Clinical trial NCT04000009
Conditions: Adjunctive Treatment of Major Depressive Disorder
Sponsor: ACADIA Pharmaceuticals Inc.
Start date: 2019-06-06; Completion date: 2021-02-22
Enrollment: 235 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
To assess the safety and tolerability of long-term pimavanserin treatment in subjects with major depressive disorder and inadequate response to antidepressant treatment.

Detailed description:

Arms: arm 1: Pimavanserin 34 mg tablets
Interventions: intervention 1: Pimavanserin
Intervention descriptions: intervention 1: Pimavanserin 34 mg (provided as 2×17 mg tablets) administered orally as a single dose once daily

Protocol documents:
Prot_000.pdf: 
Official Title: A 52-Week Open-Label Extension Study of Pimavanserin in Subjects 
With Major Depressive Disorder and Inadequate Response to Antidepressant 
Treatment 
NCT Numbers: NCT04000009 
Document Date: 11 Aug 2020 


 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 1 of 66 
 
 
CLINICAL STUDY PROTOCOL 
 
A 52-Week Open-Label Extension Study of Pimavanserin in Subjects With 
Major Depressive Disorder and Inadequate Response to Antidepressant 
Treatment 
 
Protocol Number: ACP-103-055 
Amendment 4 
EudraCT Number: 2018-003252-20 
 
Original Protocol Date: 30 August 2018 
Protocol Amendment 1 Date: 05 December 2018 
Protocol Amendment 2 Date: 18 March 2019 
Protocol Amendment 3 Date: 12 November 2019 
Protocol Amendment 4 Date: 11 August 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-103-055 
Final Version: 1.0 
Clinical Study Protocol Amendment 4 
 
Date: 11 August 2020 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
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SPONSOR SIGNATURE PAGE 
Title: A 52-Week Open-Label Extension Study of Pimavanserin in Subjects With Major 
Depressive Disorder and Inadequate Response to Antidepressant Treatment 
 
ACADIA Head of Clinical Development: 
 
 
 
 
 
 
  
 
 
 
See appended electronic signature page 
 
Signature 
 
Date 
 
 
ACADIA Study Lead: 
 
 
 
 
 
 
 
 
 
See appended electronic signature page 
 
Signature 
 
Date 


Study: ACP-103-055 
Final Version: 1.0 
Clinical Study Protocol Amendment 4 
 
Date: 11 August 2020 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
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[PLACEHOLDER FOR E-SIGNATURE PAGE] 


Study: ACP-103-055 
Final Version: 1.0 
Clinical Study Protocol Amendment 4 
 
Date: 11 August 2020 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 4 of 66 
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-103-055 
Final Version: 1.0 
Clinical Study Protocol Amendment 4 
 
Date: 11 August 2020 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
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PROTOCOL SYNOPSIS 
Protocol Number 
ACP-103-055 
EudraCT Number 
2018-003252-20 
Protocol Title 
A 52-Week Open-Label Extension Study of 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 assess the safety and tolerability of long-term 
pimavanserin treatment in subjects with major 
depressive disorder and inadequate response to 
antidepressant treatment  
Primary Endpoint 
Treatment-emergent adverse events 
(TEAEs) 
Exploratory Objectives 
• 
To explore the safety and tolerability of long-
term pimavanserin treatment in subjects with 
major depressive disorder and inadequate 
response to antidepressant treatment on the 
following: 
o suicidality 
o extrapyramidal symptoms 
o general health assessments 
• 
To explore the benefits of long-term 
pimavanserin treatment in subjects with 
major depressive disorder and inadequate 
response to antidepressant treatment on the 
following: 
o improvement of depression 
symptoms 
o clinical global impression of severity 
of depressive symptoms 
Exploratory Endpoints 
Safety and tolerability endpoints: 
• 
Columbia–Suicide Severity 
Rating Scale (C-SSRS) 
• 
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 
• 
Vital signs 
• 
Body weight 
• 
Potentially clinically important 
laboratory values 


Study: ACP-103-055 
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Clinical Study Protocol Amendment 4 
 
Date: 11 August 2020 
 
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o functional impairment 
o sexual functioning 
 
