine (5-HT [serotonin]) 2A (5-HT2A) 
receptor. At higher doses, pimavanserin may block 5-HT2C receptors (Vanover et al. 2006). 
Pimavanserin shows no appreciable activity at dopaminergic, adrenergic, histaminergic, or 
muscarinic receptors. Activity at these receptors has been implicated in a range of dose-
limiting side effects associated with existing antipsychotic drugs including cognitive dulling 
(Saeedi et al. 2006; Mehta et al. 2004; Peretti et al. 1997) and an increased risk of mortality 
in elderly patients with dementia (Wang et al. 2005). On the basis of its novel receptor 
binding profile, pimavanserin may have benefits with regard to overall tolerability relative to 
other antipsychotic agents. 
1.3 
Previous Clinical Experience 
Pimavanserin is an atypical antipsychotic that is approved for the treatment of hallucinations 
and delusions associated with PDP. Studies have also been conducted in Alzheimer’s disease 
psychosis (ADP), dementia-related psychosis and schizophrenia, and studies in Alzheimer’s 
disease agitation and aggression, dementia-related psychosis, and schizophrenia are ongoing. 
A more complete discussion of these studies is available in the current pimavanserin 
Investigator’s brochure. 
Pimavanserin is considered to be generally well tolerated and has an acceptable safety 
profile. In single and multiple dose studies in healthy subjects, the highest doses administered 
were 255 mg and 136 mg/day, respectively. In Phase 1 studies in subjects who received 
pimavanserin without concomitant medication, the most common TEAEs (>3%) were 
postural dizziness (7.7%), headache (6.9%), somnolence (4.6%), nausea (3.8%), and 
dizziness (3.1%) in the single-dose studies (N=130) and headache (15.1%), dizziness (8.6%), 
nausea (7.4%), somnolence (5.1%), and postural dizziness (3.7%) in the multiple-dose 
studies (N=350). Nausea and vomiting were considered dose-limiting. Pimavanserin doses 
≤34 mg generally had a low incidence of TEAEs, with only small differences versus placebo. 
In controlled studies of pimavanserin in subjects with PDP, the most frequent TEAEs 
experienced by subjects in the pimavanserin 34 mg group compared with the placebo group 


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were urinary tract infection (7.4% pimavanserin 34 mg vs. 6.9% placebo), nausea 
(6.9% pimavanserin 34 mg vs. 4.3% placebo), peripheral edema (6.9% pimavanserin 34 mg 
vs. 2.2% placebo), fall (6.4% pimavanserin 34 mg vs. 9.1% placebo), and confusional state 
(5.9% pimavanserin 34 mg vs. 2.6% placebo). In the long-term open-label studies in subjects 
with PDP (as of 28 April 2019), the most frequent TEAEs include fall (31.1%), urinary tract 
infection (19.1%), hallucination (14.5%), decreased weight (13.3%), confusional state 
(11.4%), and constipation (11.2%). It is difficult to interpret these incidence rates in the 
absence of a concurrent control group. The overall incidence of TEAEs appears within what 
would be expected in subjects with the underlying neurodegenerative disease, psychosis, and 
advanced age. 
As of 28 April 2019, 74 subjects have died during participation in the PDP studies, with the 
majority of deaths considered not related or unlikely related to study drug. Five of these deaths 
occurred in 6-week double-blind studies (1 subject received placebo, 1 subject received 8.5 mg 
pimavanserin, and 3 subjects received 34 mg pimavanserin), and 69 deaths occurred in the 
multi-year, long-term open-label extension studies. 
Medical reviews of all deaths occurring in the pimavanserin PDP program, including 
placebo-controlled (6-week) and open-label (long-term) studies, found no common etiology 
or unifying pathology to attribute these deaths to pimavanserin treatment. The causes of death 
(e.g., cardiovascular, respiratory, infection) were consistent with the advanced age, stage of 
illness, and comorbidities of this elderly, medically frail population. Additional information is 
provided in the current pimavanserin Investigator’s brochure. 
In a frail, elderly population of 181 nursing home patients with ADP (90 treated with 
pimavanserin; 91 with placebo), pimavanserin was well tolerated, with no new safety 
observations. There were 8 post-randomization deaths, 4 (4.4%) in each treatment group. 
More subjects had SAEs with pimavanserin (15 subjects, 16.7%) than with placebo 
(10 subjects, 11.0%), but there were fewer discontinuations due to AEs with pimavanserin 
(8 subjects, 8.9%) than with placebo (11 subjects, 12.1%). TEAEs reported in ≥10% of 
subjects in either group were (pimavanserin; placebo) fall (23.3%; 23.1%), urinary tract 
infection (22.2%; 27.5%), agitation (21.1%; 14.3%), lower respiratory tract infection (14.4%; 
13.2%), contusion (12.2%; 15.4%), aggression (10.0%; 4.4%), anemia (10.0%; 8.8%), blood 
lactate dehydrogenase decreased (4.4%; 11.0%), and hyperglycemia (4.4%; 12.1%). Mean 
weight change from Baseline to Day 85 was comparable for the two treatment groups. 
Weight loss ≥7% was more common with pimavanserin (pimavanserin, 14.6%; placebo, 
1.8%). Treatment with pimavanserin had no negative effects on cognition or motor function. 
Pimavanserin increases QT interval. The magnitude of effect in humans has been assessed in 
a thorough QT study with doses of pimavanserin ranging from 17 to 68 mg and in the Phase 3 


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PDP program with a clinical dose of 34 mg. An average prolongation of approximately 5-8 ms 
was observed. No clinically significant patterns have been observed in SAEs and there has 
been no evidence of pimavanserin-related laboratory abnormalities.  
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 drug 
metabolism, pharmacokinetics (PK), efficacy, and safety. 
1.4 
Study Rationale 
5-HT2A serotonin receptors represent important targets for depression. A variety of studies 
have shown antidepressant activity from compounds with potent antagonist or inverse agonist 
activity at 5-HT2A receptors, and to varying degrees 5-HT2C receptors, but low affinity to 
SERT, NET, and DAT, either alone or when coadministered with SSRIs (Table 1-1). These 
compounds include volinanserin, pruvanserin, ketanserin, ritanserin, mirtazapine, mianserin, 
and trazodone (Table 1-1). Pimavanserin, with its potent activity as a 5-HT2A 
antagonist/inverse agonist and lesser activity as a 5-HT2C antagonist/inverse agonist, has a 
similar receptor profile to many compounds with antidepressant activity. Therefore, although 
there are no preclinical data on pimavanserin in animal models of depression, it would also 
be expected to have antidepressant activity. 
Table 1-1 
Receptor Profiles of Pimavanserin and Compounds With 
Antidepressant Activity 
Target 
PIM 
RIT 
VOL 
PRUV 
PIP 
KET 
MIRT 
MIAN 
TRAZ 
SERT 
Low 
Low 
Low 
Low 
N/A 
Low 
Low 
Low 
350 
NET 
Low 
Low 
Low 
Low 
N/A 
Low 
Low 
70 
Low 
DAT 
Low 
Low 
Low 
Low 
N/A 
Low 
Low 
Low 
Low 
5-HT2A 
0.4 
0.1 
0.2 
0.7 
5 
2 
70 
3 
35 
5-HT2C 
16 
3 
125 
Low 
120 
125 
40 
3 
200 
Other 
noteworthy 
targets 
None 
None 
None 
None 
D4 (5) 
α2 (35) 
α1 (15-20) α2 (15-20) 
H1 (1) 
α2 (4-20) 
H1 (1) 
5-HT1A 
(100) 
Sources: Data on file, except for pipamperone (Schotte et al. 1996); trazodone and mianserin (PDSP Ki 
database, see Roth et al. 2000); and mirtazepine (Brayfield 2014 and Wikström et al. 2002) 
Abbreviations: α1=alpha1 adrenergic receptor; α2=alpha2 adrenergic receptor; DAT=dopamine transporter; 
H1=histamine 1 receptor; KET=ketanserin; MIAN=mianserin; MIRT=mirtazepine; N/A=not available; 
NET=norepinephrine transporter; PIM=pimavanserin; PIP=pipamperone; PRUV=pruvanserin; 
RIT=ritanserin; SERT=serotonin transporter; TRAZ=trazodone; VOL=volinanserin 
Note: Values represent the affinity (Ki) in nM of the indicated ligands and transporters/receptors. For 
“Other noteworthy targets,” Ki values are provided in parentheses. “Low” denotes a Ki >1000 nM. 
Clinical data with pimavanserin have been consistent with these preclinical data, 
demonstrating efficacy in PDP and ADP with an acceptable tolerability and safety profile. 
Furthermore, the robustness of the clinical evidence for efficacy and favorable tolerability 


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observed in Study ACP-103-042 supports further investigation of pimavanserin in the 
treatment of subjects with major depressive disorder who have had an inadequate response to 
antidepressant therapy. 
1.5 
Benefit/Risk Assessment 
This study will examine a range of symptoms to explore the efficacy and safety of adjunctive 
pimavanserin in the treatment of patients with MDD.  
Pimavanserin, with its potent activity as a 5-HT2A antagonist/inverse agonist and lesser 
activity as a 5-HT2C antagonist/inverse agonist, has a receptor profile similar to that of many 
compounds with antidepressant activity. In a randomized, double-blind, placebo-controlled 
Phase 2 study (ACP-103-042) exploring adjunctive pimavanserin, adult MDD patients with 
inadequate response to antidepressant therapy showed improvements in measures of 
depression, disability, clinical global impression, sleepiness, and sexual functioning, as 
summarized in Section 1.1.  
Clinical studies conducted in a range of patient populations (approximately 2720 exposed 
subjects, including patients with PDP, ADP, Alzheimer’s disease agitation and aggression, 
schizophrenia, and MDD, as well as healthy subjects) have shown that pimavanserin is 
generally well tolerated and has an acceptable safety profile. In the Phase 2 study 
(ACP-103-042) no new safety signals were observed in the MDD patient population that 
were not already described in the approved NUPLAZID® prescribing information 
(ACADIA Pharmaceuticals Inc. 2019).  
On the basis of nonclinical and clinical data, it is therefore believed that pimavanserin has 
potential for benefit in the adjunctive treatment of MDD, with an acceptable safety profile. 
A more complete assessment of the overall benefit/risk profile of pimavanserin is provided in 
the current Investigator’s Brochure. 
2 STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objective 
The primary objective of this study is to evaluate the efficacy of adjunctive pimavanserin 
compared to placebo in subjects with major depressive disorder who have an inadequate 
response to antidepressant therapy. 
2.1.1 
Primary Endpoint 
The primary endpoint of this study is the change from Baseline to Week 5 in the Hamilton 
Depression Scale (17 items) (HAMD-17) total score. 


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2.2 
Secondary Objective 
The secondary objective of this study is to evaluate the efficacy and benefits of adjunctive 
pimavanserin compared to placebo in subjects with major depressive disorder who have an 
inadequate response to antidepressant therapy on the following: 
• Functional impairment 
• Clinician’s global impression of severity and improvement of depressive symptoms 
• Sexual functioning 
• Sleepiness 
• Treatment response and remission 
• Anxiety 
• Impulsiveness 
• Early response to treatment 
2.2.1 
Secondary Endpoints 
The secondary endpoints of this study are the following: 
• Change from Baseline to Week 5 in Sheehan Disability Scale (SDS) score 
• Change from Baseline to Week 5 in Clinical Global Impression–Severity (CGI-S) 
score for depressive symptoms 
• Clinical Global Impression–Improvement (CGI-I) score for depressive symptoms at 
Week 5 
• Change from Baseline to Week 5 in the Changes in Sexual Functioning Questionnaire 
Short Form (CSFQ-14) 
• Change from Baseline to Week 5 in Karolinska Sleepiness Scale (KSS) score 
• Treatment responder rates at Week 5. Treatment response is defined as a reduction 
from Baseline in HAMD-17 total score of 50% or more. 
• Treatment remission rates at Week 5. Treatment remission is defined as a HAMD-17 
total score ≤7. 
• Change from Baseline to Week 5 in the Hamilton Depression (HAMD) 
Anxiety/Somatization factor score 
• Change from Baseline to Week 5 in the Barratt Impulsiveness Scale (BIS-11) 
• Change from Baseline to Week 1 in the HAMD-17 total score 
2.3 
Safety Objective 
The safety objective of this study is to assess the safety and tolerability of pimavanserin 
compared to placebo in subjects with major depressive disorder who have an inadequate 
response to antidepressant therapy.  


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2.3.1 
Safety Assessments 
The safety assessments in this study include the following: 
• Treatment-emergent adverse events (TEAEs) 
• Potentially clinically important laboratory abnormalities, vital signs, and 
electrocardiogram (ECG) results 
• Columbia–Suicide Severity Rating Scale (C-SSRS) score 
• Change from Baseline in Extrapyramidal Symptom Rating Scale–Abbreviated 
(ESRS-A) score 
• Sexual dysfunction defined as a CSFQ-14 total score of ≤47 for men and ≤41 for 
women 
3 STUDY DESCRIPTION 
3.1 
Overview of Study Design 
This study will be conducted as a multicenter, randomized, double-blind, placebo-controlled, 
parallel-group study in subjects with MDD and inadequate response to antidepressant 
treatment. Approximately 40 sites in the US will participate in this study. The duration of 
participation for individual study subjects will be up to 15 weeks.  
The study will have three periods (Figure S–1): 
• Screening period (3-28 days) 
• Double-blind treatment period (6 weeks) 
• Safety follow-up period (at least 30 days) 
The study completion date (or when a subject is considered to have completed the study) is 
defined as the date the final subject, across all sites, completes their final protocol-defined 
assessment. Please note that this includes the safety follow-up visit/contact, whichever is 
later. Procedures for when a subject is lost to follow-up are provided in Section 4.5. 
If the study is terminated for any reason, subjects remaining in the study will return to 
standard of care. 
3.1.1 
Screening Period (3-28 Days) 
During the screening period, subjects will be assessed for study eligibility and prohibited 
medications will be discontinued if medically appropriate. Subject eligibility will be assessed 
by the site and the Sponsor through an eligibility review process. The screening period may 
be extended up to 7 days to confirm subject eligibility when discussed with and approved by 
the Medical Monitor in advance. 


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Investigators should not withdraw a subject’s prohibited medication for the purpose of 
enrolling them into the study. Medications should only be discontinued if it is deemed 
clinically appropriate to do so and in consultation with the treating physician. 
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 site and the Medical Monitor. At Visit 2, 
subjects will be randomized in a 1:1 ratio to pimavanserin 34 mg once daily or matching 
placebo. It is recommended that the subject should take the study drug at approximately the 
same time each day. Assessments will be conducted at Weeks 0 (Baseline), 1, 2, 3, 4, 5, and 
6/EOT or early termination (ET). 
3.1.3 
Safety Follow-up Period (30 Days) 
Eligible subjects who successfully complete the 6-week double-blind period will be qualified 
to enroll in an open-label extension study. For subjects who discontinue prematurely from the 
study or who do not enroll in the open-label extension study, a safety follow-up telephone 
call visit will be conducted at least 30 days after the last dose of study drug. 
3.2 
Matching Study ACP-103-054 
Study ACP-103-059, conducted only in the US, is identical in design with Study ACP-103-
054, conducted in parallel outside of the US. 
3.3 
Impact of COVID-19 Pandemic on Studies -059 and -054 
In March, 2020, the emerging coronavirus disease 2019 (COVID-19) pandemic resulted in 
the implementation of measures designed to ensure subject safety in both studies. Screening 
and randomization of new subjects into studies ACP-103-054 and ACP-103-059 were 
temporarily paused. All randomized subjects that were ongoing in the studies at the time 
screening was paused were allowed to complete as per protocol and enroll in the OLE 
provided that the subject, investigator and medical monitor agreed that it was in the best 
interest of the subject to do so, and the investigator could assure the site’s ability to properly 
monitor the safety and well-being of the study subject, in accordance to study protocol. 
3.3.1 
Combination of Databases of Studies -059 and -054 
At the time screening was paused, approximately half of the planned subjects had been 
randomized in each study. ACADIA decided to combine the two studies, ACP-103-059 and 
ACP-103-054, into one study with a pre-specified statistical analysis plan. As a result, both 
studies closed and are proceeding with database lock and statistical analysis. No new patients 
were enrolled into these studies. The modifications to the statistical handling of the study are 
described briefly in Section 9 and in detail in the Statistical Analysis Plan. 


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3.3.2 
Remote Clinical Assessments 
In the interim between the pause in screening and the termination of the studies, several 
subjects remained in the study who could not attend clinic visits. These subjects were allowed 
to conduct remote visits via telephone or video, or site personnel could conduct the visit in a 
subject’s home. Remote visits were not recommended for the Week 1 and Week 6 visits as 
these visits required ECGs. Subjects were not allowed to roll over into the open-label 
extension study unless they came to the research site to conduct an in-person Week 6 visit.  
Sites were required to document details of all visits that were administered remotely.  
Further details about accommodations and modifications to assessments, relating to the 
COVID-19 pandemic, can be found in Sections 6.2.7 (efficacy assessments), 6.3.8 (safety 
assessments) and 6.5.1 (unscheduled visits) and Section 9 (additional sensitivity analyses). 
3.3.3 
Roll Over Into Open-Label Study ACP-103-055  
Subjects may have rolled over into the ACP-103-055 study (open-label extension) provided 
that the subject, Investigator and medical monitor agreed that it was in the best interest of the 
patient, and the study site could assure its ability to properly monitor the safety and well-
being of the patient in accordance with the study protocol.  
Additionally, all inclusion/exclusion criteria must have been verified prior to rollover and the 
subject must have presented to the clinic in person to sign the ACP-103-055 informed 
consent form (ICF) and have all ACP-103-059 end of treatment procedures. 
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 to be eligible for participation in 
the study: 
1. Is a male or female ≥18 years of age 
2. Can understand the nature of the study and protocol requirements and is willing to 
comply with study drug administration requirements and discontinue prohibited 
concomitant medications  
3. Provides written informed consent to participate in the study 
4. Is capable of communicating with the site personnel, able to complete subject-reported 
outcome measures and can be reliably rated on assessment scales (in the opinion of the 
Investigator) 


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5. Has a clinical diagnosis of major depressive disorder with or without anxious distress by 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria 
and confirmed by the Mini-International Neuropsychiatric Interview (MINI) during the 
screening period. Subject may have either recurrent or single episode of major 
depressive disorder. 
6. Is treated during the current major depressive episode with one of the following 
SSRI/SNRI antidepressants at a minimally effective dose for at least 8 weeks with at 
least the same stable dose over 4 weeks prior to the SAFER (State versus trait, 
Assessability, Face validity, Ecological validity, and Rule of three Ps [pervasive, 
persistent, and pathological]) remote interview: 
a. Citalopram 
b. Escitalopram 
c. Paroxetine 
d. Fluoxetine 
e. Sertraline 
f. Duloxetine 
g. Venlafaxine 
h. Desvenlafaxine 
i. Venlafaxine XR 
The dose level of the antidepressant is expected to remain stable throughout the study.2 
Adherence to the antidepressant should be reviewed throughout the study. 
7. Must have a detectable blood level of a prescribed SSRI/SNRI during Screening. A 
negative screening test may be repeated as assessed by the Medical Monitor when the 
subject and/or site can provide additional evidence of subject adherence to 
antidepressant treatment or evidence of sample or laboratory error. 
8. During the screening period, the subject’s inadequate response to SSRI/SNRI 
antidepressant treatment is confirmed by the Massachusetts General Hospital 
Antidepressant Treatment Response Questionnaire (MGH ATRQ) through the SAFER 
remote interview and the subject continues to exhibit an inadequate response to 
treatment at the time of the SAFER interview. 
9. Subjects who are currently taking a second antidepressant or antidepressant 
augmentation agent at a subtherapeutic dose or for inadequate duration at Screening 
are eligible for inclusion in the study if it is clinically appropriate to discontinue the 
                                                 
 
 