Efficacy endpoints: 
• 
Change from Baseline in 
Hamilton Depression Scale 
(17 items) (HAMD-17) total 
score 
• 
Treatment responder rates. 
Treatment response is defined as 
a reduction from Baseline in 
HAMD-17 total score of 50% or 
more. 
• 
Treatment remission rates. 
Treatment remission is defined as 
a HAMD-17 total score ≤7. 
• 
Change from Baseline in Clinical 
Global Impression–Severity 
(CGI-S) score for depressive 
symptoms 
• 
Change from Baseline in 
Sheehan Disability Scale (SDS) 
score 
• 
Change from Baseline in the 
Changes in Sexual Functioning 
Questionnaire Short Form 
(CSFQ-14) score 
• 
Change from Baseline in 
Karolinska Sleepiness Scale 
(KSS) score 
Number of Study Sites 
Up to approximately 80 sites will participate in this study. 
Number of Subjects Planned 
Up to approximately 420 male and female subjects from 
the antecedent studies, Study ACP-103-054 and Study 
ACP-103-059 
Test Product, Dose, and 
Administration 
Pimavanserin 34 mg is provided as 2×17 mg tablets. 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 a 52-week open-label extension study to 
evaluate the long-term safety and tolerability of 
pimavanserin in subjects with major depressive disorder 
and inadequate response to antidepressant treatment.  
The study will have two periods (Figure S-1): 
• Open-label treatment period (52 weeks) 


Study: ACP-103-055 
Final Version: 1.0 
Clinical Study Protocol Amendment 4 
 
Date: 11 August 2020 
 
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• Safety follow-up period (at least 30 days) 
The end of treatment (EOT) visit for the antecedent study, 
Study ACP-103-054 or Study ACP-103-059, is the 
Baseline visit for the present study. 
Open-label Treatment Period (Baseline through 
Week 52) 
Eligible subjects will begin pimavanserin once-daily 
dosing at 34 mg. 
During the treatment period, clinic visits will be conducted 
at Baseline and Weeks 2, 4, 8, 12, 16, 28, 40, and 52 
(EOT), or upon early termination (ET) from the study. 
Study drug will be dispensed to the subject to take home at 
the Baseline visit. The subject will be instructed to take 
the first dose of study drug on the day after the Baseline 
visit. 
All concomitant permitted medications should remain 
stable during the study, including the background 
antidepressant. 
Safety Follow-up Period (30 Days) 
A safety follow-up telephone call to the subject 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 approximately 56 weeks.  
Each subject will participate in a 52-week treatment period 
followed by a safety follow-up period of at least 30 days 
(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.  
The total duration of exposure to pimavanserin may be 
greater than 52 weeks (e.g., up to 58 weeks) as subjects 
may have been treated with pimavanserin in a previous 
study. 
Main Criteria for Inclusion 
and Exclusion 
To be eligible for this study subjects must meet all of the 
inclusion and none of the exclusion criteria.  
Inclusion Criteria: 
1. Completed the antecedent study, Study 
ACP-103-054 or Study ACP-103-059 


Study: ACP-103-055 
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Date: 11 August 2020 
 
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2. May benefit from longer term therapy with 
open-label pimavanserin treatment in the judgment 
of the Investigator 
3. Is willing and able to provide informed consent. 
Consent for the present study must be obtained 
prior to the procedures being performed at the Week 
6/EOT visit of Study ACP-103-054 or 
Study ACP-103-059 
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. 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 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. Is judged by the Investigator or the Medical 
Monitor to be inappropriate for the study, due to 
adverse events, medical condition, or 
noncompliance with investigational product or 
study procedures in Study ACP-103-054 or Study 
ACP-103-059, or is judged to be a danger to self or 
others 
2. Has any of the following electrocardiogram (ECG) 
results at Baseline (i.e., Week 6/EOT visit of Study 
ACP-103-054 or Study ACP-103-059): 
a. If the subject is not on citalopram, 
escitalopram, or venlafaxine (immediate or 
extended release): 


Study: ACP-103-055 
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Date: 11 August 2020 
 
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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 
3. Has a heart rate (as measured by peripheral pulse 
rate) <50 beats per minute at Baseline (i.e., the 
Week 6/EOT visit of Study ACP-103-054 or Study 
ACP-103-059) not explained by regular exercise or 
medication, in discussion with the Medical Monitor 
4. Has a body mass index (BMI) <18.5 kg/m2 or 
known unintentional clinically significant weight 
change (i.e., +/- ≥7% of body weight) in Study 
ACP-103-054 or Study ACP-103-059 as assessed 
by the Investigator 
5. Has clinically significant laboratory abnormalities 
that, in the judgment of the Investigator or Medical 
Monitor, would either: 
a. jeopardize the safe participation of the 
subject in the study; OR  
b. would interfere with the conduct or 
interpretation of safety or efficacy 
evaluations in the study  
6. Is suicidal as defined below at Visit 1 (Baseline) of 
the present study: 
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 (Baseline); OR 
c. Is actively suicidal in the Investigator’s 
judgment 
7. Has developed delirium or a neurologic, 
cardiovascular, respiratory, gastrointestinal, renal, 
hepatic, hematologic, or other medical or mental 
disorder, including cancer or malignancies that, in 
the judgment of the Investigator or the Medical 
Monitor, would increase the risk associated with 


Study: ACP-103-055 
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Date: 11 August 2020 
 
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taking study medication or significantly interfere 
with the conduct or interpretation of the study 
8. Requires treatment with a medication or other 
substance that is prohibited by the protocol 
9. Has a significant sensitivity or allergic reaction to 
pimavanserin or its excipients 
10. Is an employee or is a family member of an 
employee of ACADIA Pharmaceuticals Inc.  
Sample Size Calculations 
It is estimated that approximately 420 subjects from 
Studies ACP-103-054 and ACP-103-059 will be eligible to 
enter this study. The sample size for this study is not based 
on statistical power, but will depend on the number of 
subjects who transition into this open-label extension 
study from the antecedent studies, Study ACP-103-054 
and Study ACP-103-059. 
Statistical Methods 
The purpose of this study is to collect safety data from 
subjects exposed to pimavanserin for up to 52 weeks in 
this study. Exploratory objectives include assessment of 
efficacy outcome measures over time. No statistical testing 
is planned. 
All endpoints will be summarized for the Safety Analysis 
Set. Additional summaries by prior treatment may be 
included. 
Data from the EOT visit procedures of Study 
ACP-103-054 and Study ACP-103-059 will be carried 
over as baseline information in the present study, as 
applicable. 
Descriptive Statistics 
Continuous measurement results will be reported using the 
number of subjects with data values, mean, standard error 
of the mean, median, standard deviation, minimum, and 
maximum. For each categorical outcome, the frequency 
and percentage of subjects in each category will be 
reported.  
Primary Analyses 
All 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 


Study: ACP-103-055 
Final Version: 1.0 
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Date: 11 August 2020 
 
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Page 11 of 66 
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. 
Exploratory Analyses 
For the C-SSRS, the number and percentage of subjects 
with suicidal ideation or suicidal behavior during this 
study will be tabulated. 
Descriptive summary statistics for ESRS-A observed 
values and change from Baseline will be provided by 
timepoint. 
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. 
Descriptive summary statistics for vital signs and body 
weight, and potentially clinically important laboratory 
values, including observed values and changes from 
Baseline will be tabulated by timepoint. 
Descriptive summary statistics for HAMD-17, CGI-S, 
SDS, CSFQ-14, and KSS observed values, and change 
from Baseline will also be provided by timepoint. 
Treatment responder rate and treatment remission rate will 
be summarized by timepoint. 
Other Safety Analyses 
Descriptive summary statistics for ECG observed values 
and changes from Baseline will be tabulated by timepoint. 
Additionally, categorical analyses will be conducted on the 
incidence of subjects with prolonged QTc intervals and 
changes in QTc intervals in accordance with International 
Council for Harmonisation (ICH) guidelines and Food and 
Drug Administration (FDA) E14 guidance document. 
Date 
11 August 2020 
 


Study: ACP-103-055 
 
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Date: 11 August 2020 
 
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Figure S-1 
Schematic of Study Design for ACP-103-055 
 
Abbreviation: QD=once daily 
Note: The antecedent study is either Study ACP-103-054 or Study ACP-103-059. 


Study: ACP-103-055 
 
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Clinical Study Protocol Amendment 4 
 
Date: 11 August 2020 
 
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Table S-1 
Schedule of Events and Assessments for ACP-103-055 
Period Baselinec 
Treatment Period 
 
Safety 
Follow-
Upm 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
(EOT/ET) 
9 
Unscheduled 
Visitl 
10 
Visit Weeka 
Week 
0 
Week 
2 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
28 
Week 
40 
Week  
52 
Week 
56 
Type of visitb
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Phone call 
Visit window (# days) 
 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
+7 
 
+7 
Informed consent and if applicable, 
privacy formsc 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
Medical history, medication history, 
and demographicsd 
X 
 
 
 
 
 
 
 
 
 
 
Psychiatric historyd 
X 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
X 
 
X 
 
 
Vital signs and weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECGe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Clinical laboratory testsf 
X 
 
 
 
X 
 
 
 
X 
 
 
Pregnancy testg 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Urine drug screen 
X 
 
 
 
X 
 
 
 
X 
 
 
ESRS-A 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRS  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
HAMD-17h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
CGI-S 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
SDS 
X 
 
X 
 
X 
 
X 
 
X 
 
 
CSFQ-14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
KSS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of AEsi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense study drug 
Xj,k 
 
X 
X 
X 
X 
X 
X 
 
Xm 
 
Study drug accountability 
Xk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Review of background 
antidepressant adherence  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Table footnotes and abbreviations on next page. 