2 Please see Appendix C for medication restrictions. 


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drug before the Baseline visit (in the opinion of the Investigator); the second 
antidepressant/augmentation agent must be discontinued and washed out at least 
5 half-lives prior to Baseline. This second antidepressant/augmentation agent should 
not be discontinued solely to make the subject eligible for enrollment in the study. 
10. Has a Montgomery-Asberg Depression Rating Scale (MADRS) total score >20 at both 
Screening and Baseline 
11. Has a Clinical Global Impression–Severity (CGI-S) score ≥4 (moderately ill or worse) 
for depression at both Screening and Baseline 
12. If the subject is female, she must not be pregnant or breastfeeding. She must also be of 
non-childbearing potential (defined as either surgically sterilized or at least 1 year 
postmenopausal) OR must agree to use TWO clinically acceptable methods of 
contraception for at least 1 month prior to Visit 2 (Baseline), during the study, and 
1 month following completion of the study. 
Acceptable methods of contraception include the following: 
a. A barrier method (condom, diaphragm, or cervical cap) with spermicide 
b. Hormonal contraception, including oral, injectable, transdermal, or 
implantable methods 
c. Intrauterine device (IUD) 
Only one of the two clinically acceptable methods can be a hormonal method. 
4.2 
Exclusion Criteria 
A subject must meet none of the following exclusion criteria to be eligible for the study: 
1. Has a history of schizophrenia or other psychotic disorder, major depressive disorder 
with psychotic features, bipolar I or II disorder. Subjects who are currently being 
treated or require treatment for post-traumatic stress disorder, acute stress disorder, 
panic disorder, or obsessive compulsive disorder are also not eligible. 
2. Has a current primary diagnosis of borderline, antisocial, paranoid, schizoid, 
schizotypal, or histrionic personality disorder, according to DSM-5 criteria 
3. Has met DSM-5 criteria for substance use disorders within the last 6 months prior to 
Screening, except for disorders related to the use of caffeine or nicotine 
4. Is suicidal at Visit 1 (Screening) or Visit 2 (Baseline) as defined below: 
a. An answer of “yes” to C-SSRS questions 4 or 5 (current or over the last 
6 months); OR 
b. Has attempted suicide within 1 year prior to Visit 1 (Screening); OR 
c. Is actively suicidal in the Investigator’s judgment 
5. Has current evidence of delirium or an unstable neurological, cardiovascular, 
respiratory, gastrointestinal, renal, hepatic, hematologic, or other medical disorder, 


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including cancer or malignancies that, in the judgment of the Investigator or the 
Medical Monitor, would jeopardize the safe participation of the subject in the study or 
significantly interfere with the conduct or interpretation of the study 
6. Has a history of epilepsy 
7. Has atrial fibrillation unless adequately anti-coagulated 
8. Has a history of myocardial infarction, unstable angina, acute coronary syndrome, or 
cerebrovascular accident   
9. Has a history of any of the following: 
a. Greater than New York Heart Association (NYHA) Class II congestive heart 
failure (Appendix A) 
b. Grade II or greater angina pectoris (by Canadian Cardiovascular Society 
Angina Grading Scale) (Appendix B) 
c. Sustained ventricular tachycardia 
d. Ventricular fibrillation 
e. Torsade de pointes 
f. Syncope due to an arrhythmia 
g. An implantable cardiac defibrillator 
10. Has laboratory evidence of hypothyroidism 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 enrolled 
11. Has current unstable diabetes or glycosylated hemoglobin (HbA1c) >8% at Screening 
12. Has a known history of a positive hepatitis B virus (HBV), hepatitis C virus (HCV), or 
human immunodeficiency virus (HIV) test  
13. Has a history of neuroleptic malignant syndrome or serotonin syndrome 
14. Has a known personal or family history of long QT syndrome or family history of 
sudden cardiac death 
15. Has any of the following ECG results at Visit 1 (Screening) or Visit 2 (Baseline): 
a. If the subject is not on citalopram, escitalopram, or venlafaxine (immediate or 
extended release): 
i. QTcF >450 ms, if QRS duration <120 ms 
ii. QTcF >470 ms, if QRS duration ≥120 ms 
b. If the subject is on citalopram, escitalopram, or venlafaxine (immediate or 
extended release): 
i. QTcF >425 ms, if QRS duration <120 ms 
ii. QTcF >450 ms, if QRS duration ≥120 ms 


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At Screening, if the set of triplicate ECGs has a prolonged QTcF due to an identifiable 
cause, and it is medically appropriate to address that cause, a repeat set of triplicate 
ECGs may be performed during Screening at the discretion of the Medical Monitor. 
16. Has a heart rate <50 beats per minute, as measured by peripheral pulse rate, not 
explained by regular exercise or medication, in discussion with the Medical Monitor. 
If bradycardia is secondary to iatrogenic or treatable causes and these causes are 
treated, a heart rate assessment can be repeated during the screening period. 
17. Requires treatment with a medication or other substance that is prohibited by the 
protocol 
18. At Screening, has a body mass index (BMI) <18.5 kg/m2 or >35 kg/m2 or known 
unintentional clinically significant weight loss (i.e., ≥7%) over past 6 months 
19. Has a positive test for an illicit drug or cannabis at Screening or Baseline. Subjects 
who test positive for a controlled substance and who have a valid prescription may be 
retested during Screening if they agree to abstain from the medication for the length of 
their participation in the study. The repeat test during Screening must be negative for 
them to participate in the study. Additionally, DSM-5 criteria for substance use 
disorders should not be met. 
20. Has received electroconvulsive therapy, transcranial magnetic stimulation, or vagal 
nerve stimulation, or has received deep brain stimulation in the current episode of 
depression 
21. Has received new-onset psychotherapy or had a change in the intensity of 
psychotherapy within 8 weeks prior to Screening 
22. Has participated in or is participating in a noninterventional study or clinical trial of 
any investigational or marketed drug, device, or intervention, within 30 days or 
5 half-lives, whichever is longer, of Visit 2 (Baseline) 
23. Has previously been enrolled in any prior clinical study with pimavanserin or is 
currently taking pimavanserin 
24. Has a significant sensitivity or allergic reaction to pimavanserin or its excipients 
25. Is an employee or is a family member of an employee of ACADIA Pharmaceuticals 
Inc. 
26. Is judged by the Investigator or the Medical Monitor to be inappropriate for the study 
for any reason, including if the subject is judged to be a danger to self or others 
4.3 
Subject Withdrawal of Consent 
In accordance with the Declaration of Helsinki and other applicable regulations, a subject has 
the right to withdraw from the study at any time, and for any reason, without prejudice to his 
or her future medical care. 


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Should a subject request or decide to withdraw consent, every reasonable effort should be 
made to complete and report observations as thoroughly as possible up to the date of 
withdrawal, including the evaluations specified at the ET or safety follow-up visit (whichever 
visit is applicable), as outlined in Table S–1. 
4.4 
Subject or Study Discontinuation 
Subjects may be discontinued from the study for a number of reasons, including, but not 
limited to, those listed below: 
• Adverse event 
• Death 
• Lack of efficacy 
• Lost to follow-up (Section 4.5) 
• Non-compliance with study drug 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Study terminated by Sponsor 
• Use of prohibited medication 
• Other 
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. 
4.4.1 
Handling of Subject Discontinuation During the Treatment Period 
Unless the subject has withdrawn consent to be contacted for this 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 for 
any reason. All information will be reported on the applicable pages of the electronic case 
report form (eCRF). 


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If a subject is discontinued from the study because of an AE, every reasonable attempt should 
be made to follow the subject until the AE resolves or until the Investigator deems the AE to 
be chronic or stable. For subjects who continue to be followed for safety, SAEs should 
continue to be reported as described in Section 7.4.2. All SAEs will continue to be followed 
until such events have resolved or the Investigator deems them to be chronic or stable. 
4.5 
Subject Lost to Follow-up 
A subject will be considered lost to follow-up if they fail to attend a scheduled visit 
(including the safety follow-up visit) and is unable to be contacted by the study site. 
Every reasonable effort should be made to contact the subject and will include a minimum of 
three documented phone calls (each performed at different times of the day) and, if necessary, 
a certified letter to the subject’s last known mailing address or local equivalent methods. All 
contact attempts are to be documented in the source documents. 
4.6 
Prior and Concomitant Therapy 
All medications used from study screening until completion of the safety follow-up visit are 
to be recorded. 
4.6.1 
Prior Medication 
Prior medication is defined as any medication taken before the date of the first dose of study 
drug. 
4.6.2 
Concomitant Medication 
Concomitant medication is defined as any medication taken on or after the date of the first 
dose of study drug. 
In order to ensure that appropriate concomitant therapy is administered, it is essential that 
subjects be instructed not to take any medication without prior consultation with the 
Investigator (unless the subject is receiving treatment for a medical emergency). 
The Investigator may prescribe appropriate medication to treat AEs. Relationship to 
COVID-19 will be assessed for selected medications. The Sponsor and Investigator or 
designee will confer to determine whether it is appropriate to continue such a subject in the 
trial if a prohibited medication is prescribed.  
4.6.2.1 
Permitted, Restricted, and Prohibited Medications 
Prohibitions and restrictions for concomitant medications should be followed between the 
initial screening visit and Visit 8/ET as specified in Appendix C and Appendix D. 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. 


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Use of medications that could interfere with study conduct or any questions regarding 
prohibited and restricted concomitant medications should be reviewed and/or discussed with 
the Medical Monitor or designee. 
Medications that can prolong QT interval are prohibited (or restricted if approved by the 
Medical Monitor) as specified in Appendix C. 
Permitted concomitant medications should remain at a stable dose throughout the study.  
If a subject is on a medication restricted by the protocol, the medication should be adjusted if 
it is determined by the Investigator to be clinically appropriate (e.g., if the subject’s 
symptoms are not well-controlled or if the subject cannot tolerate the current medication) in 
consultation with the treating physician. 
Subjects who require current treatment with a prohibited medication will be withdrawn from 
the study. 
Subjects who have 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 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. 
5 INVESTIGATIONAL PRODUCT 
5.1 
Investigational Product Description 
The investigational product will be pimavanserin 34 mg (provided as 2×17 mg tablets) or 
matching placebo (2×placebo tablets). Placebo tablets will be size- and color-matched to the 
pimavanserin tablets. Tablets will be administered orally as a single dose once daily. 
5.1.1 
Formulation, Appearance, Packaging, and Labeling 
The Sponsor will supply pimavanserin 17 mg tablets and matching placebo tablets. 
Pimavanserin tartrate is a white to off-white powder. Pimavanserin 17 mg tablets include the 
active compound (pimavanserin tartrate) and the following excipients: pregelatinized starch, 
magnesium stearate, and microcrystalline cellulose, and the tablet coating is 
 
 
. The drug product is formulated with standard pharmaceutical excipients at 
17 mg strength (20 mg of pimavanserin tartrate). 


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Placebo tablets contain all of the same excipients as pimavanserin 17 mg tablets but do not 
contain any pimavanserin tartrate. 
Pimavanserin and placebo tablets are manufactured under current Good Manufacturing 
Practices. 
During the treatment period, study drug will be distributed in a quantity sufficient to ensure 
the subject has an adequate supply of study drug between study visits. 
5.1.2 
Product Storage and Stability 
Investigational product must be stored between 15°C and 30°C (59°F and 86°F) in a secure 
area with restricted access and according to local and national regulations. 
5.1.3 
Dosing and Administration 
The first dose of study drug will be administered at the site. Study drug kits will then be 
dispensed to the subject to take home. Each daily dose consists of two individual tablets that 
should be taken together. Subjects should be instructed to take two whole tablets, orally, once 
daily. Subjects should be instructed to not crush the tablets. The tablets may be taken with or 
without food. 
5.1.4 
Method of Assigning Subjects to Treatment Groups 
At Week 0 (Visit 2), eligible subjects who meet inclusion and do not meet exclusion criteria 
will be randomized in a 1:1 ratio to receive either 34 mg pimavanserin once daily or placebo. 
5.1.5 
Blinding 
Treatment assignments will be blinded to all study subjects, Investigators, raters, site 
personnel, and Sponsor personnel. In the event of a potential suspected unexpected serious 
adverse reaction (SUSAR), in accordance with current health authority guidance, treatment 
assignments for the affected subject may be unblinded to a controlled group of the Sponsor’s 
Safety and/or Regulatory personnel for reporting purposes.  
Details regarding medical emergency unblinding procedures are provided in Section 9.8. 
5.1.6 
Study Drug Compliance 
If a subject misses one dose of study drug, he or she should not take an extra dose the next 
day. Subjects who are less than 80% compliant with study drug as assessed at more than one 
study visit should be discussed with the Medical Monitor or designee. 
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, irrespective of outcome, 


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even if toxic effects were not observed (Section 7.4.4). All events of overdose are to be 
captured as protocol deviations. 
5.2 
Investigational Product Accountability Procedures 
The Investigator or designee will keep current and accurate records of the study drug product 
dispensed, used, and returned for each subject to assure the regulatory authority and the 
Sponsor that the study drug is being handled appropriately. Subjects should be instructed to 
return all packaging and unused study drug to the Investigator at regularly scheduled clinic 
visits and ET visits. Any study drug supplied is for use in this study only and should not be 
used for any other purpose. 
At appropriate intervals during the study, study drug reconciliation will be performed by the 
Sponsor (or designee) who may return appropriate unused study drug and used and unused 
packaging to the Sponsor’s designee for destruction. 
At the conclusion of the study, final study drug reconciliation will be conducted at the site. 
Final study drug accountability documentation will be maintained at both the site and at the 
Sponsor. Any remaining unused study drug and all used and unused packaging will be sent 
back to the Sponsor’s designee for destruction, as allowed by country specific regulations. 
Documentation of study drug destruction will be recorded and maintained by both the 
Sponsor and the Sponsor’s designee. 
6 STUDY PROCEDURES 
Study specific procedures 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. 
6.1 
Screening Assessments 
Subject eligibility will be assessed during the Screening period by the site and the Sponsor 
through an eligibility review process. The Screening period (between the Screening and 
Baseline visit) may be extended by up to 7 days when awaiting results to confirm subject 
eligibility when discussed with the Medical Monitor in advance. 
6.1.1 
Medical History, Medication History, and Demographics 
A complete medical history and medication history will be obtained from each potential 
subject. Demographic information, including date of birth, gender, race, and ethnicity 
(if allowed by local regulations) will be recorded as well. Any new medical condition 
beginning after the ICF has been signed will be captured as an AE. In addition, a history of 
the medications that the subject has taken for the current depressive episode should be 


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obtained. Subjects may be asked to provide pharmacy or medical records to substantiate the 
medication history. 
6.1.2 
Psychiatric History 
Details of the subject’s psychiatric history and treatment will be collected. 
6.1.3 
Background Antidepressant Blood Level 
At Screening, blood samples for the analysis of the concomitant selective serotonin reuptake 
inhibitor (SSRI)/serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressants will be 
collected. At Screening, the presence of SSRI or SNRI must be confirmed in order to qualify 
the subject for further consideration in the study. Review of subject adherence with 
background antidepressant therapy should be conducted at screening visit and all visits.  
6.1.4 
Massachusetts General Hospital Antidepressant Treatment Response 
Questionnaire 
The MGH ATRQ (Fava and Davidson 1996; Fava 2003) is a clinician-assisted questionnaire 
that examines a patient’s antidepressant treatment history using specific anchor points to 
define the adequacy of both the dose and duration of each antidepressant course, as well as 
the degree of symptomatic improvement obtained with each course. This validated 
questionnaire allows for the determination of inadequate response to antidepressant therapy 
in MDD (Chandler et al. 2010). Inadequate response is defined as a response of <50% to a 
course of treatment of at least 8 weeks at the minimum effective dose (as listed on the 
ATRQ), which has been stable for the 4 weeks prior to the SAFER interview.  
6.1.5 
State versus trait, Assessability, Face validity, Ecological validity, and Rule of 
three Ps (pervasive, persistent, and pathological) (SAFER) Remote Interview 
To ensure that appropriate subjects are entered into the study, an interview will be conducted 
. 
The interview may be conducted via telephone off-site or on-site, during Screening. If 
conducted on-site, the site staff should not be present during the interview. The assessments 
administered will be the SAFER Interview, which will include the MADRS, the CGI-S, and 
the MGH ATRQ. Sites will be notified of the results within 24 hours of the interview. 
6.1.6 
Mini-International Neuropsychiatric Interview 
The MINI is a brief, structured, diagnostic interview covering a broad range of major 
psychiatric disorders in DSM-5 and ICD-10 (Sheehan et al. 1998). The MINI is divided into 
modules, with each module corresponding to a diagnostic category. After completing the 
questions in each module, the interviewer (i.e., the Investigator or designee) assesses whether 
the diagnostic criteria are met. 


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In addition, one module for depressive disorders from the MINI-Plus will be used in 
conjunction with the MINI. The MINI-Plus is a more extensive version of the MINI, 
including additional disorders and disorder subtyping (Sheehan et al. 1998). 
MINI Version 7.0.2 for DSM-5 will be used in this study and will be conducted during 
Screening. 
6.1.7 
Montgomery-Asberg Depression Rating Scale 
The MADRS (Montgomery and Asberg 1979) is a 10-item, clinician-rated instrument 
measuring depression severity. It will be administered during Screening and at Baseline by 
the Investigator or designee with a Structured Interview Guide for the Montgomery-Asberg 
Depression Rating Scale (SIGMA) (Williams and Kobak 2008). The timeframe for this scale 
is the past 7 days. 
6.2 
Efficacy Assessments 
6.2.1 
Hamilton Depression Scale (17 Items) 
The HAMD-17 (Hamilton 1960) is completed with the Structured Interview Guide for the 
Hamilton Depression Rating Scale (SIGH-D) (Williams 1988) by the Investigator or designee 
based on an assessment of a patient’s symptoms. The timeframe for this scale is the past 
7 days. The HAMD-17 is to be the first scale completed at each visit. The HAMD-17 will be 
used as the primary efficacy analysis. 
The anxiety/somatization factor of the HAMD-17 (Cleary and Guy 1977) includes six items: 
psychic anxiety, somatic anxiety, gastrointestinal somatic symptoms, general somatic 
symptoms, hypochondriasis, and insight, and will be used for secondary efficacy analyses. 
6.2.2 
Sheehan Disability Scale 
The SDS (Sheehan et al. 1996) is a three-item patient-facing questionnaire used to evaluate 
impairments in the domains of work, social life/leisure, and family life/home responsibility. 
All items are rated on an 11-point continuum (0=no impairment to 10=most severe). The 
timeframe for this scale is the past week. The SDS will be used for secondary efficacy 
analyses. 
6.2.3 
Clinical Global Impression–Severity and Clinical Global Impression–
Improvement Scales 
The CGI-S and CGI-I (Guy 1976) are scales used by the Investigator or designee to rate the 
severity of the disorder and the global improvement since beginning of the study. The CGI-S 
rates the severity of a patient’s depression over the past 7 days and will be completed with a 
structured interview guide for global impressions (SIGGI) (Targum et al. 2013). The CGI-S 
will be used for secondary efficacy analyses. The CGI-I rates the change in a patient’s 


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depression over the past 7 days relative to the patient’s symptoms at Baseline and will be 
used for secondary efficacy analyses. 
6.2.4 
Changes in Sexual Functioning Questionnaire Short Form 
Sexual functioning will be assessed using the CSFQ-14 (Keller et al. 2006), a 14-item version 
of the CSFQ (Clayton et al. 1997). This is a patient-facing questionnaire, with a male version 
and a female version, that provides scores for three scales corresponding to the phases of the 
sexual response cycle (i.e., desire, arousal, and orgasm) and the five scales of the original 
CSFQ (sexual desire, sexual frequency, sexual satisfaction, sexual arousal, and sexual 
completion). The CSFQ-14 will be used for secondary efficacy analyses. 
6.2.5 
Karolinska Sleepiness Scale 
The KSS (Akerstedt and Gillberg 1990) is a patient-facing scale that measures the patient’s 
drowsiness and is frequently used in studies measuring subjective sleepiness. Scoring is 
based on a 9-point verbally anchored scale ranging from “extremely alert” to “very sleepy, 
great effort to keep awake, fighting sleep.” The timeframe for this scale is the past 7 days. 
The KSS will be used for secondary efficacy analyses. 
6.2.6 
Barratt Impulsiveness Scale 
The BIS-11 (Patton et al. 1995) is a questionnaire designed to assess the 
personality/behavioral construct of impulsiveness. It is composed of 30 items describing 
common impulsive or non-impulsive (for reverse scored items) behaviors and preferences. 
Items are scored on the following 4-point scale: Rarely/Never=1; Occasionally=2; Often=3; 
Almost Always/Always=4. The BIS-11 will be used for secondary efficacy analyses. 
6.2.7 
Impact of COVID-19 Pandemic on Efficacy Assessments 
In the interim between the pause in screening and the termination of the studies due to the 
COVID-19 pandemic, several subjects remained in the study who could not attend clinic 
visits. These subjects were allowed to participate in remote visits via telephone or video, or 
site staff could have visited subjects in their homes.  
6.3 
Safety Assessments 
6.3.1 
Physical Examinations 
A general physical examination will be conducted at Screening, Baseline, and Week 6/ET. 
6.3.2 
Vital Signs 
Vital signs will include body temperature, resting respiration rate, sitting systolic and 
diastolic blood pressure, and pulse rate. The sitting blood pressure should be measured after 
the subject has been sitting for ≥3 minutes. 
Vital signs will be measured at all scheduled and unscheduled visits. 


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6.3.3 
Height, Weight, and Body Mass Index 
Height will be measured at Screening. 
Weight will be measured at all scheduled and unscheduled visits. 
Body mass index will be calculated using the following formula: 
Weight (kg) / [height (m)]2. 
6.3.4 
Electrocardiograms 
All 12-lead ECGs will be complete, standardized recordings. At Visit 1 (Screening), the ECG 
should be completed in triplicate and collected within a 3-minute period. At all other visits, a 
single 12-lead ECG should be completed. All ECGs will be centrally read; the interpretation 
by the central cardiologist is considered the official result. 
At Visit 1 (Screening) the mean QTcF/QRS values of all the tracings of adequate quality will 
be used to determine eligibility. If a site performs additional ECGs beyond the set of triplicate 
ECGs prescribed at Screening or the single ECG prescribed at Baseline, the mean QTcF/QRS 
values of all the tracings of adequate quality will be used to determine eligibility. 
• At Screening, if the set of triplicate ECGs has a prolonged QTcF due to an identifiable 
cause, and it is medically appropriate to address that cause, a repeat set of triplicate 
ECGs may be performed during Screening at the discretion of the Medical Monitor if 
time permits during the Screening period. 
• At Baseline, a subject who met the eligibility criteria during the central read of the 
screening ECGs may be enrolled based on the machine read of the locally completed 
ECG. If the interpretation of the ECG by the central cardiologist returned after 
randomization indicates QTcF outside of the allowable range, the subject will be 
discontinued from the study, but this will not be considered a protocol deviation. 
Electrocardiograms should be performed before blood sampling or at least 30 minutes after 
blood sampling. The subject must rest in a supine position for 5 minutes before the ECG is 
obtained. ECG tracings (paper or electronic) will be reviewed and interpreted by a qualified 
clinician. ECG tracings and results (ventricular rate, PR, QRS, QT, QTcF, and QTcB 
intervals) will be included and summarized in the subject’s study records. 
6.3.5 
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 Baseline/Screening version will be administered at Visit 1 (Screening), and the Since 
Last Visit version will be administered at all subsequent visits, including unscheduled visits. 


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The C-SSRS results for each subject should be reviewed by the Investigator at each visit. If at 
any time the C-SSRS results for a given subject reveal potential suicidality, then the 
Investigator should assess the clinical significance of such results. If a clinically significant 
risk of suicidality is identified for a subject, then the Investigator should discontinue the 
subject and implement appropriate treatment (Section 4.4). 
6.3.6 
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.  
6.3.7 
Laboratory Evaluations 
Clinical laboratory sample collection (including HbA1c at Screening only) is encouraged, but 
not required to be completed under fasting conditions. The laboratory evaluations will 
include, but are not limited to, the following: 
• Clinical chemistry serum tests 
o Sodium (Na), potassium (K), chloride (Cl), phosphorus (P), calcium (Ca), 
magnesium (Mg), carbon dioxide (CO2), blood urea nitrogen (BUN), 
creatinine (CR), uric acid 
 Mg should only be performed at Visit 1 (Screening) 
o Alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), total 
bilirubin (TBIL), lactate dehydrogenase (LDH) 
o HbA1c 
 HbA1c should only be performed at Visit 1 (Screening) 
o Glucose 
o Albumin (ALB), total protein 
o Prolactin 
o Creatine kinase (CK)/creatine phosphokinase (CPK) 
o Lipid panel 
 Total cholesterol, HDL-cholesterol, triglycerides, LDL-cholesterol, 
cholesterol/HDL ratio, non-HDL cholesterol 


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• Thyroid stimulating hormone (TSH) and free thyroxine (free T4), if TSH is out of 
range 
o TSH/free T4 should only be performed at Visit 1 (Screening) 
• 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 
• Urine toxicity (drug) screen 
o Urine toxicity (drug) screen will test for controlled substances according to the 
schedule presented in Table 6-1. Negative drug screens are required for study 
eligibility. 
o Sites will be supplied with instant-read dipstick urine toxicity (drug) screen 
tests to utilize as a tool at the Baseline and Week 6 visit in order to determine 
if the subject continues to meet eligibility. This test will not take the place of 
the urine toxicity (drug) screening performed by the central laboratory. 


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o Subjects who test positive for a controlled substance in the urine toxicity 
(drug) screen performed by the central laboratory and who have a valid 
prescription may be retested during Screening if they agree to abstain from the 
medication for the length of their participation in the study and if abstinence 
from medication usage is achieved at least 7 days prior to Visit 2 (Baseline). 
The repeat test during Screening must be negative for them to participate in 
the study. Additionally, DSM-5 criteria for substance use disorders should not 
be met.  
o Subjects who test positive in the urine toxicity (drug) screen performed by the 
central laboratory for benzodiazepines, tetrahydrocannabinol (THC), or 
opiates will be withdrawn from the study unless any prohibited medication or 
substance has been discontinued and withdrawal from the study presents an 
unacceptable medical risk for 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 a subject is 
allowed to remain in the trial, this will be reported as a major protocol 
deviation, not a waiver. In addition, restrictions listed in Appendix C should be 
followed. 
o Reasonable efforts should be made to collect a urine sample at applicable 
scheduled visits as described in “Urinalysis” above 
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 
Testsa,b 
Visit 1 (Screening) 
CHEM, TSH/free T4, CBC, UA, urine toxicity (drug) screen, and serum 
pregnancy test 
Visit 2 (Baseline) 
CHEM, CBC, UA, urine toxicity (drug) screen, and urine pregnancy test 
Visit 8 (ET/EOT) 
CHEM, CBC, UA, urine toxicity (drug) screen, and urine pregnancy test 
Abbreviations: CBC=complete blood count; CHEM=clinical chemistry serum tests; EOT=end of treatment; ET=early 
termination; HbA1c=glycosylated hemoglobin; TSH=thyroid stimulating hormone; UA=urinalysis 
a 
A pregnancy test is only required for women of childbearing potential. If urine cannot be obtained in women of 
childbearing potential, a serum pregnancy test should be done in its place. 
b 
An Mg level, HbA1c test, and TSH/free T4 test are only required at Visit 1 (Screening). 
6.3.8 
Impact of COVID-19 Pandemic on Safety Assessments 
In the interim between the pause in screening and the termination of the studies due to the 
COVID-19 pandemic, several subjects remained in the study who could not attend clinic 


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visits. These subjects were allowed to conduct remote visits via telephone or video, or site 
staff could have visited subjects in their homes.  
Some safety assessments may not have been performed, or may have been performed under 
different circumstances, due to the subject not being able to come to the clinic. Modifications 
and accommodations for safety assessments in the context of remote visits are described 
briefly below:  
6.3.8.1 
Priority Medical Assessments in Remote Visits 
The C-SSRS was to be performed as a priority, along with an assessment of AEs and 
COVID-19 symptoms. Additionally, subjects were to be queried about concomitant 
medications, and their background antidepressant and IP compliance. 
6.3.8.2 
Physical Examinations, Vital Signs, Height, and Weight 
Physical examinations, vitals, height, and weight may not have been performed because the 
visit had to be conducted remotely. If the visit was remote, subject may have reported vitals 
obtained on home devices.   
6.3.8.3 
Electrocardiograms 
ECGs may have been performed by site staff during a home visit.  
6.3.8.4 
Columbia-Suicide Severity Rating Scale 
See Section 6.3.8.1 above.  
6.3.8.5 
Extrapyramidal Symptom Rating Scale-Abbreviated 
When the ESRS-A motor examination could not be performed (e.g., when the visit was 
performed via telephone with no video component) then no scoring of symptoms was to be 
completed. The clinical interview questions were to be asked for all symptom areas in order 
to obtain information about the presence and severity of involuntary movements experienced 
by the patient and this was to be documented in the source record. The clinical significance of 
any symptoms was to be evaluated by the investigator and the adverse event page updated 
when new or worsening symptoms were reported. 
6.3.8.6 
Laboratory Evaluations 
If subjects could not attend clinic visits for laboratory evaluations, they were allowed to use 
local laboratories, or to have site staff visit them at their homes for blood draws. 
6.4 
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 


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not eligible for the open-label study, as well as those who discontinue prematurely from the 
study. Subjects should have the following completed at least 30 days after last dose of study 
drug: 
• Assessment of concomitant medications/treatments 
• Assessment of AEs 
6.5 
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 concomitant medications/treatments, measurement of vital signs and weight, 
ESRS-A, and completion of the C-SSRS (Since Last Visit version). The Investigator may 
perform any additional safety evaluations deemed by the Investigator to be clinically 
indicated. Study drug may be dispensed to the subject at unscheduled visits if needed. 
6.5.1 
Impact of COVID-19 on Unscheduled Visits 
If subjects were not able to attend the clinic for an unscheduled visit, this may have occurred 
remotely or by site staff visit to the subject’s home. 
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). The condition that leads to the procedure is an AE if not present at 
Baseline. 
• Overdose of concomitant medication without any signs or symptoms unless the subject 
is hospitalized for observation 
• Hospitalization for elective surgery planned prior to study (situation where an 
untoward medical occurrence has not occurred) 
• Pregnancy will not be considered an AE, but if it occurs, it will be reported on a 
pregnancy form 
7.1.2 
Definition of Serious Adverse Event 
In addition to the severity rating, each AE will be classified by the Investigator as “serious” 
or “not serious.” The seriousness of an event will be defined according to the applicable 
regulations and generally refers to the outcome of an event. An SAE is one that meets one or 
more of the following: 
• Is fatal 
• Is immediately life threatening 
• Results in disability or permanent damage 
• Requires hospitalization 
• Prolongs existing hospitalization 
• Is a congenital anomaly or birth defect (in an offspring) 
• Is medically significant 
Definition of Life Threatening 
A life-threatening event places the subject at immediate risk of death from the event as it 
occurred. This does not include an AE, which, had it occurred in a more severe form, might 
have caused death. 
Definition of Hospitalization 
Hospitalization is defined by 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 


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• 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, or convulsions that do not result in hospitalization or 
development of drug dependency or drug abuse. 
An SAE may also include any other event that the Investigator or Medical Monitor judges to 
be serious or that suggests a significant hazard, contraindication, side effect, or precaution. 
7.2 
Classification of an Adverse Event 
7.2.1 
Severity of Event 
The severity of each AE will be graded on a 3-point scale and reported in detail as indicated 
on the eCRF: 
• Mild: awareness of sign or symptom but easily tolerated, causing minimal discomfort, 
and not interfering with normal everyday activities 
• Moderate: sufficiently discomforting to interfere with normal everyday activities 
• Severe: incapacitating and/or preventing normal everyday activities 
7.2.2 
Relationship to Study Drug 
The causality of each AE should be assessed and classified by the Investigator as “related” or 
“not related.” An event is considered related if there is a reasonable possibility that the event 
may have been caused by the product under investigation (i.e., there are facts, evidence, or 
arguments to suggest possible causation). 
Consider the following when assessing causality: 
• Temporal associations between the agent and the event 


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• Response to 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 
7.2.2.1 
Duration 
The start and stop dates for AEs will be recorded using the following criteria: 
• Start: Date of the first episode of the AE or date of significant sustained worsening in 
severity 
• Stop: Date when AE either ceased permanently or changed in severity 
7.2.2.2 
Frequency 
The frequency of the AE should be indicated according to the following definitions: 
• Single: Experienced once, without recurrence 
• Recurrent: More than one discrete episode with the same severity 
7.2.2.3 
Action Taken with Study Drug 
• Dose not changed: No change in study drug 
• Drug interrupted: Study drug temporarily stopped 
• Drug withdrawn: Study drug discontinued permanently 
7.2.2.4 
Therapy 
• None: No new treatment instituted 
• Medication: New treatment initiated as a direct result of AE 
• Other: Other action required 
7.2.2.5 
Outcome 
• Recovered/resolved: Recovered or resolved 
• Recovered/resolved with sequelae: Recovered or resolved with sequelae 
• Not recovered/not resolved: Not recovered or not resolved 
• Fatal: Death due to an AE 
• Unknown: Unknown 


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7.2.2.6 
Seriousness 
• Not serious 
• Serious 
7.2.3 
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. All AEs must be either resolved or stable at the end of the 
study safety follow-up period. If ongoing at the end of the study safety follow-up period, the 
subject should be referred for appropriate treatment. 
In the event that a subject discontinues and has an ongoing AE at the time of discontinuation 
(Section 4.4.1) or is withdrawn from the study because of an AE, the subject should be 
followed and treated by the Investigator until the AE has resolved, stabilized, or a new 
chronic baseline has been established. 
7.4 
Reporting Procedures 
7.4.1 
Adverse Event Reporting 
The Investigator must record all observed AEs and all reported AEs. At each visit, the 
Investigator should ask the subject a nonspecific question (e.g., “Have you noticed anything 
different since your last visit?”) to assess whether any AEs have been experienced since the 
last report or visit. 
Note that any use of medication (and specifically any newly prescribed medication) during 
the course of a study may indicate the occurrence of an AE that may need to be recorded on 
both the AE and the concomitant medication page. 
All AEs, 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. 


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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; use 
the appropriate form for initial and/or follow-up reporting.  
At a minimum, events identified by the Sponsor to require expedited reporting as serious, 
unexpected, and related to study drug must be brought to the attention of the responsible 
institutional review board/ethics committee (IRB/EC), as per applicable regulations. These 
will be provided by the Sponsor after their assessment. For European Union member states, 
the Sponsor or its designee will provide reports of suspected unexpected serious adverse 
reactions (SUSARs) directly to the ECs, as required by local legislation. In all other 
countries, it is the Investigator’s responsibility to provide these expedited reports to the 
responsible IRB/EC. It is also the Investigator’s responsibility to notify the responsible 
IRB/EC regarding any new and significant safety information. 
When an SAE occurs, Investigators will review all documentation related to the event and 
will complete the paper SAE form (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 for 30 days after last dose of 
study drug for any SAEs and/or other reportable information until such events have resolved 
or the Investigator, in conjunction with the Sponsor, 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 study follow-up period of 30 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 
withdrawn 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. 


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Any AEs that are the consequence of pregnancy and which meet the criteria for serious 
should also be reported via the SAE form. 
7.4.3.1 Reporting Paternal Drug Exposure 
Paternal drug exposure is defined as a father’s exposure to a medicinal product before or 
during his partner’s pregnancy. Any paternal drug exposure cases must be reported to the 
Sponsor within 24 hours of discovery via the Pregnancy form. Any AEs that are the 
consequence of paternal drug exposure and which meet the criteria for serious must also be 
reported to the Sponsor within 24 hours of discovery via the SAE form. 
7.4.4 
Reporting of Overdose 
An overdose is a deliberate or inadvertent administration of a treatment at a dose higher than 
the maximum recommended dose per protocol. It must be reported to the Sponsor or 
designee on the Overdose form within 24 hours of discovery. In addition, all events of 
overdose are to be captured as protocol deviations. 
8 CLINICAL 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. 
9.2 
Statistical Hypotheses 
The hypotheses for the primary endpoint are the following: 
• The null hypothesis: There is no difference in the mean change from Baseline to 
Week 5 in the HAMD-17 total score between the pimavanserin and the placebo 
treatment groups. 
• The alternative hypothesis: There is a difference in the mean change from Baseline to 
Week 5 in the HAMD-17 total score between the pimavanserin and the placebo 
treatment groups. 


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9.3 
Sample Size Determination 
This study plans to screen approximately 560 adult subjects to randomize approximately 
280 subjects, allowing for a 50% screen failure rate. These approximately 280 subjects will 
be randomized in a 1:1 ratio to either the pimavanserin or the placebo treatment groups 
(i.e., 140 subjects in each treatment group). 
A total sample size of 266 evaluable subjects was estimated to provide at least 90% power at 
a two-sided significance level of 0.05 when assuming a treatment effect size of 0.4 for 
pimavanserin compared to placebo on the change from Baseline to Week 5 in the HAMD-17 
total score. Adjusting for a potential non-evaluable rate of up to 5%, approximately 
280 subjects will be randomized. 
9.4 
Subject Populations for Analysis 
The Full Analysis Set includes all subjects who were randomized, received at least one dose 
of study drug, and have both a Baseline (Week 0) value and at least one post-Baseline value 
for the HAMD-17 total score in the two studies. The Full Analysis Set will be used for the 
analysis of all efficacy endpoints. 
The Per-protocol Analysis Set includes a subset of subjects in the Full Analysis Set without 
any protocol deviations that could have a significant effect on the study conclusions. The 
Per-protocol Analysis Set will be determined prior to unblinding the studies for the final 
analysis and will be used for supportive analysis of selected efficacy endpoints. 
The Safety Analysis Set includes all subjects who received at least one dose of study drug in 
the two studies.  
Any other analysis sets, if necessary, will be defined in the SAP. 
9.5 
Statistical Analyses 
9.5.1 
Primary Analyses 
The primary efficacy endpoint, change from Baseline to Week 5 in the HAMD-17 total score, 
will be evaluated using a mixed-effect model repeated measures (MMRM). The model will 
include effects for treatment group, visit, treatment-by-visit interaction, baseline HAMD-17 
total score, the baseline HAMD-17 total score-by-visit interaction, and study. An unstructured 
covariance matrix will be used and the Kenward-Roger approximation will be used to adjust 
the denominator degrees of freedom. 
A hierarchical approach will be used to control for multiple endpoints (primary and 
secondary). Details will be provided in the SAP. 