Study: ACP-103-055 
 
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Clinical Study Protocol Amendment 4 
 
Date: 11 August 2020 
 
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Abbreviations: AE=adverse event; 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; ECG=electrocardiogram; 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; SDS=Sheehan Disability Scale 
a 
Study visits are designated by weeks and have a ±3-day window (Visits 2 through 5), or a ±7-day window (Visits 6 through 8), or a +7-day window (Visits 9 
and 10), and are calculated from the Baseline Visit. 
b 
If visit is performed remotely due to the COVID-19 pandemic, please refer to Sections 3.1.3 (impact of COVID-19 pandemic), 6.2.6 (exploratory efficacy 
assessments), 6.3.8 (safety assessments) and 6.5.1 (unscheduled visits) for further information. 
c 
Subject consent for the present study must be obtained for entry into the present study prior to the final procedures being performed at the end of treatment 
(EOT) visit in the antecedent study, Study ACP-103-054 or Study ACP-103-059. Data from the EOT visit procedures of Study ACP-103-054 and Study 
ACP-103-059 will be carried over as baseline information in the present study, as applicable. 
d 
Relevant information collected from Study ACP-103-054 and Study ACP-103-059 will be rolled over to the present study; any updates to this information 
should be collected during the Baseline visit of the present study. 
e 
A single 12-lead ECG can be performed any time before blood sampling or at least 30 minutes after blood sampling during clinic visits. ECGs should be 
completed with the subject in a supine position after 5 minutes of rest. In the US and UK, a 6-lead ECG device will be given to subjects in order to perform 
ECGs on themselves at home when they cannot go to the clinic and site staff cannot go to their home. This should be done in discussion with the Medical 
Monitor. When an ECG is performed outside of the investigator site, this should be documented in the source record. 
f 
To include hematology, serum chemistry, prolactin levels, and urinalysis. 
g 
A urine pregnancy test should be performed for female study subjects of childbearing potential. If urine cannot be obtained in women of childbearing 
potential, a serum pregnancy test should be done in its place. 
h 
The HAMD-17 is to be the first scale completed at each visit. 
i 
All ongoing AEs from Study ACP-103-054 and Study ACP-103-059 will be carried over after informed consent has been obtained for the present study and 
recorded from Baseline for the present study until resolution or the follow-up safety assessment. An AE occurring after the completion of procedures at the 
EOT visit in Study ACP-103-054 or Study ACP-103-059 will be recorded as an AE in the present study. 
j 
Study drug will be dispensed to the subject to take home at the Baseline visit. The subject will be instructed to take the first dose of study drug on the 
following day. 
k 
The used and unused treatment kits, blister cards, and tablets from Study ACP-103-054 and Study ACP-103-059 are to be collected by the Investigator as 
part of the EOT visit of Study ACP-103-054 and Study ACP-103-059 before study drug for the present study can be dispensed. 
l 
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. 
m 
Study drug may be dispensed to the subject at unscheduled visits if needed. In addition to the study drug dispensed at the site, investigational product may be 
delivered to the subject’s home. 
n 
This visit is a safety follow-up telephone call visit for subjects who discontinue prematurely from the study or who complete the present study. This visit will 
occur at least 30 days after the last dose of study drug. 
 


Study: ACP-103-055 
 
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Date: 11 August 2020 
 
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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ............................................................................................... 2 
DECLARATION OF INVESTIGATOR ................................................................................... 4 
PROTOCOL SYNOPSIS ........................................................................................................... 5 
TABLE OF CONTENTS ......................................................................................................... 15 
LIST OF TABLES ................................................................................................................... 20 
LIST OF FIGURES ................................................................................................................. 20 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................. 21 
1 
INTRODUCTION ...................................................................................................... 22 
1.1 
Background Information ............................................................................................ 22 
1.2 
Investigational Product ............................................................................................... 24 
1.3 
Previous Clinical Experience ..................................................................................... 24 
1.4 
Study Rationale .......................................................................................................... 26 
1.5 
Benefit/Risk Assessment ............................................................................................ 27 
2 
STUDY OBJECTIVES AND ENDPOINTS .............................................................. 27 
2.1 
Primary Objective ...................................................................................................... 27 
2.1.1 
Primary Endpoint ....................................................................................................... 27 
2.2 
Exploratory Objectives ............................................................................................... 28 
2.2.1 
Exploratory Endpoints ................................................................................................ 28 
3 
STUDY DESCRIPTION ............................................................................................ 29 
3.1 
Overview of Study Design ......................................................................................... 29 
3.1.1 
Open-label Treatment Period (52 Weeks) .................................................................. 29 
3.1.2 
Safety Follow-up Period (30 Days) ............................................................................ 30 
3.1.3 
Impact of COVID-19 Pandemic ................................................................................. 30 
4 
SUBJECT ELIGIBILITY AND WITHDRAWAL CRITERIA .................................. 30 
4.1 
Inclusion Criteria ........................................................................................................ 30 
4.2 
Exclusion Criteria ....................................................................................................... 31 
4.3 
Subject Withdrawal of Consent .................................................................................. 32 
4.4 
Subject or Study Discontinuation ............................................................................... 32 
4.4.1 
Handling of Subject Discontinuation During the Treatment Period .......................... 33 
4.5 
Subject Lost to Follow-up .......................................................................................... 33 