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Sensitivity analyses will be performed to assess the impact of missing data, including 
analyses based on a missing not at random assumption. Additional sensitivity analyses will be 
performed to assess the impact of COVID-19.   
9.5.2 
Secondary Analyses 
Each of the secondary endpoints, other than response and remission, will be analyzed using 
the MMRM method similar to that used for the analysis of the primary efficacy endpoint. For 
CGI-I, the baseline CGI-S score will be used as the covariate in the MMRM model. The 
response and remission rates will be compared between the pimavanserin and placebo groups 
using the Cochran-Mantel-Haenszel (CMH) test stratified by study. 
9.5.3 
Safety Analyses 
Safety results will be summarized by treatment group using descriptive statistics. Adverse 
events will be classified into standard terminology using the Medical Dictionary for 
Regulatory Activities (MedDRA). 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 the first administration of study drug and no later than the 
last administration of study drug plus 30 days. Summaries by maximum severity and by 
relationship to study drug will also be provided. Serious TEAEs, fatal AEs, and TEAEs 
leading to discontinuation will also be summarized. The relationship of selected AEs to 
COVID-19 will also be assessed and COVID-19 related TEAEs will be tabulated. 
Clinical laboratory values for hematology, chemistry, and urinalysis (specific gravity and pH) 
will be summarized by treatment group using descriptive statistics at Baseline and the end of 
the treatment period visits. The change from baseline values will also be summarized by 
treatment group. The overall minimum and maximum post-baseline observed and change 
from baseline values will also be summarized. 
The number and percentage of subjects with potentially clinically important (PCI) laboratory 
values at the end of the treatment period and overall post-baseline will be summarized by 
treatment group for selected parameters. The PCI criteria will be specified in the SAP. 
Vital signs including weight, height, and the derived BMI 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. 
Observed values of electrocardiogram parameters and the changes from Baseline will be 
summarized by treatment group and visit. 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 Food and Drug Administration (FDA) E14 guidance 
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For the C-SSRS, the number and percentage of subjects with suicidal ideation or suicidal 
behavior during the study will be tabulated. 
Observed values and change from Baseline in the ESRS-A score will be summarized by 
treatment group and visit. The change from Baseline in the ESRS-A score will be analyzed 
using the MMRM method, similar to the MMRM method used to analyze the primary 
endpoint. 
Number and percentage of subjects with sexual dysfunction (a total score of <47 for men and 
<41 for women) will be summarized and shift tables will be presented.   
9.5.4 
Subgroup Analyses 
Selected analyses may be performed in subgroups. Details will be provided in the SAP. 
9.6 
Interim Analyses 
No interim analyses are planned.  
9.7 
Measures to Minimize Bias 
9.7.1 
Masking Procedures 
This unmasked protocol version provides details of certain study design elements, 
procedures, and statistical methods that are not available in the masked version of the 
protocol. 
This document is intended for use only by the unmasked Sponsor and restricted Worldwide 
Clinical Trials personnel and their designated agents for purposes of regulatory document 
preparation in conjunction with review by IRBs, IECs and regulatory authorities. Access to 
this document by other entities may be considered on a case-by-case basis by the Sponsor. 
The information contained herein is UNMASKED and CONFIDENTIAL. Therefore, it must 
NOT be shared with or communicated to any individual at an investigational site or from site 
facing members of the clinical operations team of the contract research organization except 
with explicit and fully documented authorization from the Sponsor. 
The key element revealed but that is masked in the masked protocol is that the key timepoint 
for analysis of the efficacy endpoints is Week 5. 
Investigators will receive the masked version of the clinical study protocol. 
9.7.2 
Randomization Procedures 
Eligible subjects will be randomized into one of two treatment groups (pimavanserin or 
placebo) in a 1:1 ratio using an interactive response technology (IRT) system. The 
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 


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designee to the treatment codes, and providing identical tablets and packaging for the 
pimavanserin and placebo treatments. 
9.8 
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. 
Unblinding of individual treatment assignment during the study is discouraged. The 
Investigator may break the blind in the event of a medical emergency if it is considered 
necessary for the care of the subject. The Investigator should attempt whenever possible to 
contact the Medical Monitor before unblinding a subject’s treatment to discuss the event. 
Lack of Medical Monitor contact does not preclude the Investigator from unblinding the 
subject. In an emergency situation, the subject’s treatment assignment may be obtained by the 
Investigator from the IRT system. Details of the process to be followed are provided in a 
separate IRT manual. In the event that the IRT system is used to perform a code break, the 
Sponsor or designee will be notified immediately via an automated notification from the 
IRT system that an unblinding has occurred. The notification only alerts the Sponsor or 
designee that the unblinding occurred, and does not include any information about the 
unblinded subject’s treatment assignment. 
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). Direct 
access includes permission to examine, analyze, verify, and reproduce any records and 
reports that are needed for the evaluation of the study. The Investigator must ensure the 
reliability and availability of source documents from which the information on the eCRF was 
derived. 
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 electronic data capture 
(EDC) database by trained site personnel. The source documentation may consist of source 


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notes captured by site personnel as well as laboratory reports, ECG reports, and electronic 
source data. 
10.3 Case Report Forms 
Subject data required by this protocol are to be recorded in an EDC system on eCRFs. 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 at 
the site. 
10.4 Confidentiality 
The Investigator must ensure that each subject’s anonymity is maintained as described below. 
On the eCRFs 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, medical records submitted 
with SAE reporting) 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), where applicable. The Sponsor 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, 
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. 


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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-randomization 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 6.4). 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. 
Protocol deviations will be reviewed periodically over the course of the study. The review 
process, definition of the deviation categories, and the classification of a deviation as major 
or minor are detailed in the Protocol Deviation Management Plan. Protocol deviations will 
also be assessed with respect to relationship to COVID-19, and COVID-19 related protocol 
deviations will be tabulated.  
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 
activities with a focus on critical processes and critical study data:  


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• 
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 reduced (e.g., mitigating) or can be 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 to be 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 are 
ongoing during trial execution and risk outcomes are reported 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. Some remote monitoring of study sites was also 
performed as a result of the travel and visiting restrictions caused by the COVID-19 
pandemic. 
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, a certain percentage 
of sites participating in this study will be audited. These audits may include a review of site 
facilities (e.g., pharmacy, drug storage areas, and laboratories) and review of study-related 
records may occur in order to evaluate the trial conduct and compliance with the protocol, 
ICH guidance on GCP, and applicable regulatory requirements. 


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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, and any subject information or advertising materials. 
The study will not be initiated until the IRB/EC provides written approval of the protocol and 
the informed consent and until approved documents have been obtained by the Investigator 
and copies received by the Sponsor. All amendments will be sent to the IRB/EC for 
information (minor amendment) or for submission (major amendment) before 
implementation. The Investigator will supply the IRB/EC and the Sponsor with appropriate 
reports on the progress of this study, including any necessary safety updates, in accordance 
with the applicable government regulations and in agreement with policy established by the 
Sponsor. 
12.3 Informed Consent Process 
Properly executed, written informed consent must be obtained from each subject prior to any 
screening procedures. 
The informed consent must, at a minimum, include the elements of consent described in the 
ICH guidance on GCP and the US CFR 21 part 50.25. A copy of the ICF planned for use will 
be reviewed by the Sponsor or designee for acceptability and must be submitted by the 
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approval prior to the start of the study at that investigational site. Consent forms must be in a 
language fully comprehensible to the prospective subject. The Investigator must provide the 
Sponsor or designee with a copy of the IRB/EC letter approving the protocol and the ICF 
before the study drug supplies will be shipped and the study can be initiated. 
The consent form must be revised if new information becomes available during the study that 
may be relevant to the subject's willingness to continue participation. Any revision must be 
submitted to the appropriate IRB/EC for review and approval in advance of use. 
12.3.1 
Consent and Other Informational Documents Provided to Subjects 
The subject must be given a copy of the signed informed consent and the original maintained 
in the designated location at the site. 
12.3.2 
Consent Procedures and Documentation 
It is the Investigator or designee’s responsibility to obtain written informed consent from the 
subject after adequate explanation of the aims, methods, anticipated benefits, and potential 
hazards of the study. The subject must be given ample time to decide about study participation 
and opportunity to inquire about details of the study. The IRB/EC-approved consent form must 
be personally signed and dated by the subject and by the person who conducted the informed-
consent discussion. The Investigator or appropriate site personnel must document the details of 
obtaining informed consent in the subject’s study documents. 
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. 
13 PUBLICATION PLAN 
All publication rights are delineated in the Clinical Study Agreement and/or other separate 
agreements with the Investigator and/or Institution, as applicable. 
14 CONFLICT OF INTEREST POLICY 
14.1 Finance, Insurance, and Indemnity 
Arrangements for finance, insurance, and indemnity are delineated in the Clinical Study 
Agreement and/or other separate agreements with the Investigator and/or Institution, as 
applicable. 
 
 


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15 LITERATURE REFERENCES 
ACADIA Pharmaceuticals Inc. NUPLAZID® [package insert]. San Diego, CA, May 2019. 
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2018. 
Brayfield A. Mirtazapine. In: Brayfield A, ed. Martindale: The Complete Drug Reference. 
38th ed. London, UK: Pharmaceutical Press. 2014. 
Bromet E, Andrade LH, Hwang I, et al. Cross-national epidemiology of DSM-IV major 
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Campeau L. Letter: Grading of angina pectoris. Circulation. 1976;54(3):522-523. 
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Chandler GM, Iosifescu DV, Pollack MH, Targum SD, Fava M. Validation of the 
Massachusetts General Hospital Antidepressant Treatment History Questionnaire (ATRQ). 
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Chouinard G, Margolese HC. Manual for the Extrapyramidal Symptom Rating Scale (ESRS). 
Schizophr Res. 2005;76(2-3):247-265. 
Clayton AH, McGarvey EL, Clavet GJ. The Changes in Sexual Functioning Questionnaire 
(CSFQ): Development, reliability and validity. Psychopharmacology Bulletin. 
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Cleary P, Guy W. Factor analysis of the Hamilton depression scale. Drugs Exp Clin Res. 
1977;1:115-120. 
Fava M. Diagnosis and definition of treatment-resistant depression. Biol Psychiatry. 
2003;53(8):649-659. 


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Fava M, Davidson KG. Definition and epidemiology of treatment-resistant depression. 
Psychiatr Clin North Am. 1996;19(2):179-200. 
Fava M, Memisoglu A, Thase ME, et al. Opioid modulation with buprenorphine/samidorphan 
as adjunctive treatment for inadequate response to antidepressants: a randomized 
double-blind placebo-controlled trial. Am J Psychiatry. 2016;173(5):499-508. 
Guy W. ECDEU Assessment Manual for Psychopharmacology—Revised (DHEW Publ No. 
ADM 76-338). Rockville, MD, US Department of Health, Education, and Welfare Public 
Health Service, Alcohol, Drug Abuse, and Mental Health Administration, NIMH 
Psychopharmacology Research Branch, Division of Extramural Research Programs, 
1976:218-222. 
Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56-62. 
Keller A, McGarvey EL, Clayton AH. Reliability and construct validity of the Changes in 
Sexual Functioning Questionnaire short-form (CSFQ-14). J Sex Marital Ther. 
2006;32:43-52. 
Mehta MA, Manes FF, Magnolfi G, Sahakian BJ, Robbins TW. Impaired set-shifting and 
dissociable effects on tests of spatial working memory following the dopamine D2 receptor 
antagonist sulpiride in human volunteers. Psychopharmacology. 2004;176(3-4):331-342. 
Montgomery SA, Asberg M. A new depression rating scale designed to be sensitive to 
change. Br J Psychiatry. 1979;134:382-389. 
Murray CJ, Lopez AD. Evidence-based health policy: lessons from the Global Burden of 
Disease Study. Science. 1996;274(5288):740-743. 
Patton JH, Stanford MS, Barratt ES. Factor structure of the Barratt impulsiveness scale. 
J Clin Psychol. 1995;51(6):768-774. 
Peretti CS, Danion JM, Kauffmann-Muller F, Grange D, Patat A, Rosenzweig P. Effects of 
haloperidol and amisulpride on motor and cognitive skill learning in healthy volunteers. 
Psychopharmacology. 1997;131(4):329-338. 
Posner K, Brown GK, Stanley B, et al. The Columbia–Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry. 2011;168(12):1266-1277. 
Roth BL, Lopez E, Patel S, Kroeze WK. The multiplicity of serotonin receptors: uselessly 
diverse molecules or an embarrassment of riches? Neuroscientist. 2000;6(4):252-262. 
Rush AJ, Kraemer HC, Sackeim HA, et al. Report by the ACNP Task Force on Response and 
Remission in Major Depressive Disorder. Neuropsychopharmacology. 2006;31:1841-1853. 


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Saeedi H, Remington G, Christensen BK. Impact of haloperidol, a dopamine D2 antagonist, 
on cognition and mood. Schizophr Res. 2006;85(1-3):222-231. 
Schotte A, Janssen PF, Gommeren W, et al. Risperidone compared with new and reference 
antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology. 
1996;124(1-2):57-73. 
Sheehan DV, Harnett-Sheehan K, Raj BA. The measurement of disability. Int Clin 
Psychopharmacol. 1996;11(suppl 3):89-95. 
Sheehan DV, Lecrubier Y, Sheehan KH, et al. The Mini-International Neuropsychiatric 
Interview (M.I.N.I.): the development and validation of a structured diagnostic interview for 
DSM-IV and ICD-10. J Clin Psychiatry. 1998;59(suppl 20):22-33. 
Targum SD, Houser C, Northcutt J, Little JA, Cutler AJ, Walling DP. A structured interview 
guide for global impressions: increasing reliability and scoring accuracy for CNS trials. Ann 
Gen Psychiatry. 2013;12(1):2. 
Vanover KE, Weiner DM, Makhay M, et al. Pharmacological and behavioral profile of N-(4-
fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl) 
carbamide (2R,3R)-dihydroxybutanedioate (2:1) (ACP-103), a novel 5-
hydroxytryptamine(2A) receptor inverse agonist. J Pharmacol Exp Ther. 
2006;317(2):910-918. 
Wang PS, Schneeweiss S, Avorn J, et al. Risk of death in elderly users of conventional vs. 
atypical antipsychotic medications. N Engl J Med. 2005;353(22):2335-2341. 
Wikström HV, Mensonides-Harsema MM, Cremers TI, Moltzen EK, Arnt J. Synthesis and 
pharmacological testing of 1,2,3,4,10,14b-hexahydro-6-methoxy-2-
methyldibenzo[c,f]pyrazino[1,2-a]azepin and its enantiomers in comparison with the two 
antidepressants mianserin and mirtazapine. J Med Chem. 2002;45(15):3280–3285. 
Williams JB. A structured interview guide for the Hamilton Depression Rating Scale. Arch 
Gen Psychiatry. 1988;45(8):742-747. 
Williams JB, Kobak KA. Development and reliability of a structured interview guide for the 
Montgomery-Asberg Depression Rating Scale (SIGMA). Br J Psychiatry. 
2008;192(1):52-58. 


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Appendix C Prohibited and Restricted Medications 
Subjects taking prohibited medications at study entry will not be eligible for the study.  
Subjects who require current treatment with a prohibited medication will be withdrawn from 
the study. 
Subjects who have previously taken a prohibited medication during the study will be 
withdrawn from the study unless:  
• the prohibited medication has been discontinued AND  
• withdrawal from the study presents an unacceptable medical risk to the subject 
The justification to allow the subject to continue in the trial will be made by the 
Sponsor/Medical Monitor with medical input from the Investigator, and will be documented. 
If allowed to remain in the trial, this will be reported as a major protocol deviation and not a 
waiver. 
The table below lists prohibitions and restrictions by medication class, including 
representative medications within class. A prohibited medication is not allowed. A restricted 
medication is allowed only under certain conditions. 
Medication Class 
Medicationa 
Prohibition/restrictions 
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 study 
Anticholinergics 
PROHIBITED 
• 
Centrally acting 
anticholinergics 
o 
benztropine 
o 
biperiden 
o 
trihexiphenidyl 
• 
Anticholinergic medications whose 
primary mechanism of action is 
centrally acting are prohibited and 
should be washed out and discontinued 
at least 2 weeks or 5 half-lives 
(whichever is longer) prior to Baseline 
UNRESTRICTED 
• 
Peripherally acting 
anticholinergics 
• 
Peripherally acting anticholinergic 
medications are allowed without 
restriction 
Anticonvulsant and 
mood stabilizers 
PROHIBITED 
• 
carbamazepine 
• 
lamotrigine 
• 
lithium 
• 
phenytoin 
• 
valproate 
• 
Must be washed out 5 half-lives prior to 
Baseline 
• 
Prohibited throughout the study 
Antidepressants 
other than 
PROHIBITED 
• 
mirtazapine 
• 
Prohibited throughout the study 


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Medication Class 
Medicationa 
Prohibition/restrictions 
background therapy 
(see Inclusion 
Criterion #6) 
• 
nefazadone 
• 
fluvoxamine 
• 
mianserin 
• 
trazodone 
• 
amitriptyline 
• 
nortriptyline 
• 
imipramine 
• 
trimipramine 
• 
desipramine 
• 
clomipramine 
• 
bupropion 
• 
levomilnacipran 
• 
vilazodone 
• 
vortioxetine 
• 
ketamine 
• 
esketamine 
• 
Must be discontinued at least 2 weeks 
or 5 half-lives (whichever is longer) 
prior to the Baseline visit 
RESTRICTED 
• 
citalopram 
• 
escitalopram 
• 
venlafaxine 
• 
If subject is remaining on these 
medications, the dose of the permitted 
antidepressants on the left must be 
unchanged for at least 4 weeks prior to 
the SAFER Remote Interview and 
should be expected to remain 
unchanged until the subject’s final visit. 
If the medication is being discontinued, 
it must be discontinued at least 2 weeks 
or 5 half-lives (whichever is longer) 
prior to the Baseline visit. 
o 
Citalopram is restricted to a 
maximum dose of 20 mg/day  
o 
Escitalopram is restricted to a 
maximum dose of 10 mg/day  
o 
Venlafaxine is restricted to a 
maximum dose of 225 mg/day 
Antihistamines 
RESTRICTED 
• 
diphenhydramine 
• 
brompheniramine 
• 
chlorpheniramine  
 
• 
Prohibited at Baseline 
• 
First generation antihistamines are not 
allowed during the study to treat 
insomnia 
• 
Limited short-term use of first 
generation antihistamines for a few days 
is allowed during the study for 
treatment of allergies and as 
antihistamine-decongestant for colds 
only 
• 
First generation antihistamines should 
not be used within 12 hours of an 
efficacy assessment 


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Medication Class 
Medicationa 
Prohibition/restrictions 
UNRESTRICTED 
• 
cetirizine 
• 
loratadine 
• 
fexofenadine  
• 
Second and third generation 
antihistamines are allowed without 
restriction 
Anxiolytics 
PROHIBITED 
• 
chlordiazepoxide 
• 
diazepam 
• 
flurazepam 
• 
alprazolam 
• 
clonazepam 
• 
lorazepam 
• 
oxazepam 
• 
temazepam 
• 
midazolam 
• 
triazolam 
• 
Prohibited at study entry and throughout 
the study 
Hypnotics and 
sleeping agents 
PROHIBITED 
• 
zolpidem 
• 
zopiclone 
• 
eszopiclone 
• 
zaleplon 
• 
ramelteon 
• 
Prohibited at study entry and throughout 
the study 
Stimulants and 
wake-promoting 
agents 
PROHIBITED 
• 
methylphenidate 
• 
modafinil 
• 
armodafinil 
• 
amphetamine 
• 
Prohibited at study entry and throughout 
the study (see Section 6.3.7 for 
procedures related to a positive 
amphetamine test at study entry) 
Non-stimulant 
ADHD medications 
PROHIBITED 
• 
atomoxetine 
• 
Prohibited at study entry and throughout 
the study 
Serotonin 
antagonists  
PROHIBITED 
• 
cyproheptadine 
• 
Prohibited throughout the study 
• 
Must be discontinued at least 3 weeks 
prior to the Baseline visit 
Antiarrhythmic 
drugs 
PROHIBITED 
• 
ajmaline 
• 
amakalant, semantilide 
• 
amiodarone 
• 
bretylium 
• 
disopyramide 
• 
dofetilide 
• 
dronedarone 
• 
flecainide 
• 
Prohibited at study entry and throughout 
the study 


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Medication Class 
Medicationa 
Prohibition/restrictions 
• 
ibutilide 
• 
procainamide 
• 
propafenone 
• 
quinidine 
• 
sotalol, d-sotalol 
Opioids 
PROHIBITED 
• 
methadone 
• 
hydrocodone 
• 
oxycodone 
• 
codeine 
• 
morphine 
• 
Prohibited at Baseline 
• 
Subjects who require chronic treatment 
with opioid medication or who have a 
substance use disorder are not eligible 
for this study 
• 
Limited short term use of opioids for a 
few days only is allowed during the 
study for treatment of acute pain 
following trauma or surgical procedure 
• 
Opioids should not be used within 
12 hours of an efficacy assessment 
Antimicrobials, 
antifungals, and 
antimalarials 
PROHIBITED 
• 
clarithromycin 
• 
erythromycin 
• 
levofloxacin 
• 
moxifloxacin 
• 
pentamidine 
• 
roxithromycin 
• 
Prohibited at study entry and throughout 
the study 
RESTRICTED 
• 
artenimol/piperaquine 
• 
azithromycin 
• 
bedaquiline 
• 
ciprofloxacin 
• 
gemifloxacin 
• 
norfloxacin 
• 
ofloxacin 
• 
fluconazole 
• 
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 
Principal Investigator. 
• 
The medications on the left 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 
a 
Medications within each class include but are not limited to the examples listed in this table. 


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Appendix D 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 (peak) observed drug concentration (Cmax) of approximately 1.5-fold 
and area under the plasma concentration-time curve (AUC) of approximately 3-fold.  
Strong inhibitors of CYP3A4 are to be stopped at least 7 days or 5 half-lives prior to 
investigational product administration, whichever is longer. Strong inducers of CYP3A4 are 
to be stopped 30 days or 5 half-lives prior to investigational product administration, 
whichever is longer. Moderate inhibitors and inducers of CYP3A4 are allowed but should be 
used with caution. 


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STRONG 
INHIBITORS 
grapefruit juice
a 
boceprevir (Victrelis®) 
clarithromycin (Biaxin®) 
cobicistat (part of Stribild®) 
conivaptan (Vaprisol®) 
fluvoxamine (Luvox®) 
indinavir (Crixivan®) 
itraconazole (Sporanox®) 
ketoconazole (Nizoral®) 
lopinavir and ritonavir (Kaletra®) 
mibefradil (Posicor®) 
nefazodone (Serzone®) 
nelfinavir (Viracept®) 
posaconazole (Noxafil®) 
quinupristin (Synercid®) 
ritonavir (Norvir®, part of Viekira 
Pak™) 
saquinavir (Invirase®) 
telaprevir (Incivek®) 
telithromycin (Ketek®) 
voriconazole (Vfend®) 
MODERATE 
INHIBITORS 
grapefruit juice
a 
amprenavir (Agenerase®) 
aprepitant (Emend®) 
atazanavir (Reyataz®) 
ciprofloxacin (Cipro®) 
darunavir/ritonavir 
(Prezista®/Ritonavir) 
diltiazem 
erythromycin (Erythrocin® 
Lactobionate) 
fluconazole (Diflucan®) 
fosamprenavir (Lexiva®) 
imatinib (Gleevec®) 
verapamil (Calan®) 
STRONG 
INDUCERS 
avasimibe 
carbamazepine (Tegretol®) 
phenobarbital (Luminal®, Solfoton®) 
phenytoin (Dilantin®)  
rifampin (Rifadin®, Rifadin® IV, 
Rimactane®) 
St. John’s Wort 
MODERATE 
INDUCERS 
bosentan (Tracleer®) 
efavirenz (Sustiva®) 
etravirine (Intelence®) 
modafinil (Provigil®) 
nafcillin (Unipen®, Nallpen®) 
a 
The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-
dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain 
preparation was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when another 
preparation was used (e.g., low dose, single strength). (FDA Drug Development and Drug Interactions 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabelin
g/ucm093664.htm#classInhibit). 
 

SAP_001.pdf: 
Official Title: A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled 
Study to Evaluate the Efficacy and Safety of Adjunctive Pimavanserin in Subjects 
With Major Depressive Disorder and Inadequate Response to Antidepressant 
Treatment (Sponsor Protocol Numbers: ACP-103-054, ACP-103-059) 
NCT Numbers: NCT03999918, NCT03968159 
Document Date: 22 Jun 2020 
 


 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
Protocol No.: 
ACP-103-059 and ACP-103-054 
Protocol Title: 
A Phase 3, Multicenter, Randomized, Double-blind, 
Placebo-controlled Study to Evaluate the Efficacy and 
Safety of Adjunctive Pimavanserin in Subjects With 
Major Depressive Disorder and Inadequate Response to 
Antidepressant Treatment 
Drug: 
Pimavanserin 
Sponsor:  
ACADIA Pharmaceuticals Inc. 
Version No. and Date 
Version 1.0, 22 June 2020 
 
 
 
 
 
 
 
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hot:ocot ACP-103--059 and ACP-l 03-054 
St:afu:tical Analysis Plan 
SIGNATURE/APPR.OVALPAGE 
IAUTIIORS 
Seniot Diirecto:F, Biostatistics. 
ACADIA Ph0011aceu.tic.als Inc. 
j APPROVERS 
I 
I
j E~eQlltive Di11ecim: Clmicali. R.eserurch 
j ACADIA Pharmace,uticals foe. 
l
Executive DilrectoiF. Biostai.tistics 
ACADIA Phro:maceuticats: I:ne. 
Date 
Vernon U) 
22June202:0 
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Protocol ACP-103-059 and ACP-103-054 
 
Version 1.0 
Statistical Analysis Plan 
 
22 June 2020 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS ........................................................................................................... 3 
LIST OF TABLES ..................................................................................................................... 6 
ABBREVIATIONS ................................................................................................................... 7 
1. INTRODUCTION ............................................................................................................... 9 
2. OBJECTIVES ...................................................................................................................... 9 
2.1 Primary Objective ................................................................................................................ 9 
2.2 Secondary Objective ............................................................................................................ 9 
2.3 Safety Objective................................................................................................................... 9 
3. STUDY DESIGN .............................................................................................................. 10 
3.1 General Study Design ........................................................................................................ 10 
3.2 Schedule of Assessments ................................................................................................... 11 
3.3 Randomization ................................................................................................................... 11 
3.4 Blinding ............................................................................................................................. 11 
3.5 Determination of Sample Size ........................................................................................... 11 
3.6 Coronavirus Disease 2019 ................................................................................................. 11 
4. Analysis SETS ................................................................................................................... 12 
5. DATA HANDLING CONVENTIONS .............................................................................. 12 
5.1 General Data Reporting Conventions ................................................................................ 12 
5.2 Derived Efficacy Variables ................................................................................................ 13 
5.2.1 Hamilton Rating Scale for Depression – 17 Items ......................................................... 13 
5.2.2 Sheehan Disability Scale (SDS) ..................................................................................... 14 
5.2.3 Clinical Global Impressions – Severity (CGI-S) and Clinical Global Impressions – 
Improvement (CGI-I) Scales .......................................................................................... 14 
5.2.4 Changes in Sexual Functioning Questionnaire Short Form (CSFQ-14) ........................ 15 
5.2.5 Karolinska Sleepiness Scale (KSS) ................................................................................ 15 
5.2.6 Barratt Impulsiveness Scale (BIS-11) ............................................................................. 15 
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Protocol ACP-103-059 and ACP-103-054 
 
Version 1.0 
Statistical Analysis Plan 
 
22 June 2020 
 
5.2.7 Montgomery Asberg Depression Rating Scale (MADRS) ............................................. 16 
5.2.8 Extrapyramidal Symptom Rating Scale–Abbreviated (ESRS-A) .................................. 16 
5.3 Analysis Visit Windows ..................................................................................................... 16 
5.3.1 Unscheduled Assessments .............................................................................................. 17 
5.3.2 Multiple Measurements within Visit Windows .............................................................. 17 
5.4 Missing or Incomplete Date for Last Dose of Study Drug ................................................ 17 
5.5 Missing or Incomplete Dates for Prior or Concomitant Medications................................ 18 
5.6 Missing or incomplete Date for Adverse Events ............................................................... 18 
5.7 Missing Severity Assessment for Adverse Events ............................................................. 18 
5.8 Missing Relationship to Study Drug for Adverse Events .................................................. 18 
5.9 Character Values of Clinical Laboratory Variables ............................................................ 18 
6. SUBJECT DISPOSITION ................................................................................................. 19 
7. PROTOCOL DEVIATIONS .............................................................................................. 19 
8. DEMOGRAPHICs AND OTHER BASELINE CHARACTERISTICS ........................... 20 
9. Medical History ................................................................................................................. 21 
10. EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE ................................... 21 
10.1 Exposure to Study drug ................................................................................................... 21 
10.2 Measurement of Treatment Compliance .......................................................................... 21 
11. PRIOR, CONCOMITANT, AND POST-TREATMENT MEDICATION ......................... 21 
12. EFFICACY ANALYSES ................................................................................................... 22 
12.1 Efficacy Variables ............................................................................................................ 22 
12.2 Adjustment for Covariates ............................................................................................... 23 
12.3 Handling of Missing Data ................................................................................................ 23 
12.4 Multiple Comparisons / Multiplicity ............................................................................... 24 
12.5 Examination of Subgroups .............................................................................................. 24 
13. METHODS OF EFFICACY ANALYSES ........................................................................ 25 
13.1 Primary Efficacy Analysis ............................................................................................... 25 
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Protocol ACP-103-059 and ACP-103-054 
 
Version 1.0 
Statistical Analysis Plan 
 
22 June 2020 
 
13.1.1 Primary Analysis ........................................................................................................... 25 
13.1.2 Sensitivity Analyses ...................................................................................................... 27 
13.2 Secondary Efficacy Analyses .......................................................................................... 29 
13.3 Exploratory Efficacy Analyses ........................................................................................ 31 
14. SAFETY ANALYSES ....................................................................................................... 31 
14.1 Adverse Events ................................................................................................................ 31 
14.2 Clinical Laboratory Variables .......................................................................................... 32 
14.3 Vital Signs ........................................................................................................................ 36 
14.4 Electrocardiogram (ECG) ................................................................................................ 36 
14.5 Physical Examination ...................................................................................................... 37 
14.6 Other Safety Endpoints .................................................................................................... 37 
15. CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES ........ 39 
16. INTERIM ANALYSIS ...................................................................................................... 39 
17. DATA MONITORING/REVIEW COMMITTEE ............................................................. 39 
18. COMPUTER METHODS ................................................................................................. 39 
19. CHANGES TO ANALYSES SPECIFIED IN PROTOCOL ............................................. 39 
20. REFERENCES .................................................................................................................. 39 
21. APPENDICES ................................................................................................................... 40 
Appendix A  Schedule of Assessments .................................................................................... 41 
Appendix B Summary of Version Changes ............................................................................. 44 
 
 
 
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LIST OF TABLES 
Table 1 Analysis Visit Windows .............................................................................................. 17 
Table 2 Imputation Predictors – Placebo-based Pattern Imputation ........................................ 27 
Table 3 Imputation Predictors – Pattern Imputation with Delta Adjustment........................... 28 
Table 4 Criteria for Potentially Clinically Important Laboratory Values – Hematology and 
Chemistry ................................................................................................................... 34 
Table 5 Criteria for Potentially Clinically Important Laboratory Values – Urinalysis ............ 35 
Table 6 Criteria for Potentially Clinically Important (PCI) Vital Signs .................................. 36 
Table 7 Criteria for Potentially Clinically Important ECG Values .......................................... 37 
 
 
 
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ABBREVIATIONS 
AE 
Adverse event 
ANCOVA 
analysis of covariance 
ATC 
Anatomical/Therapeutic/Chemical 
BIS-11 
Barratt Impulsiveness Scale 
BMI 
body mass index 
CI 
Confidence Interval 
CGI-I 
Clinical Global Impressions – Global Improvement 
CGI-S 
Clinical Global Impressions – Severity of Illness 
CMH 
Cochran-Mantel-Haenszel 
COVID-19 
coronavirus disease 2019 
CRO 
CSFQ-14 
C-SSRS 
Contract Research Organization 
Changes in Sexual Functioning Questionnaire Short Form  
Columbia Suicide Severity Rating Scale 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
EDC 
electronic data capture 
ESRS-A 
Extrapyramidal Symptom Rating Scale–Abbreviated 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GSD 
Guidance for Site Documentation and Data Management Querying of 
Data Impacted by COVID-19 
HAMD-17 
Hamilton Depression Scale (17 Items) 
IRT 
Interactive Response Technology 
ITT 
Intention-to-treat 
KSS 
Karolinska Sleepiness Scale 
LOCF 
MADRS 
MDD 
MDE 
MedDRA 
MGH-ATRQ 
last observation carried forward 
Montgomery Asberg Depression Scale 
Major Depressive Disorder 
Major Depressive Episode 
Medical Dictionary for Regulatory Activities 
Massachusetts General Hospital Antidepressant Treatment Questionnaire 
MGH-SFI 
Massachusetts General Hospital Sexual Functioning Index 
MINI 
Mini-International Neuropsychiatric Interview 
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MMRM 
mixed model for repeated measures 
MNAR 
missing not at random 
OC 
observed cases 
PCI 
potentially clinically important 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PMM 
Pattern-Mixture Models 
QoL 
quality of life 
QTcB 
QT Interval Corrected for Heart Rate using Bazett’s Formula 
QTcF 
QT Interval Corrected for Heart Rate using Fridericia’s Formula 
QTcNi 
QT Interval Corrected for Heart Rate using individual corrections 
SAE 
serious adverse event 
SAFER 
State versus trait, Assessability, Face validity, Ecological validity, and 
Rule of three Ps (pervasive, persistent, and pathological) 
SAP 
SD 
SDS 
SE 
statistical analysis plan 
Standard Deviation 
Sheehan Disability Scale 
Standard Error 
SIS 
Sheehan Irritability Scale 
SNRI 
serotonin-norepinephrine reuptake inhibitors 
SOC 
SSRI 
system organ class 
selective serotonin reuptake inhibitors 
TEAE   
treatment-emergent adverse event 
 
 
 
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1. INTRODUCTION 
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the 
statistical analyses of combined efficacy and safety data as described in both ACP-103-059 
Protocol Amendment 3 dated 21 June 2020 and ACP-103-054 Protocol Amendment 4 dated 
21 June 2020.   
The two studies have exactly the same design with the exception of where they were 
conducted. Study ACP-103-059 was conducted in the United States (US) and Study 
ACP-103-054 was conducted outside of the US. Unless specified otherwise, discussions about 
study design apply to both of the 2 studies.  
2. OBJECTIVES 
2.1 
Primary Objective 
The primary objective of the two studies is to evaluate the efficacy of adjunctive 
pimavanserin compared to placebo in subjects with major depressive disorder who have an 
inadequate response to antidepressant therapy. 
2.2 
Secondary Objective 
Secondary objective of the two studies is to evaluate the efficacy and benefits of adjunctive 
pimavanserin compared to placebo in subjects with major depressive disorder who have an 
inadequate response to antidepressant therapy on the following: 
• Functional impairment 
• Clinician’s global impression of severity and improvement of depressive symptoms 
• Sexual functioning 
• Sleepiness 
• Treatment response and remission 
• Anxiety 
• Impulsiveness 
• Early response to treatment 
2.3 
Safety Objective 
The safety objective of the two studies is to assess the safety and tolerability of pimavanserin 
compared to placebo in subjects with major depressive disorder who have an inadequate 
response to antidepressant therapy. 
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3. STUDY DESIGN  
3.1 
General Study Design 
The two studies are multicenter, randomized, double-blind, placebo-controlled, parallel-group 
studies in subjects with major depressive disorder (MDD) and inadequate response to a 
selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor 
(SNRI). 
The duration of participation for individual study subjects will be up to 14 weeks, consisting 
of a screening period of up to 4 weeks (i.e., 3 weeks, with possible extension of up to 7 days), 
a 6-week double-blind treatment period, and a safety follow-up period of at least 30 days (for 
those subjects who discontinue prematurely or who do not enroll in the open-label extension 
study). The study completion date is defined as the date the final subject, across all sites, 
completes their final protocol-defined assessment, which includes the safety follow-up 
visit/contact. If the studies are terminated for any reason, subjects remaining in the studies 
will return to standard of care. 
Approximately 40 sites in the United States and approximately 40 sites outside of the United 
States will participate in ACP-103-059 and ACP-103-054 respectively. Approximately 280 
subjects will be randomized in a 1:1 ratio to either the pimavanserin or the placebo treatment 
groups in each of the two individual studies. 
The study design is summarized in Figure 1. 
Figure 1 
Schematic of Study Design 
 
 
Abbreviations: QD=once daily; R=randomization 
Note: Subjects who enroll in an open-label extension will not enter the Safety Follow-up Period. 
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3.2 
Schedule of Assessments  
Schedule of assessments can be found in Appendix A. 
3.3 
Randomization 
Eligible subjects will be randomized at the Baseline visit (Visit 2) in a 1:1 ratio to receive in 
addition to their SSRI/SNRI antidepressant: Pimavanserin (34 mg) or placebo. The 
assignments will be based on a pre-generated permuted-block randomization schedule. 
Randomization will be electronically performed using an Interactive Response Technology 
(IRT) based randomization system. 
3.4 
Blinding  
Blinding is achieved by restricting access of Investigators and Sponsor personnel and/or 
designee to the treatment codes, and providing identical tablets and packaging for the 
pimavanserin and placebo treatments.  
Unblinding of individual treatment assignment during the study is discouraged. The 
Investigator may break the blind in the event of a medical emergency if it is considered 
necessary for the care of the subject. The Investigator should attempt whenever possible to 
contact the Medical Monitor before unblinding a subject’s treatment to discuss the event. 
For the final analysis, the treatment codes for all subjects will be released to ACADIA after all 
subjects have completed the study and the clinical database is locked. 
3.5 
Determination of Sample Size 
A total sample size of 266 evaluable subjects was estimated to provide at least 90% power at a 
two-sided significance level of 0.05 when assuming a treatment effect size of 0.4 (an 
estimated common standard deviation of 8.0 based on data from the Phase 2 study ACP-103-
042) for pimavanserin compared to placebo on the change from Baseline to Week 5 in the 
HAMD-17 total score. Adjusting for a potential non-evaluable rate of up to 5%, 
approximately 280 subjects will be randomized. 
3.6 
Coronavirus Disease 2019  
In March, 2020, the emerging coronavirus disease 2019 (COVID-19) pandemic resulted in 
implementation of urgent safety measures designed to ensure subject safety. Mechanisms to 
record information on the potential impact of the COVID-19 pandemic on data itself, as well 
as data collection and integrity, were implemented (as detailed in the “Guidance for Site 
Documentation and Data Management Querying of Data Impacted by COVID-19” [GSD] of 
the Data Management Plan).  
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Screening and enrollment into studies ACP-103-054 and ACP-103-059 were temporarily 
halted.  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 includes all subjects who were randomized in the 2 studies. 
Subjects will be classified according to the randomized treatment assignment. 
Safety Analysis Set 
The Safety Analysis Set includes all subjects who received at least one dose of study drug in 
the 2 studies. Subjects will be classified according to the actual treatment received. 
Full Analysis Set 
The Full Analysis Set includes all subjects who were randomized, received at least one dose 
of study drug, and have both a Baseline (Week 0) value and at least one post-Baseline value 
for the HAMD-17 total score in the 2 studies. Subjects will be classified according to the 
randomized treatment assignment. 
Per-protocol Analysis Set 
The Per-protocol Analysis Set includes a subset of subjects in the Full Analysis Set without 
any protocol deviations that could have a significant effect on the study conclusions. The Per-
protocol Analysis Set will be determined prior to unblinding the studies for the final analysis. 
Subjects will be classified according to the randomized treatment assignment. 
5. DATA HANDLING CONVENTIONS 
All data collected in the study will be listed. 
5.1 
General Data Reporting Conventions 
Continuous variables will be summarized using the following descriptive statistics:  number 
of subjects, mean, median, standard deviation, standard error, minimum, and maximum.  
Unless specified otherwise, means, medians, and confidence intervals will be presented to one 
more decimal place than the raw data, and the standard deviations and standard errors will be 
presented to two more decimal places than the raw data.  
Categorical and count variables will be summarized by the number of subjects and the percent 
of subjects in each category. Unless specified otherwise, the denominator of the percentage is 
the number of subjects with non-missing data. Categories with zero counts will not have zero 
percentages displayed.  Percentages will be presented with one decimal place.  
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Duration in months will be calculated as ([the number of days / 365.25] *12). 
Unless specified otherwise, all statistical tests will be 2-sided hypothesis tests performed at 
the significance level of 5% for main effects and all confidence intervals will be 2-sided 95% 
confidence intervals. P-values will generally be presented to 4 decimal places; values less 
than 0.0001 will be presented as <0.0001. 
5.2 
Derived Efficacy Variables  
In general, assessment total scores and subscores will be derived within the analysis datasets. 
In the event that total scores and/or subscores are also collected on the electronic case report 
from (eCRF), the derived values will be used for all analyses. Both the raw and derived scores 
will be presented in listings. 
5.2.1 
Hamilton Rating Scale for Depression – 17 Items  
The HAMD-17 is completed with the Structured Interview Guide for the Hamilton 
Depression Rating Scale (SIGH-D) by the Investigator or designee based on an assessment of 
a patient’s symptoms. The time frame for this scale is the past 7 days.  
The HAMD-17 consists of 8 items with a score on a 3 point scale and 9 items with a score on 
a 5 point scale. The total score ranging from 0 to 52 will be calculated as the sum of the scores 
for all 17 items. Higher total scores denote more severe depression. Missing item scores will 
be imputed and rounded to the nearest integer as follows: 
• Missing scores for items with a score on a 3 point scale will be imputed using the 
arithmetic mean of the non-missing scores for items with a score on a 3 point scale 
• Missing scores for items with a score on a 5 point scale will be imputed using the 
arithmetic mean of the non-missing scores for items with a score on a 5 point scale 
The total score will be considered as missing if there are missing scores for 4 or more items.  
The Anxiety/Somatization factor of the HAMD-17 includes 6 items: psychic anxiety, somatic 
anxiety, gastrointestinal somatic symptoms, general somatic symptoms, hypochondriasis, and 
insight. The HAMD-17 Anxiety/Somatization factor score ranging from 0 to 18 will be 
calculated as the sum of the scores for the 6 items. Higher factor scores denote more severe 
anxiety/somatization condition. Missing item scores will be imputed and rounded to the 
nearest integer as follows: 
• Missing scores for items (e.g. gastrointestinal somatic symptoms, general somatic 
symptoms, and insight) with a score on a 3 point scale will be imputed using the 
arithmetic mean of the non-missing scores for items with a score on a 3 point scale 
among the 6 items 
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• Missing scores for items (e.g. psychic anxiety, somatic anxiety, and hypochondriasis) 
with a score on a 5 point scale will be imputed using the arithmetic mean of the 
non-missing scores for items with a score on a 5 point scale among the 6 items 
The HAMD-17 Anxiety/Somatization factor score will be considered as missing if there are 
missing scores for 2 or more items.  
5.2.2 
Sheehan Disability Scale (SDS) 
The SDS is a 3-item subject-facing questionnaire used to evaluate impairments in the domains 
of work, social life/leisure, and family life/home responsibility. Subjects rate each item using 
an 11-point scale ranging from 0 (not at all) to 10 (extremely).  
The primary analysis will be performed on the mean score ranging from 0 to 10 calculated as 
the arithmetic mean of the scores for all 3 items and rounded to the nearest 2 decimal places. 
Higher mean scores denote greater disability. If a subject indicates that no work/school 
occurred,  the mean score will be calculated as the arithmetic mean of the other two item 
responses (Social Life and Family Life/Home Responsibilities) and rounded to the nearest 
2 decimal places. If either of the other two item responses is missing, or if the work/school 
response is missing and the subject does not indicate that no work/school occurred, the mean 
score will be missing.  
The following supplementary analysis will be performed: 
Total Score without Imputation 
The SDS total score ranging from 0 to 30 will be calculated as the sum of the scores for all 
3 items. Higher total score denote greater disability. The total score will be missing if at least 
one of the 3 item responses is missing. 
The mean score imputed based on only two item responses (Social Life and Family 
Life/Home Responsibilities) will be flagged in data listings. These results will be considered 
observed values for data summaries and analyses. 
5.2.3 
Clinical Global Impressions – Severity (CGI-S) and Clinical Global Impressions 
– Improvement (CGI-I) Scales  
The CGI-S and CGI-I are scales used by the Investigator or designee to rate the severity of the 
disorder and the global improvement since beginning of the study.  The CGI-S rates the 
severity of a subject’s depression over the past 7 days and the CGI-S score ranges from 1 to 7: 
 