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4.6 
Prior and Concomitant Therapy ................................................................................. 34 
4.6.1 
Prior Medication ......................................................................................................... 34 
4.6.2 
Concomitant Medication ............................................................................................ 34 
4.6.2.1 Permitted, Restricted, and Prohibited Medications .................................................... 34 
5 
INVESTIGATIONAL PRODUCT ............................................................................. 35 
5.1 
Investigational Product Description ........................................................................... 35 
5.1.1 
Formulation, Appearance, Packaging, and Labeling .................................................. 35 
5.1.2 
Product Storage and Stability ..................................................................................... 35 
5.1.3 
Dosing and Administration ......................................................................................... 36 
5.1.4 
Method of Assigning Subjects to Treatment Groups.................................................. 36 
5.1.5 
Blinding ...................................................................................................................... 36 
5.1.6 
Study Drug Compliance ............................................................................................. 36 
5.1.7 
Overdose ..................................................................................................................... 36 
5.2 
Investigational Product Accountability Procedures ................................................... 36 
6 
STUDY PROCEDURES ............................................................................................ 37 
6.1 
Baseline Assessments ................................................................................................. 37 
6.1.1 
Medical History, Medication History, and Demographics ......................................... 37 
6.1.2 
Psychiatric History ..................................................................................................... 37 
6.1.3 
Background Antidepressant Adherence...................................................................... 38 
6.2 
Exploratory Efficacy Assessments ............................................................................. 38 
6.2.1 
Hamilton Depression Scale (17 Items) ....................................................................... 38 
6.2.2 
Clinical Global Impression–Severity Scale ................................................................ 38 
6.2.3 
Sheehan Disability Scale ............................................................................................ 38 
6.2.4 
Changes in Sexual Functioning Questionnaire Short Form ....................................... 38 
6.2.5 
Karolinska Sleepiness Scale ....................................................................................... 38 
6.2.6 
Impact of COVID-19 Pandemic on Exploratory Efficacy Assessments .................... 39 
6.3 
Safety Assessments .................................................................................................... 39 
6.3.1 
Physical Examinations ............................................................................................... 39 
6.3.2 
Vital Signs .................................................................................................................. 39 
6.3.3 
Weight and Body Mass Index..................................................................................... 39 
6.3.4 
Electrocardiograms ..................................................................................................... 39 
6.3.5 
Columbia–Suicide Severity Rating Scale................................................................... 40 
6.3.6 
Extrapyramidal Symptom Rating Scale–Abbreviated ............................................... 40 
6.3.7 
Laboratory Evaluations .............................................................................................. 40 
6.3.8 
Impact of COVID-19 Pandemic on Safety Assessments ........................................... 42 
6.3.8.1 Priority Medical Assessments in Remote Visits ......................................................... 43 