1 = Normal, not at all ill  
 
5 = Markedly ill 
2 = Borderline mentally ill  
 
6 = Severely ill 
3 = Mildly ill   
 
 
7 = Among the most extremely ill patients 
4 = Moderately ill  
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The CGI-I rates the change in a subject's depression over the past 7 days relative to the 
subject’s symptoms at Baseline and the CGI-I score ranges from 1 to 7: 
 
1 = Very much improved  
 
5 = Minimally worse 
2 = Much improved   
 
6 = Much worse 
3 = Minimally improved  
 
7 = Very much worse 
4 = No change 
Higher CGI-S and CGI-I scores denote more severe depression and less improvement in 
depression respectively. Missing CGI-S and CGI-I scores will not be imputed. 
5.2.4 
Changes in Sexual Functioning Questionnaire Short Form (CSFQ-14) 
The CSFQ-14 is a 14-item version of the CSFQ. This is a patient-facing questionnaire, with a 
male version and a female version. The total score ranging from 14 to 70 will be calculated as 
the sum of the scores for all 14 items. Higher total scores denote better sexual functioning. 
Missing item scores will be imputed using the arithmetic mean of the non-missing item scores 
and rounded to the nearest integer. The total score will be considered as missing if there are 
missing scores for 3 or more items. 
5.2.5 
Karolinska Sleepiness Scale (KSS) 
The KSS is a scale that measures the subject's drowsiness and is frequently used in studies 
measuring subjective sleepiness. Scoring is based on a 9-point verbally anchored scale going 
from "1 = extremely alert" to "9 = very sleepy, great effort to keep awake, fighting sleep". 
Higher scores denote more drowsiness. Missing scores will not be imputed. 
5.2.6 
Barratt Impulsiveness Scale (BIS-11) 
The BIS-11 is a questionnaire designed to assess the personality/behavioral construct of 
impulsiveness.  It is composed of 30 items describing common impulsive or non-impulsive 
(reverse scored items: 1, 7, 8, 9, 10, 12, 13, 15, 20, 29, and 30) behaviors and preferences.  
Items are scored on the following 4-point scale:  Rarely/Never = 1; Occasionally = 2; 
Often = 3; Almost Always/Always = 4. For reverse scored items, a response of 1 is recoded to 
4; 2 is recoded to 3; 3 is recoded to 2; and 4 is recoded to 1. The BIS-11 score ranging from 
30 to 120 will be calculated as the sum of the scores for all 30 items. Higher scores denote 
more impulsiveness. Missing item scores will be imputed with the arithmetic mean of the 
non-missing item scores and rounded to the nearest integer. The BIS-11 score will be 
considered as missing if there are missing scores for 7 or more items. 
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5.2.7 
Montgomery Asberg Depression Rating Scale (MADRS) 
The MADRS is a 10-item, clinician-rated instrument measuring depression severity. It is 
scored on a fixed scale of 7 points (0-6) following a structured clinician interview. The total 
score ranging from 0 to 60 will be calculated as the sum of the scores for all 10 items. Higher 
scores reflect more severe symptomatology. The total score will be considered missing if 
there are at least one missing item scores.  
5.2.8 
Extrapyramidal Symptom Rating Scale–Abbreviated (ESRS-A) 
The ESRS was developed to assess drug induced movement disorders such as parkinsonism, 
akathisia, dystonia and tardive dyskinesia with established reliability, validity, and sensitivity. 
The ESRS-A, an accepted modified form of the original ESRS, is used during the study to 
monitor for any worsening in extrapyramidal symptoms or signs at scheduled and 
unscheduled visits. The CGI-S for each movement subtype (i.e., parkinsonism, dystonia, 
dyskinesia, and akathisia) rates the severity of a subject’s movement disorder and the CGI-S 
score for each movement subtype ranges from 0 to 5: 
 
0 = Absent  
 
1 = Minimal  
2 = Mild 
 
  
3 = Moderate  
4 = Severe 
 
5 = Extreme 
Higher CGI-S scores denote more severe movement disorder. Missing scores will not be 
imputed. 
5.3 
Analysis Visit Windows  
Baseline of the study is defined as the last non-missing result, including results from repeated 
and unscheduled measurements, before first dosing.  
Efficacy, safety, and PK assessments will be summarized by analysis visit as presented in 
Table 1 below.  
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Table 1 
Analysis Visit Windows 
Analysis Visit  
Study Visit 
Target Study Day 
@ 
Study Day Interval 
Baseline (Day 1) 
2 (Week 0) 
1 
< 1 
Week 1 
3 (Week 1) 
8 
2 – 11 
Week 2 
4 (Week 2) 
15 
12 – 18 
Week 3 
5 (Week 3) 
22 
19 – 25 
Week 4 
6 (Week 4) 
29 
26 – 32 
Week 5  
7 (Week 5) 
36 
33 – 39 
Week 6 
8 (Week 6) 
43 
40 – 46 
Safety Follow-up 
9 (Week 10) 
73 
>47 
@ Derivation of study day: study day = assessment date - first dose date + 1 if the assessment date ≥ first dose 
date, otherwise study day = assessment date – first dose date. Study day 1 is the day of first administration of 
study drug (pimavanserin or placebo). 
5.3.1 
Unscheduled Assessments 
Both Scheduled and Unscheduled assessments, including the assessments at early termination 
visits, will be used for planned timepoint analyses. All assessments will be presented in data 
listings. 
5.3.2 
Multiple Measurements within Visit Windows 
In the event that more than one assessment falls within a given window the assessment closest 
to the target study day will be selected for the by-visit analysis. If two assessments are 
equidistant from the target study day then the chronologically last assessment  will be used. 
Exceptions may be made for incomplete assessments, in which case, more complete 
assessments may be given priority.  Details are provided in a separate programming 
conventions document. 
For safety analyses where the 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 assessments will be presented in data listings. 
5.4 
Missing or Incomplete Date for Last Dose of Study Drug  
In the Safety Analysis Set, if the last dose date of study drug is missing for a subject who 
completed or early terminated from the study, then the missing last dose date of study drug 
will be imputed using the last expected dosing date which is defined as the minimum of 
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(last drug dispense date + 7) or EOT/ET date, whichever occurs earlier. For the incomplete 
last dose date of study drug, the imputation algorithms will be detailed in the analysis dataset 
specification document. The missing or incomplete dates will be displayed in the data listings 
as reported on the eCRF rather than the imputed dates. 
5.5 
Missing or Incomplete Dates for Prior or Concomitant Medications  
Missing or incomplete medication start or stop dates will be imputed for the purpose of 
determining whether the medication is taken concomitantly or not (see Section 11 for 
definition). When the chronological order of medication use relative to the study drug 
treatment period is unclear due to missing or incomplete date(s), the medication will be 
considered as concomitant. The imputation algorithms will be detailed in the analysis dataset 
specification document. The missing or incomplete dates as captured on the eCRF will be 
displayed in the data listings.    
5.6 
Missing or incomplete Date 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 or not (see Section 14.1 for definition). 
When the chronological order of an AE onset relative to the study drug treatment period is 
unclear due to missing or incomplete date(s), the AE will be considered as treatment-
emergent. The imputation algorithms will be detailed in the analysis dataset specification 
document. The missing or incomplete dates captured on the eCRF will be displayed in the 
data listings.    
5.7 
Missing Severity Assessment for Adverse Events 
If the severity is missing for an AE starting on or after the date of the first dose of study drug, 
then a severity of “Severe” will be assigned.  The imputed values for severity assessment will 
be used for incidence summaries, while the actual values will be used in data listings. 
5.8 
Missing Relationship to Study Drug for Adverse Events 
If the relationship to study drug is missing for an AE starting on or after the date of the first 
dose of study drug, a causality of “Related” will be assigned.  The imputed values for 
relationship to study drug will be used for incidence summaries, while the actual values will 
be presented in data listings.  
5.9 
Character Values of Clinical Laboratory Variables  
If the reported value of a clinical laboratory variable cannot be used in a statistical analysis 
due to, for example, a character string reported for a numeric variable, an appropriately 
determined coded value may be used in the statistical analysis. The coding algorithms will be 
detailed in the analysis dataset specification document. The actual values as reported in the 
database will be presented in data listings. 
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6. SUBJECT DISPOSITION 
For subjects who participate in the screening phase but are not randomized (screen failures), 
their demographics information (including age, sex, and primary race), screen failure reasons 
(the specific inclusion/exclusion criterion (or criteria) not met or other reasons including the 
reason due to coronavirus disease 2019 [COVID-19]) and protocol version will be listed. If a 
subject is re-screened, then the re-screening subject ID and the final enrollment status 
(whether eventually enrolled) will also be displayed in this listing. In addition, the frequency 
that the screen failure reasons are reported will also be summarized. Note that one subject 
may be deemed ineligible for multiple inclusion/exclusion criteria and may be allowed to 
rescreen with the permission of the Medical Monitor, provided the screen failure was due to a 
temporary condition that subsequently resolved. 
The number of sites (and the countries the sites belongs to) that screened at least 1 subject, 
number of sites that randomized at least 1 subject, number of subjects screened, and number of 
unique subjects screened will be tabulated. In addition, the number of subjects enrolled at each 
site (and the country the site belongs to) will also be tabulated by analysis set and by treatment 
group and overall. 
For randomized subjects, number and percentage of subjects in the Safety Analysis Set, Full 
Analysis Set, and Per-protocol Analysis Set will be summarized by treatment group and overall. 
A listing will be provided displaying all subjects excluded from the Safety, Full or Per-protocol 
Analysis Sets, and will include reason(s) for exclusion. The number and percentage of subjects 
who are excluded from the Per-protocol Analysis Set will be presented in a summary table by 
reason, and by treatment group and overall. 
Within each analysis set, the number and percentage of subjects who completed the studies or 
discontinued (all discontinued and by discontinuation reasons including the reason due to 
COVID-19) will also be summarized by treatment group and overall. 
7. PROTOCOL DEVIATIONS 
Protocol deviations will be reviewed periodically over the course of the studies. 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 for the Randomized Analysis Set in 
three ways: all protocol deviations, COVID-19 related protocol deviations, and non 
COVID-19 related protocol deviations.  
Two listings of major protocol deviations will be provided: all deviations and non COVID-19 
related protocol deviations. A listing of all COVID-19 related protocol deviations including 
the major and the minor will be provided. 
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8. DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
Demographics and baseline characteristics will be summarized by treatment group and overall 
for the Randomized, Safety, Full, and Per-Protocol Analysis Sets using descriptive statistics. 
In addition, demographics and baseline characteristics will also be summarized by treatment 
group and overall for both ACP-103-054 and ACP-103-059 separately using the Full Analysis 
Set. Variables include age, age group (18-40 years and > 40 years), sex, race, ethnicity, 
height, weight, BMI, Baseline Montgomery Asberg Depression Rating Scale (MADRS) total 
score, Baseline HAMD-17 total score, Baseline HAMD-17 total score < 24 and ≥ 24, 
Baseline SDS mean score, and Baseline Clinical Global Impressions-Severity Illness (CGI-S). 
Baseline CGI-S will be summarized as both a continuous variable and a categorical variable. 
Race will also be categorized by White vs. Non-White. The reported age reflects a subject’s 
age at the informed consent date.  
Depression history will be summarized by treatment group for the Randomized, Safety, Full, 
and Per-protocol Analysis Sets using descriptive statistics. Variables include:  
• Age at first onset of depression symptoms (years) 
• Age at MDD diagnosis (years) 
• Number of depression episodes during the subject's lifetime 
o Summary statistics for both the continuous variable and the 
categorical variable (1 to 5 and ≥6) 
• Number of hospitalizations for depression during the subject's lifetime  
o Summary statistics for both the continuous variable and the 
categorical variable ( 0; 1 to 5; and ≥6) 
• Duration of the current episode of depression (months relative to the informed 
consent date) 
• Ever had suicidal ideation or behavior in the past 6 months or lifetime (yes or no) 
Depression history as described above, date of last hospitalization (if number of 
hospitalizations is greater than 0), and onset date for the current episode of depression will 
also be presented in a data listing. 
The Mini-International Neuropsychiatric Interview (MINI) is performed at Screening visit. 
The MINI data will be summarized separately.  
The data captured in SAFER remote interview at Screening visit including the percentage 
improvement, MADRS score, and CGIS score will be summarized. 
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9. MEDICAL HISTORY 
Medical history reported terms will be coded with Medical Dictionary for Regulatory 
Activities (MedDRA), version 19.0 or newer. The subject incidence will be summarized for 
each system organ class (SOC) and preferred term by treatment group and overall for the 
Safety, Full, and Per-protocol Analysis Sets. 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 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 
Extent of exposure and treatment compliance will be summarized as continuous variables by 
treatment group for the Safety Analysis Set.  
10.1 
Exposure to Study drug  
Duration of exposure to study drug will be calculated for each subject as (last dose date – first 
dose date + 1). The number and percentage of subjects within each of the following exposure 
levels in terms of duration of exposure will also be tabulated: <1 week (1 to 6 days), 1 to 
<2 weeks (7 to 13 days), 2 to <3 weeks (14 to 20 days), 3 to <5 weeks (21 to 34 days), and 
>5 weeks (35 days or longer).  Kaplan-Meier curves of duration on study drug will also be 
presented for each treatment group. 
10.2 
Measurement of Treatment Compliance 
Study drug dosing compliance is defined as the total number of tablets actually taken by a 
subject divided by the number of tablets expected to be taken and then multiplied by 100. The 
total number of tablets actually taken is calculated by the total number of tablets dispensed 
minus the number of tablets returned.  The number of tablets expected to be taken is 
calculated as the duration of exposure multiplied by 2 (the planned number of tablets taken 
per day).  
Treatment compliance will also be summarized as a categorical variable. The number and 
percentage of subjects within each of the following compliance levels will be tabulated: 
<80%, 80 to 120%, and >120%.  
11. PRIOR, CONCOMITANT, AND POST-TREATMENT MEDICATION  
Prior medication is defined as any medication with the start and stop dates prior to the date of 
the first dose of study drug. Concomitant medication is defined as any medication with a start 
date prior to the date of the first dose of study drug and continuing past 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 
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considered as post-treatment medication. Medications will be coded using WHO Drug 
Dictionary March 2020.  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 the Safety Analysis Set. Multiple medication usage by a subject in the same 
category will be counted only once. 
Psychiatric Medication History 
The number and percentage of subjects having psychiatric medication history collected on the 
Psychiatric Medication History CRF pages will be tabulated by 
Anatomical/Therapeutic/Chemical (ATC) Level 3, preferred term, treatment group, and 
overall for the Safety Analysis set. Multiple medication usage by a subject in the same 
category will be counted only once. Listing of all psychiatric medications will be provided. 
Prior and Concomitant Medications 
Prior and concomitant medications will be summarized separately in the same way as the 
psychiatric medication history.  
Post-Treatment Medications 
Post-treatment medications will be summarized for the Safety Analysis Set by ATC Level 3, 
preferred term, and the study drug (placebo vs. pimavanserin) of which subjects received their 
last doses. 
COVID-19 Related Medications 
Relationship to COVID-19 will be assessed for selected medications as detailed in the GSD. 
Concomitant and post-treatment medication analyses described above will also be 
summarized by relationship to COVID-19 (Not related to COVID-19 vs. Related to 
COVID-19). 
12. EFFICACY ANALYSES 
Unless otherwise specified, 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 to Week 5 in the HAMD-17 total 
score.   
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Secondary Efficacy Endpoints 
The secondary efficacy endpoints are the following: 
• Change from Baseline to Week 5 in the SDS mean score  
• Change from Baseline to Week 5 in Clinical Global Impression–Severity (CGI-S) 
score for depressive symptoms  
• Clinical Global Impression–Improvement (CGI-I) score for depressive symptoms 
at Week 5  
• Change from Baseline to Week 5 in the Changes in Sexual Functioning 
Questionnaire Short Form (CSFQ-14)  
• Change from Baseline to Week 5 in Karolinska Sleepiness Scale (KSS) score  
• Treatment responder rates at Week 5. Treatment response is defined as a reduction 
from Baseline in HAMD-17 total score of 50% or more. 
• Treatment remission rates at Week 5. Treatment remission is defined as a 
HAMD-17 total score ≤7. 
• Change from Baseline to Week 5 in the Hamilton Depression (HAMD) 
Anxiety/Somatization factor score 
• Change from Baseline to Week 5 in the Barratt Impulsiveness Scale (BIS-11) 
• Change from Baseline to Week 1 in the HAMD-17 total score 
12.2 
Adjustment for Covariates 
The corresponding baseline value will be included as a covariate and study (ACP-103-059 
and ACP-103-054) will be included as a factor for the analysis of HAMD-17 total score, 
CGI-S score, SDS mean score, CSFQ-14 score, KSS score, and BIS-11 score using the mixed 
model for repeated measures (MMRM) as described in Section 13.  
12.3 
Handling of Missing Data 
The primary analyses of  
• Change from Baseline to Week 5 in the HAMD-17 total score  
• Change from Baseline to Week 5 in CGI-S score for depressive symptoms  
• Change from Baseline to Week 5 in the SDS mean score  
• Change from Baseline to Week 5 in the CSFQ-14 score  
• Change from Baseline to Week 5 in KSS score  
• Change from Baseline to Week 1 in the HAMD-17 total score  
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will be performed assuming missing at random (MAR) using the direct likelihood-based 
MMRM. Scores that are missing, after any imputation of individual missing items as 
described in Section 5.2, 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 full study duration (EMA, 2009). 
12.4 
Multiple Comparisons / Multiplicity 
Family-wise type I error will be controlled at the 2-sided significance level of 5% in 
hypothesis testing for 6 efficacy endpoints as a family using a sequential testing strategy. 
The 6 efficacy endpoints will be tested sequentially in the following order:  
1. Change from Baseline to Week 5 in the HAMD-17 total score (primary 
efficacy endpoint) 
2. Change from Baseline to Week 5 in CGI-S score for depressive symptoms 
(secondary efficacy endpoint) 
3. Change from Baseline to Week 5 in the SDS mean score (secondary efficacy 
endpoint) 
4. Change from Baseline to Week 5 in the CSFQ-14 score (secondary efficacy 
endpoint) 
5. Change from Baseline to Week 5 in KSS score (secondary efficacy endpoint) 
6. Change from Baseline to Week 1 in the HAMD-17 total score (secondary 
efficacy endpoint) 
The hypothesis testing for the primary efficacy endpoint will be performed first. If the 
primary efficacy endpoint is not statistically significant at the 2-sided significance level of 
5%, no further testing for the secondary efficacy endpoints will be performed. Otherwise, the 
hypothesis testing for the CGI-S score will be performed. In general, the hypothesis testing 
for an endpoint in the sequence will be performed only if the preceding hypothesis test is 
statistically significant at the 2-sided significance level of 5%. P-values for endpoints not 
formally tested will be interpreted as exploratory. Unadjusted p-values will be reported and 
the testing sequence will be used to determine statistical significance. 
12.5 
Examination of Subgroups 
Treatment effect will be examined with respect to the primary and the selected secondary 
efficacy endpoints listed in Section 12.4 within the subgroups of study (ACP-103-059 and 
ACP-103-054), sex (male and female), race (white and non-white), age (18-40 years and 
> 40 years), the severity of depression at Baseline (Baseline HAMD-17 total score < 24 and 
≥ 24), and the background antidepressant type (SSRI and SNRI). 
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13. METHODS OF EFFICACY ANALYSES 
13.1 
Primary Efficacy Analysis  
13.1.1 Primary Analysis 
Estimand  
Treatment difference in the change from Baseline to Week 5 in the HAMD-17 total score if 
all subjects tolerated or adhered.  
Population: Subjects with MDD and inadequate response to an SSRI/SNRI, as defined by the 
inclusion/exclusion criteria of the study. 
Variable: Change from Baseline to Week 5 in the HAMD-17 total score. 
Intercurrent events: Possible intercurrent events include, but are not limited to, treatment 
discontinuation due to various reasons, treatment non-compliance, and COVID-19.  The 
treatment policy and hypothetical strategies will be used in the primary analysis. Observations 
on the primary efficacy endpoint will be used regardless of the occurrence of intercurrent 
events. Subjects who discontinued early with missing data will be assumed to follow the same 
clinical course as those in the same treatment group who complete the study treatment.   
Summary measure: Treatment difference in the mean change from Baseline to Week 5 in the 
HAMD-17 total score. 
The estimand addresses the hypothesis about the causal effects of the initially randomized 
study drug. It is assumed that all subjects take the study drug as instructed, when in fact there 
will always be some subjects that fail to adhere.  
Hypotheses 
Let Δ ( 𝝁𝝁𝑃𝑃𝑃𝑃𝑃𝑃−𝝁𝝁𝑃𝑃𝑃𝑃𝑃𝑃) be the difference in the mean change from Baseline to Week 5 in the 
HAMD-17 total score between the pimavanserin (µPIM) and placebo (µPBO) groups.  
The null hypothesis is: Δ = 0. 
The alternative hypothesis is: Δ ≠ 0.  
Analysis 
The hypothesis testing will be performed for the Full Analysis Set using the direct likelihood, 
MMRM method assuming missing data are missing at random (MAR). The response variable 
of the MMRM is the change from Baseline in the HAMD-17 total score and the effects 
include treatment group, visit, treatment-by-visit interaction, Baseline HAMD-17 total score, 
the Baseline HAMD-17 total score-by-visit interaction, and study. An unstructured covariance 
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matrix will be used and the Kenward-Roger approximation will be used to adjust the 
denominator degrees of freedom. 
The following is sample SAS code for the MMRM: 
 