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6.3.8.2 Physical Examinations, Vital Signs, Height, and Weight ........................................... 43 
6.3.8.3 Electrocardiograms ..................................................................................................... 43 
6.3.8.4 Columbia-Suicide Severity Rating Scale ................................................................... 43 
6.3.8.5 Extrapyramidal Symptom Rating Scale-Abbreviated ................................................ 43 
6.3.8.6 Laboratory Evaluations .............................................................................................. 43 
6.4 
Safety Follow-up ........................................................................................................ 43 
6.5 
Unscheduled Visits ..................................................................................................... 44 
6.5.1 
Impact of COVID-19 on Unscheduled Visits ............................................................. 44 
7 
ADVERSE EVENTS ................................................................................................. 44 
7.1 
Specification of Safety Parameters ............................................................................ 44 
7.1.1 
Definition of Adverse Event ....................................................................................... 44 
7.1.2 
Definition of Serious Adverse Event .......................................................................... 45 
7.2 
Classification of an Adverse Event ............................................................................ 46 
7.2.1 
Severity of Event ........................................................................................................ 46 
7.2.2 
Relationship to Study Drug ........................................................................................ 46 
7.2.2.1 Duration ...................................................................................................................... 47 
7.2.2.2 Frequency ................................................................................................................... 47 
7.2.2.3 Action Taken with Study Drug ................................................................................... 47 
7.2.2.4 Therapy ....................................................................................................................... 47 
7.2.2.5 Outcome ..................................................................................................................... 47 
7.2.2.6 Seriousness ................................................................................................................. 48 
7.2.3 
Definition of Unexpectedness .................................................................................... 48 
7.3 
Time Period and Frequency for Event Assessment and Follow-up ........................... 48 
7.4 
Reporting Procedures ................................................................................................. 48 
7.4.1 
Adverse Event Reporting ........................................................................................... 48 
7.4.2 
Serious Adverse Event Reporting............................................................................... 49 
7.4.3 
Reporting of Pregnancy .............................................................................................. 50 
7.4.4 
Reporting of Overdose ............................................................................................... 50 
8 
CLINICAL MONITORING ....................................................................................... 50 
9 
STATISTICAL METHODS AND DATA ANALYSIS .............................................. 51 
9.1 
Statistical and Analytical Plans .................................................................................. 51 
9.2 
Statistical Hypotheses ................................................................................................ 51 
9.3 
Sample Size Determination ........................................................................................ 51 
9.4 
Subject Populations for Analysis ................................................................................ 51 
9.5 
Statistical Analyses ..................................................................................................... 51 


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9.5.1 
Primary Analyses ........................................................................................................ 51 
9.5.2 
Exploratory Analyses ................................................................................................. 52 
9.5.3 
Other Safety Analyses ................................................................................................ 52 
9.5.3.1 Exposure to Study Drug ............................................................................................. 52 
9.5.3.2 Electrocardiograms ..................................................................................................... 52 
9.5.3.3 Physical Examinations ............................................................................................... 53 
9.5.4 
Subgroup Analyses ..................................................................................................... 53 
9.6 
Interim Analyses ......................................................................................................... 53 
9.7 
Measures to Minimize Bias ........................................................................................ 53 
9.8 
Breaking the Study Blind/Subject Code ..................................................................... 53 
10 
STUDY MANAGEMENT AND DATA COLLECTION .......................................... 53 
10.1 
Data Collection and Management Responsibilities ................................................... 53 
10.2 
Source Documents ...................................................................................................... 53 
10.3 
Case Report Forms ..................................................................................................... 54 
10.4 
Confidentiality ............................................................................................................ 54 
10.5 
Study Records Retention ............................................................................................ 54 
10.6 
Protocol Exceptions and Deviations .......................................................................... 54 
10.7 
Protocol Amendments ................................................................................................ 55 
11 
QUALITY MANAGEMENT .................................................................................... 55 
11.1 
Risk Management ....................................................................................................... 55 
11.2 
Quality Control and Quality Assurance ..................................................................... 56 
12 
ETHICAL CONSIDERATIONS ................................................................................ 57 
12.1 
Ethical Standard ......................................................................................................... 57 
12.2 
Institutional Review Board/Ethics Committee ........................................................... 57 
12.3 
Informed Consent Process .......................................................................................... 57 
12.3.1 Consent and Other Informational Documents Provided to Subjects .......................... 58 
12.3.2 Consent Procedures and Documentation .................................................................... 58 
13 
PUBLICATION PLAN .............................................................................................. 58 
14 
CONFLICT OF INTEREST POLICY ....................................................................... 58 
14.1 
Finance, Insurance, and Indemnity ............................................................................ 58 
15 
LITERATURE REFERENCES .................................................................................. 59 
16 
APPENDICES ............................................................................................................ 61 
Appendix A Prohibited and Restricted Medications ............................................................. 61 


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Appendix B Prohibited and Restricted Concomitant Medications: Inhibitors and 
Inducers of Cytochrome P450 Enzyme 3A4 .............................................................. 65 
 


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LIST OF TABLES 
Table S-1 
Schedule of Events and Assessments for ACP-103-055 .................................. 13 
Table 1–1 
Receptor Profiles of Pimavanserin and Compounds With Antidepressant 
Activity ............................................................................................................ 26 
Table 6–1 
Safety Laboratory Evaluations......................................................................... 42 
 
LIST OF FIGURES 
Figure S-1 
Schematic of Study Design for ACP-103-055 ................................................. 12 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Term 
Definition 
5-HT 
5-hydroxytryptamine (serotonin) 
5-HT2A 
5-hydroxytryptamine (serotonin) 2A 
AE 
adverse event 
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 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOT 
end of treatment 
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 
KSS 
Karolinska Sleepiness Scale 
MDD 
major depressive disorder 
NET 
norepinephrine transporter 
PDP 
Parkinson’s disease psychosis 
PR 
PR interval of ECG 
QRS 
QRS interval of ECG 
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 
SDS 
Sheehan Disability Scale 
SAP 
statistical analysis plan 
SERT 
serotonin transporter 
TEAE 
treatment-emergent adverse event 
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 to evaluate the long-term 
safety of pimavanserin as adjunctive treatment in MDD. 


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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, 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 


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Phase 3 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 
serious adverse events (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, 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 
N/A 
Low 
Low 
Low 
350 
NET 
Low 
Low 
Low 
N/A 
Low 
Low 
70 
Low 
DAT 
Low 
Low 
Low 
N/A 
Low 
Low 
Low 
Low 
5-HT2A 
0.1 
0.2 
0.7 
5 
2 
70 
3 
35 
5-HT2C 
3 
125 
Low 
120 
125 
40 
3 
200 
Other 
noteworthy 
targets 
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. 


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Furthermore, the robustness of the clinical evidence for efficacy and favorable tolerability 
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 assess the safety, tolerability, and benefits of long-term 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, AD-AA, 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 long-term 
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 the study is to assess the safety and tolerability of long-term 
pimavanserin treatment in subjects with major depressive disorder and inadequate response 
to antidepressant treatment. 
2.1.1 
Primary Endpoint 
The primary safety measure for this study is treatment-emergent adverse events (TEAEs). 


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2.2 
Exploratory Objectives 
The exploratory objectives of this study are: 
• To explore the safety and tolerability of long-term pimavanserin treatment in subjects 
with major depressive disorder and inadequate response to antidepressant treatment on 
the following: 
o suicidality 
o extrapyramidal symptoms 
o general health assessments 
• To explore the benefits of long-term pimavanserin treatment in subjects with major 
depressive disorder and inadequate response to antidepressant treatment on the 
following: 
o improvement of depression symptoms 
o clinical global impression of severity of depressive symptoms 
o functional impairment 
o sexual functioning 
2.2.1 
Exploratory Endpoints 
The exploratory endpoints for this study include the following: 
• Safety and tolerability endpoints: 
o Columbia–Suicide Severity Rating Scale (C–SSRS) 
o Extrapyramidal Symptom Rating Scale–Abbreviated (ESRS-A) score 
o Sexual dysfunction defined as a CSFQ-14 total score of ≤47 for men and 
≤41 for women  
o Vital signs 
o Body weight 
o Potentially clinically important laboratory values 
• Efficacy endpoints: 
o Change from Baseline in Hamilton Depression Scale (17 items) (HAMD-17) 
total score 
o Treatment responder rates. Treatment response is defined as a reduction from 
Baseline in HAMD-17 total score of 50% or more. 
o Treatment remission rates. Treatment remission is defined as a HAMD-17 
total score ≤7. 


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o Change from Baseline in Clinical Global Impression–Severity (CGI-S) score 
for depressive symptoms 
o Change from Baseline in Sheehan Disability Scale (SDS) score 
o Change from Baseline in the Changes in Sexual Functioning Questionnaire 
Short Form (CSFQ-14) score 
o Change from Baseline in Karolinska Sleepiness Scale (KSS) score 
3 STUDY DESCRIPTION 
3.1 
Overview of Study Design 
This study will be a 52-week open-label extension study to evaluate the long-term safety and 
tolerability of pimavanserin in subjects with major depressive disorder and inadequate 
response to antidepressant treatment. Up to approximately 80 sites will participate in this 
study. The total duration of exposure to pimavanserin may be greater than 52 weeks (e.g., up 
to 58 weeks) as subjects may have been treated with pimavanserin in the antecedent studies, 
ACP-103-054 and ACP-103-059. The duration of participation for individual study subjects 
will be up to approximately 56 weeks. 
The study will have two periods (Figure S-1): 
• Open-label treatment period (52 weeks) 
• Safety follow-up period (at least 30 days) 
The end of treatment (EOT) visit for the antecedent study, Study ACP-103-054 or Study 
ACP-103-059, is the Baseline visit for the present study. 
Subject consent for the present study must be obtained prior to the final procedures being 
performed at the antecedent study’s (ACP-103-054 or ACP-103-059) end of treatment (EOT) 
visit. Data from the EOT procedures of Studies ACP-103-054 and ACP-103-059 will be 
carried over to the ACP-103-055 study to be included as baseline information for the present 
study and this visit will be considered Baseline (Visit 1). 
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. 
3.1.1 
Open-label Treatment Period (52 Weeks) 
Eligible subjects will begin pimavanserin once-daily dosing at 34 mg. Subject eligibility will 
be assessed by the site and the Sponsor through an eligibility review process. 