        
 
        
 
        
 
        
 
 
In the event that the model fails to converge using the unstructured covariance matrix, the 
following covariance structures will be modeled in the order given (i.e., from least 
parsimonious to most parsimonious): heterogeneous Toeplitz, heterogeneous compound 
symmetry, heterogeneous autoregressive(1), Toeplitz, compound symmetry, 
autoregressive(1), variance components. The first covariance structure that allows for 
convergence will be selected for the final model and the asymptotically consistent sandwich 
estimator for the variance-covariance matrix will be used. 
Summary statistics for the HAMD-17 total score (observed and change from Baseline), 
LS means, the between-group difference in LS mean with the corresponding 95% confidence 
interval, p-value, and the effect size (Cohen’s d) will be presented at each post-Baseline visit 
for the Full Analysis Set.  
The treatment effect size (Cohen’s d) is calculated using the following formula: 
Effect Size = LS mean difference / SD 
 
 
 
 
 
SD is the model-based estimate, i.e., the estimated standard deviation from the unstructured 
covariance matrix. The sign (+ or -) of the effect size will be chosen so that a positive value 
favors pimavanserin.  
LS mean ± SE from the MMRM model over time for the change from Baseline values by 
treatment group will be displayed in line plots for the Full Analysis Set.   
The analysis will also be performed for the subgroups of study (ACP-103-059 and ACP-103-
054), sex (male and female), race (white and non-white), age (18-40 years and > 40 years), 
the severity of depression at Baseline (Baseline HAMD-17 total score < 24 and ≥ 24), and the 
background antidepressant type (SSRI [Citalopram, Escitalopram, Paroxetine, Fluoxetine, or 
Sertraline] and SNRI [Duloxetine, Venlafaxine, Desvenlafaxine, or Venlafaxine XR]). 
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13.1.2 Sensitivity Analyses 
The following 4 sensitivity analyses of the HAMD-17 total score are planned. 
Pattern-Mixture Models (PMM) Assuming Missing Not At Random (MNAR) - Placebo-
based Pattern Imputation 
The sensitivity analysis is implemented for the Full Analysis Set using multiple imputations. 
The underlying assumption is that subjects with missing data due to early withdrawal evolve 
in the same way as placebo subjects that remain in the study.   
The following steps are involved and the imputed values will be constrained to be within the 
limits of 0 - 52: 
1 Non-monotone (intermediate) missing data at Baseline, Week 1, Week 2, …, and 
Week 6 will be multiply imputed using the Markov chain Monte Carlo (MCMC) 
method and a random seed of 103059 to create 100 monotone datasets. The imputation 
model will include the effect for treatment group. 
2 The monotone missing data will be imputed using a parametric, sequential linear 
regression method in which the missing data are imputed only on data from the 
placebo arm. A single imputation will be performed sequentially at each visit for each 
of the 100 imputed datasets using the random seed of 103059. The predictors and their 
order in the PROC MI VAR statement for each visit are summarized in Table 2. 
Table 2 
Imputation Predictors – Placebo-based Pattern Imputation 
Visit (Week) 
Predictors  
1 
Study and Baseline HAMD-17 total score 
2 
Study, Baseline, and Week 1 HAMD-17 total scores 
3 
Study, Baseline, Week 1, and Week 2 HAMD-17 total scores 
4 
Study, Baseline, Week 1, Week 2, and Week 3 HAMD-17 total scores 
5 
Study, Baseline, Week 1, Week 2, …, and Week 4 HAMD-17 total scores 
 
3 The change from Baseline to Week 5 values will then be calculated and analyzed for 
each of the 100 fully imputed datasets using the analysis of co-variance (ANCOVA) 
model. The ANCOVA model will have treatment group and study as factors and 
Baseline HAMD-17 total score as a covariate.  
4 The results will be summarized using the SAS MIANALYZE procedure to yield a 
combined estimate for treatment effect with its associated 95% confidence interval  
and p-value. 
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PMM Assuming MNAR - Pattern Imputation with Delta Adjustment 
The sensitivity analysis is implemented for the Full Analysis Set using multiple imputations. 
The underlying assumption is that subjects with missing data due to early withdrawal from the 
pimavanserin treatment would have, on average, their unobserved/imputed HAMD-17 total 
score worse by a delta amount (+1, +2, and +3 to be evaluated). Subjects with missing data 
due to early withdrawal from the placebo treatment will have their imputed values following 
the projection as if they continue in the study.   
The following steps are involved and the imputed values will be constrained to be within the 
limits of 0 - 52: 
1 Non-monotone (intermediate) missing data at Baseline, Week 1, Week 2, …, and 
Week 6 will be multiply imputed using the Markov chain Monte Carlo (MCMC) 
method and a random seed of 103059 to create 100 monotone datasets. The imputation 
model will include the effect for treatment group. 
2 The monotone missing data will be imputed using a parametric, sequential linear 
regression method in which the missing data are imputed on data from their own 
treatment groups. A single imputation will be performed sequentially at each visit for 
each of the 100 imputed datasets using the random seed of 103059. The predictors and 
their order in the PROC MI VAR statement for each visit are summarized in Table 3. 
Penalties will then be applied to subjects on the pimavanserin treatment with missing 
data by shifting their multiply-imputed HAMD-17 total score at Week 5 by +1, +2, 
and +3 (with the limit of no more than 52). 
Table 3 
Imputation Predictors – Pattern Imputation with Delta Adjustment 
Visit (Week) 
Predictors  
1 
Study, Treatment, Baseline HAMD-17 total score 
2 
Study, Treatment, Baseline, and Week 1 HAMD-17 total scores 
3 
Study, Treatment, Baseline, Week 1, and Week 2 HAMD-17 total scores 
4 
Study, Treatment, Baseline, Week 1, Week 2, and Week 3 HAMD-17 total scores 
5 
Study, Treatment, Baseline, Week 1, Week 2, …, and Week 4 HAMD-17 total scores 
 
3 The change from Baseline to Week 5 values will then be calculated and analyzed for 
each of the 100 fully imputed datasets using the ANCOVA model. The ANCOVA 
model will have treatment group and study as factors and Baseline HAMD-17 total 
score as a covariate.  
4 The results will be summarized using the SAS MIANALYZE procedure to yield a 
combined estimate for treatment effect with its associated 95% CI and p-value. 
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COVID-19 Related Sensitivity Analysis 1 
The sensitivity analysis will be performed for the Full Analysis Set. The underlying 
assumption is that the subjects with HAMD-17 completed at Week 5 clinic visit are different 
from those with HAMD-17 completed remotely due to COVID-19 with respect to the 
measurement of HAMD-17 total score at Week 5.   
An indicator variable of remote will be created. The values of the indicator variable are: 
 
“Yes” = subjects with Week 5 HAMD-17 completed remotely due to COVID-19 or 
 
“No ” = subjects with HAMD-17 completed at Week 5 clinic visit or 
 
“N/A” = subjects with missing HAMD-17 total score at Week 5  
The following MMRM that is similar to that in the primary analysis will be performed: The 
response variable of the MMRM is the change from Baseline in the HAMD-17 total score and 
the effects include treatment group, visit, treatment-by-visit interaction, Baseline HAMD-17 
total score, the Baseline HAMD-17 total score-by-visit interaction, study, and remote. An 
unstructured covariance matrix will be used and the Kenward-Roger approximation will be 
used to adjust the denominator degrees of freedom. 
COVID-19 Related Sensitivity Analysis 2 
The sensitivity analysis will be performed using the data cut on March 20, 2020 when the 
official notification was sent to sites to stop screening/randomization in the studies due to 
COVID-19. The underlying assumption is that HAMD-17 completed after the date of 
notification may be drastically different such that the measure of HAMD-17 total score no 
longer measures the treatment effect correctly as on or before the date of notification. 
The MMRM exactly the same as that in the primary analysis will be performed. 
A supportive analysis similar to the primary analysis will be performed for the Per-protocol 
Analysis Set. 
13.2 
Secondary Efficacy Analyses 
Analyses for the secondary efficacy endpoints in this section will be performed for the Full 
Analysis Set using the observed values. Missing data will not be imputed. 
SDS Mean Score, CGI-S Score, CSFQ-14 Total Score, KSS Score, HAMD 
Anxiety/Somatization Factor Score, and BIS-11 Score  
The change from Baseline will be analyzed using the MMRM method similar to the primary 
analysis for the primary efficacy endpoint. The MMRM model will include effects for 
treatment group, visit, the treatment-by-visit interaction, the corresponding Baseline 
(mean/total) score, the Baseline (mean/total) score-by-visit interaction, and study.  
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Summary statistics (observed and change from Baseline), LS means, the between-treatment 
difference in LS mean with the corresponding 95% confidence interval,  p-value, and the 
effect size (Cohen’s d) will be presented at each post-Baseline visit. 
For the SDS mean score, the analysis will also be performed for the subgroups of the 
background antidepressant type (SSRI and SNRI). 
For the CSFQ-14 total score, the analysis will also be performed for the subgroups of the 
background antidepressant type (SSRI and SNRI), sex (male and female), the background 
antidepressant type by sex (SSRI and male, SSRI and female, SNRI and male, and SNRI and 
female), and the sexual dysfunction status at Baseline (dysfunction and not dysfunction; Refer 
to Section 14.6 for the definition of sexual dysfunction). 
CGI-I Score 
The CGI-I score will be analyzed in a similar way as the primary analysis of the primary 
efficacy endpoint. The differences are (1) the response is CGI-I score (as opposed to the 
change from Baseline) and (2) the Baseline CGI-S score will be used as the covariate in the 
MMRM model. 
Treatment Response Rate 
Treatment response is defined as a reduction from Baseline in the HAMD-17 total score of 
50% or more. Missing HAMD-17 total scores will be considered as non-responses and the 
subjects with missing HAMD-17 total scores will be included in the denominator of the 
response rate. The response rate will be compared between the pimavanserin and placebo 
groups using the Cochran-Mantel-Haenszel (CMH) test stratified by study. The treatment 
difference in the response rate and the corresponding Newcombe 95% confidence interval 
will be presented. 
Treatment Remission Rate 
Treatment remission is defined as a HAMD-17 total score ≤7. The analysis method for 
treatment remission rate is the same as that for the treatment response rate but with remission 
replacing response. 
Change from Baseline to Week 1 in the HAMD-17 total score 
The treatment comparison with respect to the mean change from Baseline to Week 1 in the 
HAMD-17 total score will be performed using the estimates from the primary analysis 
MMRM model for the primary efficacy endpoint described in Section 13.1.1. 
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13.3 
Exploratory Efficacy Analyses  
Exploratory analyses will be performed using the methods discussed in Sections 13.1 and 
13.2 for the following: 
• Change from Baseline to Weeks other than Weeks 1 and 5 in HAMD-17 total score 
• Change from Baseline to Weeks other than Week 5 in SDS mean score, CGI-S score, 
CSFQ-14 score, KSS score, HAMD Anxiety/Somatization factor score, and BIS-11 
score 
• CGI-I score at Weeks other than Week 5 
• Treatment responder rate and remission rate at Weeks other than Week 5 
14. SAFETY ANALYSES 
All safety analyses will be performed using the actual treatment for the Safety Analysis Set.  
14.1 
Adverse Events  
Adverse events will be coded using MedDRA dictionary, Version 19.0 or newer. 
An AE (classified by preferred term) will be considered a treatment-emergent AE (TEAE) if 
started after first study dose administration and no later than last study dose date + 30. AEs 
reported on Day 1 based on Baseline (pre-dose) findings (e.g., clinically significantly 
abnormal vital signs, laboratory test results, or electrocardiogram parameters) will not be 
considered as TEAEs. 
The number and percentage of subjects reporting TEAEs in each treatment group will be 
tabulated by system organ class (SOC) and preferred term; by SOC, preferred term, and 
maximum severity; and by SOC, preferred term, and relationship to study drug.  If more than 
1 AE occurs with the same preferred term for the same subject, then the subject will be 
counted only once for that preferred term using the most severe and most related occurrence 
for the summarization by severity and by relationship to study drug. 
The relationship of selected AEs to COVID-19 will be assessed as detailed in the GSD. 
TEAEs tabulated by SOC and preferred term will be presented with and without COVID-19 
related TEAEs. In addition, COVID-19 related TEAEs will also be tabulated separately. 
TEAEs will also be tabulated by treatment group without displaying the SOC terms; this table 
will be sorted in descending order of frequency of preferred term within the pimavanserin 
group.  
The incidence of most frequently reported (preferred terms reported by ≥ 5% of subjects in 
any treatment group) TEAEs, treatment emergent SAEs, and TEAEs leading to 
discontinuation of study drug will be summarized by SOC, preferred term, and treatment 
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group. The tables will be sorted alphabetically by SOC and then by descending frequency 
within each SOC. In addition, the incidence of fatal treatment-emergent AEs (i.e., events that 
cause death) will be summarized separately by preferred term and treatment group. These 
summary tables except for the most frequently reported TEAEs table will also be presented 
for COVID-19 related events.  
An AE listing by subject will display all events, including those which occur during 
screening, 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: date of 
onset, date resolved, date of last dose, severity, frequency, outcome, relationship to study 
drug, and action taken with study drug. Separate listings will be presented for subjects with 
treatment-emergent SAEs, subjects with TEAEs leading to discontinuation, subject who died 
(if any), and subjects with all COVID-19 related events. 
14.2 
Clinical Laboratory Variables 
Due to COVID-19 disruptions it is possible that some test results may be collected from a 
local laboratory. Local laboratory results will not be included in any data analysis. Local 
laboratory results will, however, be included in data listings. 
Clinical laboratory assessments are performed at Screening Visit 1, Baseline (Week 0), and 
Week 6 (EOT/ET).  
• Clinical chemistry serum tests include the following: 
o Sodium (Na), potassium (K), chloride (Cl), phosphorus (P), calcium (Ca), 
carbon dioxide (CO2), blood urea nitrogen (BUN), creatinine (CR), uric acid 
o Alanine aminotransferase (ALT/SGPT), aspartate aminotransferase 
(AST/SGOT), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase 
(ALP), total bilirubin (TBIL), lactate dehydrogenase (LDH) 
o HbA1c (Screening only) 
o Glucose 
o Albumin (ALB), total protein 
o Prolactin 
o Creatine kinase (CK)/creatine phosphokinase (CPK) 
o Lipid panel 
- Total cholesterol, HDL-cholesterol, triglycerides, LDL-cholesterol, 
Cholesterol/HDL ratio, Non-HDL cholesterol 
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• Hematology tests include the following: 
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 tests include the following: 
o Blood, RBCs, WBCs, protein, glucose, ketones, specific gravity, pH 
Clinical laboratory values (in Système International [SI] units) and the change from Baseline 
values will be summarized by treatment group at Week 6 (EOT/ET) using descriptive 
statistics. 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, the number and percentage of subjects will be tabulated by 
category at Baseline and Week 6 (EOT/ET), and the denominator is the number of subjects 
with non-missing values for the given parameter, visit and treatment group. For glucose and 
lipid panel, the summary table will also be presented by fasting status (fasting vs. 
non-fasting). 
Laboratory values will also be summarized in shift tables by treatment group, to determine the 
number and percentage of subjects with values classified as below, within, and above normal 
ranges at Week 6 (EOT/ET) visit relative to the same classification at the Baseline visit. For 
the by-visit shit 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, all post-Baseline values will be considered, 
including unscheduled and out of window values and the denominator is the number of 
subjects with non-missing Baseline value and at least 1 post-Baseline value for the given 
parameter and treatment group. For hemoglobin, hematocrit and uric acid, the shift summaries 
will be presented for each gender as well as for both genders combined. For glucose and lipid 
panel, the shift table will be presented by fasting status (fasting vs. non-fasting). 
Clinical laboratory values are potentially clinically important (PCI) if they meet either the low 
or high PCI criteria listed in Tables 4 and 5. The number and percentage of subjects with 
post-Baseline PCI values for each of the categories in Table 5 and 6 will be summarized by 
treatment group for selected parameters. 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 overall post-Baseline summary, the numerator of the 
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percentage is the number of subjects with at least 1 post-Baseline PCI laboratory value for the 
given parameter and treatment group, and the denominator is the number of subjects with at 
least 1 post-Baseline laboratory value for the given parameter and treatment group. For 
hemoglobin, hematocrit and uric acid, the count and percentage of subjects with PCI values 
will be presented for each gender as well as for both genders combined. Subjects with 
PCI values will be presented in an additional listing.  
Table 4 
Criteria for Potentially Clinically Important Laboratory Values – 
Hematology and Chemistry 
 
Analyte 
Conventional 
Unit 
Low PCI 
Criteria 
High PCI 
Criteria 
 
SI Unit 
Low PCI 
Criteria 
High PCI 
Criteria 
Hematology (whole 
blood) 
 
 
 
 
 
 
Hemoglobin (male) 
g/dL 
<11 
>18 
g/L 
<110 
>180 
Hemoglobin 
(female) 
g/dL 
<10 
>17 
g/L 
<100 
>170 
Hematocrit (male) 
% 
<30 
>55  
L/L 
<0.3 
>0.55  
Hematocrit (female) 
% 
<30 
>50  
L/L 
<0.3 
>0.5  
Leukocyte (White 
Blood Cell Count) 
x 103/uL 
≤2.8 
≥15 
x 109/L 
≤2.8 
≥15 
Neutrophils 
x 103/uL 
≤1.5 
No upper 
limit 
x 109/L 
≤1.5 
No upper 
limit 
Platelet Count 
x 103/uL 
≤75 
≥700 
109/L 
≤75 
≥700 
Chemistry (serum 
or plasma) 
 
 
 
 
 
 
ALT (SGPT) 
U/L 
No lower 
limit  
≥3 X ULN 
U/L 
No lower 
limit  
≥3 X ULN 
AST (SGOT) 
U/L 
No lower 
limit  
≥3 X ULN 
U/L 
No lower 
limit  
≥3 X ULN 
Total Bilirubin 
mg/dL 
No lower 
limit 
≥1.5 ULN 
umol/L 
No lower 
limit 
≥1.5 ULN 
BUN 
mg/dL 
No lower 
limit 
≥30.0 
mmol/L 
No lower 
limit 
≥10.71 
Creatine Kinase 
(CK) 
U/L 
No lower 
limit 
≥3 ULN 
U/L 
No lower 
limit 
≥3 ULN 
Sodium 
mEq/L 
≤125 
≥155 
mmol/L 
≤125 
≥155 
Potassium 
mEq/L 
≤3.0 
≥5.5 
mmol/L 
≤3.0 
≥5.5 
Calcium, total 
mg/dL 
<8.0 
>11.0 
mmol/L 
<2.0 
>2.75 
Lactate 
Dehydrogenase 
(LDH) 
U/L 
No lower 
limit 
≥3 X ULN 
U/L 
No lower 
limit 
≥3 X ULN 
Alkaline 
Phosphatase 
U/L 
No lower 
limit 
≥3 X ULN 
U/L 
No lower 
limit 
≥3 X ULN 
Uric acid (male) 
mg/dL 
No lower 
limit 
≥10.5 
umol/L 
No lower 
limit 
≥624.75 
Uric acid (female) 
mg/dL 
No lower 
limit 
≥8.5 
umol/L 
No lower 
limit 
≥505.75 
Albumin 
g/dL 
≤2.6 
≥6.0 
g/L 
≤26 
≥60 
Total Protein 
g/dL 
≤5.0 
≥10.0 
g/L 
≤50 
≥100 
 
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Table 4 
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 
Chloride 
mEq/L 
≤85 
≥120 
mmol/L 
≤85 
≥120 
Glucose (random) 
mg/dL 
≤45.1 
≥200.0 
mmol/L 
≤2.48 
≥11 
Serum Creatinine 
mg/dL 
Not 
Applicable 
>1.5 ULN 
umol/L 
Not 
Applicable 
>1.5 ULN 
Triglycerides 
mg/dL 
Not 
Applicable 
>300 
mmol/L 
Not 
Applicable 
>3.39 
Gamma-Glutamyl 
Transferase (GGT) 
U/L 
Not 
Applicable 
≥3 ULN 
U/L 
Not 
Applicable 
≥3 ULN 
Table 5  
Criteria for Potentially Clinically Important Laboratory Values – Urinalysis 
Urinalysis (qualitative dipstick) 
Low PCI Criteria 
High PCI Criteria 
Blood (occult blood) 
Not Applicable 
≥ Moderate 
Protein 
Not Applicable 
≥ 100 mg/dL 
Glucose 
Not Applicable 
≥ 500 mg/dL 
 
Clinical laboratory data will be displayed in data listings with date and study day of 
collection.  All units will be displayed according to SI conventions for units.  Out of range 
values will be flagged in the data listings (i.e., ‘L’ or ‘H’).  A separate listing will be provided 
for a subset of the chemistry, hematology, and urinalysis analytes with values classified as 
PCI.  
The number and percentage of subjects with the change from Baseline to Week 6 meeting the 
following criteria in the blood lipid parameters and the glucose will be summarized by 
treatment group and fasting status (fasting vs. non-fasting): 
• Total Cholesterol – (<200 mg/dL to ≥240 mg/dL) 
• Triglycerides – (<150 mg/dL to ≥200 mg/dL) 
• LDL Cholesterol – (<100 mg/dL to ≥160 mg/dL) 
• HDL Cholesterol – (≥40 mg/dL to <40 mg/dL) 
• Glucose fasting – (<100 mg/dL to ≥126 mg/dL) 
• Glucose non-fasting – (<140 mg/dL to ≥140 mg/dL) 
• Glucose fasting – (≥100 mg/dL and <126 mg/dL to ≥126 mg/dL) 
• Glucose non-fasting - (≥140mg/dL and <200 mg/dL to ≥200 mg/dL) 
The pregnancy results (positive or negative) for female subjects will be presented in a listing.  
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14.3 
Vital Signs 
Vital signs including weight and the derived BMI will be collected throughout the study at 
every visit. Observed vital signs and the changes from Baseline at each post-Baseline visit 
will be summarized by treatment group using descriptive statistics. 
Vital sign values will be considered PCI if they meet the criteria listed in Table 6. The number 
and percentage of subjects with post-Baseline vital signs that are PCI will be summarized by 
treatment group at each post-Baseline visit and for overall post-Baseline.  For the overall 
post-Baseline summaries, all post-Baseline values will be considered, including unscheduled 
and out of window values. Subjects with multiple PCI values for a given parameter will be 
counted only once for that parameter. For the by-visit summary, the numerator for the 
percentage is the number of subjects with a post-Baseline PCI vital sign for the given 
parameter, visit and treatment group, and the denominator is the number of subjects with 
non-missing values for the given parameter, visit and treatment group. For the overall 
post-Baseline summary, the numerator for the percentage is the number of subjects with at 
least 1 post-Baseline PCI vital sign for the given parameter and treatment group, and the 
denominator is the number of subjects with at least 1 post-Baseline vital sign for the given 
parameter and treatment group.   A listing of subjects with any PCI value will be provided. 
Table 6    Criteria for Potentially Clinically Important (PCI) Vital Signs 
Vital Sign Parameter 
 
Unit 
Criteria 
Observed Value 
And/Or 
Change Relative to Baseline 
Systolic blood 
pressure 
(supine or sitting) 
mmHg 
≥180 
And 
Increase of ≥20 
≤90 
And 
Decrease of ≥20 
Diastolic blood 
pressure (supine or 
sitting) 
mmHg 
≥105 
And 
Increase of ≥15 
≤50 
And 
Decrease of ≥15 
Pulse (supine or 
sitting) 
bpm 
≥120 
And 
Increase of ≥15 
≤50 
And 
Decrease of ≥15 
Weight  
kg 
Not Applicable 
Increase of ≥7% 
Decrease of ≥7% 
14.4 
Electrocardiogram (ECG) 
12-lead ECGs are collected at Screening Visit 1, Baseline (Week 0), Week 1, and Week 6 
(EOT/ET). Observed values of ECG variables (e.g., heart rate, PR interval, QRS interval, 
QT interval, and QTc interval) and the changes from Baseline at each assessment time point 
will be summarized by treatment group.  
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: 
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• Observed: ≤450, 451 - ≤480, 481 - ≤500, and >500; >450; >480. 
• Change from Baseline: ≤10, 11 – 30, 31 – 60, and >60; >30. 
The above summaries will also be presented for the following subgroups: subjects with 
background antidepressant of Citalopram, subjects with background antidepressant of 
Escitalopram, and subjects with background antidepressant of Venlafaxine. 
Electrocardiogram variable values will be considered PCI if they meet the criteria listed in 
Table 7. The number and percentage of subjects with post-baseline PCI values will be 
summarized by treatment group at each post-Baseline visit and for overall post-Baseline. For 
the by-visit summary, the numerator for the percentage is the number of subjects with a 
post-Baseline PCI ECG for the given parameter, visit and treatment group, and the 
denominator is the number of subjects with non-missing values for the given parameter, visit 
and treatment group. For the overall post-Baseline summary, the numerator for the percentage 
is the number of subjects with at least 1 post-Baseline PCI ECG for the given parameter and 
treatment group, and the denominator is the number of subjects with at least 1 post-Baseline 
ECG value for the given parameter and treatment group. A listing of all subjects with any 
PCI value will be provided.  
Table 7  
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 examinations are performed at Screening Visit 1, Baseline (Week 0), and Week 6 
(EOT/ET). Physical examination results (normal, abnormal, and not done) will be 
summarized in a frequency table by treatment group, body system and visit.  
14.6 
Other Safety Endpoints 
Unless otherwise specified, scores derived based on sub-scores for the safety endpoints in this 
section will be considered missing if any corresponding sub-scores are missing. No 
imputations will be performed.  
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Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS Baseline/Screening version will be completed at the Screening visit and the 
version assessing information since the last visit will be completed at all following visits 
(including the Baseline visit).   
There are 5 questions about suicidal ideation, representing 5 types of suicidal ideation: wish 
to be dead; non-specific active suicidal thoughts; active suicidal ideation with any methods 
(not plan) without intent to act; active suicidal ideation with some intent to act, without 
specific plan; active suicidal ideation with specific plan and intent.  If a subject answers “yes” 
to any of these 5 questions at any post-Baseline visit including unscheduled and out of 
window visits, this subject will be counted as having suicidal ideation in this study. 
There are 5 questions about suicidal behavior, representing 5 types of suicidal behavior: 
actual attempt; interrupted attempt; aborted attempt; preparatory acts or behavior; suicide.  If 
a subject answers “yes” to any of these 5 questions at any post-Baseline visit including 
unscheduled and out of window visits, this subject will be counted as having suicidal behavior 
in this study. 
Suicidality is defined as a subject who reported at least 1 occurrence of suicidal ideation or at 
least 1 occurrence of suicidal behavior at any post-Baseline visit including unscheduled and 
out of window visits.   
All data will be listed. The event counts and the number and percentage of subjects reporting 
any post-Baseline suicidal ideation, suicidal behavior, or suicidality will be summarized by 
treatment group. 
Change from Baseline to Week 5 in Extrapyramidal Symptom Rating Scale-Abbreviated 
(ESRS-A) score 
The ESRS-A will be completed at each visit throughout the study except for the Screening 
visit. Observed values and change from Baseline in the ESRS-A CGI-S score for each 
movement subtype (i.e., parkinsonism, dystonia, dyskinesia, and akathisia) will be 
summarized by treatment group and visit. The change from Baseline in the ESRS-A CGI-S 
score for each movement subtype will be analyzed using the MMRM method. The response 
variable of the MMRM is the change from Baseline in the ESRS-A CGI-S score and the 
effects include treatment group, visit, treatment-by-visit interaction, Baseline ESRS-A CGI-S 
score, the Baseline ESRS-A CGI-S score-by-visit interaction, and study. An unstructured 
covariance matrix will be used and the Kenward-Roger approximation will be used to adjust 
the denominator degrees of freedom. 
Sexual Dysfunction Based on the CSFQ-14 Total Score and Summary for Subgroups 
Sexual dysfunction is defined as a CSFQ-14 total score of <47 for men and <41 for women. 
The following analyses will be performed overall for the Safety Analysis set and for the 
subgroups of the background antidepressant type (SSRI and SNRI), sex (male and female), 
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and the background antidepressant type by sex (SSRI and male, SSRI and female, SNRI and 
male, and SNRI and female): 
1. The number and percentage of subjects with sexual dysfunction will be summarized 
by treatment group at Baseline and each post-Baseline visit. The numerator for the 
percentage is the number of subjects with sexual dysfunction for the visit and 
treatment group, and the denominator is the number of subjects with non-missing 
values for the visit and treatment group.  
 
2. The sexual dysfunction classification will also be summarized in shift tables by 
treatment group, to determine the number and percentage of subjects with and without 
sexual dysfunction at Week 5 visit and Week 6 (EOT/ET) visit relative to the same 
classification at the Baseline visit. The denominator is the number of subjects with 
non-missing values at Baseline and the given visit for the given treatment group.  
15. CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
Blood concentration for the concomitant SSRIs/SNRIs collected at the Screening visit will be 
listed.  
16. INTERIM ANALYSIS 
No formal interim analysis is planned. 
17. DATA MONITORING/REVIEW COMMITTEE 
There is no data monitoring committee in the studies. 
18. COMPUTER METHODS  
Statistical analyses will be performed using Version 9.4 (or newer) of SAS (SAS® Institute, 
Inc., Cary, North Carolina) on a suitably qualified and validated environment. 
Validation and quality control of the tables, listings and figures containing the results of the 
statistical analyses will follow appropriate standard operating procedures. 
19. CHANGES TO ANALYSES SPECIFIED IN PROTOCOL 
No changes are made to the analyses specified in the protocols.   
20. REFERENCES 
EMA (2009). Guideline on Missing Data in Confirmatory Clinical Trials, European 
Medicines Agency, London, UK. 
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FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 
Pandemic | Guidance for Industry, Investigators, and Institutional Review Boards (March 
2020). 
21. APPENDICES 
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Appendix A   
Schedule of Assessments 
Period Screening Baseline 
Double-blind Treatment Period 
 
Safety 
Follow-upa 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
(EOT/ET) 
8 
Unscheduled 
Visitj 
9 
Visit Day/Week 
Day -28 
to -3 
Week 
0 
Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
5 
Week 
6 
Week 
10 
Type of Visit 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Phone call 
Visit window (# days) 
+7 
 
±3 
±3 
±3 
±3 
±3 
±3 
 
+7 
Informed consent and if 
applicable, privacy forms 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Medical history, medication 
history, and demographics 
X 
 
 
 
 
 
 
 
 
 
Psychiatric history 
X 
 
 
 
 
 
 
 
 
 
MGH ATRQb 
X 
 
 
 
 
 
 
 
 
 
SAFER remote interviewc 
X 
 
 
 
 
 
 
 
 
 
MINI 
X 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
 
 
 
 
X 
 
 
Vital signs and weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
12-lead ECGd 
X 
X 
X 
 
 
 
 
X 
 
 
Clinical laboratory testse 
X 
X 
 
 
 
 
 
X 
 
 
Pregnancy testf 
X 
X 
 
 
 
 
 
X 
 
 
Background antidepressant blood 
levelg 
X 
 
 
 
 
 
 
 
 
 
Urine toxicity (drug) screen 
X 
X 
 
 
 
 
 
X 
 
 
MADRS 
X 
X 
 
 
 
 
 
 
 
 
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Appendix A   
Schedule of Assessments (Continued) 
Period Screening Baseline 
Double-blind Treatment Period 
 
Safety 
Follow-upa 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
(EOT/ET) 
8 
Unscheduled 
Visitj 
9 
Visit Day/Week 
Day -28 
to -3 
Week 
0 
Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
5 
Week 
6 
Week 
10 
Type of Visit 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Phone call 
Visit window (# days) 
+7 
 
±3 
±3 
±3 
±3 
±3 
±3 
 
+7 
HAMD-17h 
 
X 
X 
X 
X 
X 
X 
X 
 
 
SDS 
 
X 
X 
X 
X 
X 
X 
X 
 
 
CGI-S 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
CGI-I 
 
 
X 
X 
X 
X 
X 
X 
 
 
CSFQ-14 
 
X 
X 
X 
X 
X 
X 
X 
 
 
KSS 
 
X 
X 
X 
X 
X 
X 
X 
 
 
BIS-11 
 
X 
X 
 
X 
 
X 
X 
 
 
ESRS-A 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRSi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense study drug 
 
X 
X 
X 
X 
X 
X 
 
Xk 
 
Study drug accountability 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Review of background 
antidepressant adherence  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: BIS-11=Barratt Impulsiveness Scale; CGI-I=Clinical Global Impression–Improvement; CGI-S=Clinical Global Impression–Severity; 
CSFQ-14=Changes in Sexual Functioning Questionnaire Short Form; C-SSRS=Columbia–Suicide Severity Rating Scale; ECG=electrocardiogram; 
eCRF=electronic case report form; EOT=end of treatment; ESRS-A=Extrapyramidal Symptom Rating Scale–Abbreviated; ET=early termination; 
HAMD-17=Hamilton Depression Scale (17 items); KSS=Karolinska Sleepiness Scale; MADRS=Montgomery-Asberg Depression Rating Scale; MGH 
ATRQ=Massachusetts General Hospital Antidepressant Treatment Response Questionnaire; MINI=Mini-International Neuropsychiatric Interview; 
SAFER=State versus trait, Assessability, Face validity, Ecological validity, and Rule of three Ps (pervasive, persistent, and pathological); SDS=Sheehan 
Disability Scale; SNRI=serotonin-norepinephrine reuptake inhibitor; SSRI=selective serotonin reuptake inhibitor  
Table footnotes on next page. 
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a 
This visit is a safety follow-up telephone call visit for subjects who discontinue prematurely from the study or who do not participate in the open-label 
extension study. This visit will occur at least 30 days after the last dose of study drug. 
b 
Inadequate response is defined as a response of <50% to a course of treatment of at least 8 weeks at the minimum effective dose (as listed on the 
ATRQ), which has been stable for the 4 weeks prior to the SAFER interview. 
c 
The SAFER remote interview may be conducted via telephone off-site or on-site. If conducted on-site, the site staff should not be present during the 
interview. 
d 
At Visit 1, ECG should be completed in triplicate and collected within a 3-minute period. At all other visits, a single 12-lead ECG should be completed. 
ECGs should be completed with the subject in a supine position after 5 minutes of rest. The ECG should occur before blood sampling or at least 30 
minutes after blood sampling. 
e 
To include hematology, serum chemistry, prolactin levels, and urinalysis. 
f 
A pregnancy test is only required for women of childbearing potential. Serum pregnancy should only be performed at Visit 1; a urine pregnancy test 
should be performed at Baseline and Week 6 (EOT). If urine cannot be obtained in women of childbearing potential, a serum pregnancy test should be 
done in its place. 
g 
At Screening, blood samples will be collected for the analysis of concomitant SSRI/SNRI concentrations. The presence of SSRI or SNRI must be 
confirmed in order to qualify the subject for further consideration in the study. 
h 
The HAMD-17 is to be the first scale completed at each visit. 
i 
Suicidal assessment is required. The Baseline/Screening version of the C-SSRS will be administered at Screening. The Since Last Visit version of the 
C-SSRS will be administered at all subsequent visits. 
j 
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. 
k 
Study drug may be dispensed to the subject at unscheduled visits if needed. 
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Statistical Analysis Plan 
 
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Appendix B  
Summary of Version Changes  
Version No: 
Document History 
Description of Update 
Author(s) 
Version Date 
1.0 
 
 
22 June 2020 
  
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