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During the treatment period, clinic visits will be conducted at Baseline and Weeks 2, 4, 8, 12, 
16, 28, 40, and 52 (EOT), or upon early termination (ET) from the study. 
Study drug will be dispensed to the subject to take home at the Baseline visit. The subject 
will be instructed to take the first dose of study drug on the day after the Baseline visit. 
All concomitant permitted medications should remain stable during the study, including the 
background antidepressant. 
3.1.2 
Safety Follow-up Period (30 Days) 
A safety follow-up telephone call to the subject will be conducted at least 30 days after the 
last dose of study drug. 
3.1.3 
Impact of COVID-19 Pandemic 
The emergence of the coronavirus disease 2019 (COVID-19) pandemic has resulted in the 
implementation of measures designed to ensure subject safety.  
Subjects remaining in this study who cannot attend clinic visits are allowed to participate in 
remote visits via telephone or video, or site staff can conduct the visit in a subject’s home. 
Sites are required to document details of all visits that are administered remotely.  
Further details about accommodations and modifications to assessments, relating to the 
COVID-19 pandemic, can be found in Sections 5.1.1 (home delivery of study drug), 6.2.6 
(exploratory efficacy assessments), 6.3.8 (safety assessments) and 6.5.1 (unscheduled visits).  
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. Completed the antecedent study, Study ACP-103-054 or Study ACP-103-059 
2. May benefit from longer term therapy with open-label pimavanserin treatment in the 
judgment of the Investigator 
3. Is willing and able to provide informed consent. Consent for the present study must be 
obtained prior to the procedures being performed at the Week 6/EOT visit of Study 
ACP-103-054 or Study ACP-103-059 


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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. 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 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. Is judged by the Investigator or the Medical Monitor to be inappropriate for the study, 
due to AEs, medical condition, or noncompliance with investigational product or study 
procedures in Study ACP-103-054 or Study ACP-103-059, or is judged to be a danger 
to self or others 
2. Has any of the following electrocardiogram (ECG) results at Baseline (i.e., Week 6/ 
EOT visit of Study ACP-103-054 or Study ACP-103-059): 
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 
3. Has a heart rate (as measured by peripheral pulse rate) <50 beats per minute at 
Baseline (i.e., the Week 6/EOT visit of Study ACP-103-054 or Study ACP-103-059) 
not explained by regular exercise or medication, in discussion with the Medical 
Monitor 


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4. Has a body mass index (BMI) <18.5 kg/m2 or known unintentional clinically 
significant weight change (i.e., +/- ≥7% of body weight) in Study ACP-103-054 or 
Study ACP-103-059 as assessed by the Investigator 
5. Has clinically significant laboratory abnormalities that, in the judgment of the 
Investigator or Medical Monitor, would either: 
a. jeopardize the safe participation of the subject in the study; OR  
b. would interfere with the conduct or interpretation of safety or efficacy 
evaluations in the study  
6. Is suicidal as defined below at Visit 1 (Baseline) of the present study: 
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 (Baseline); OR 
c. Is actively suicidal in the Investigator’s judgment 
7. Has developed delirium or a neurologic, cardiovascular, respiratory, gastrointestinal, 
renal, hepatic, hematologic, or other medical or mental disorder, including cancer or 
malignancies that, in the judgment of the Investigator or the Medical Monitor, would 
increase the risk associated with taking study medication or significantly interfere with 
the conduct or interpretation of the study 
8. Requires treatment with a medication or other substance that is prohibited by the 
protocol 
9. Has a significant sensitivity or allergic reaction to pimavanserin or its excipients 
10. Is an employee or is a family member of an employee of ACADIA Pharmaceuticals 
Inc.  
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. 
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: 


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• 
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 9/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). 
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.  


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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 up through 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 Baseline visit and Visit 9/ET as specified in Appendix A and Appendix B. These 
appendices do not constitute an exhaustive list and any questions regarding prohibited and 
restricted medications should be discussed with the Medical Monitor or designee. 
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 A. 
Permitted concomitant medications should remain at a stable dose throughout the study.  
If a subject is on a medication restricted by the protocol, the medication should be adjusted if 
it is determined by the Investigator to be clinically appropriate (e.g., if the subject’s 


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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). 
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. 
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). 
Pimavanserin 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. In addition to the study 
drug dispensed at the site, investigational product may be delivered to the subject’s home.  
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. 


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5.1.3 
Dosing and Administration 
Eligible subjects will begin pimavanserin once-daily dosing at 34 mg. Study drug will be 
dispensed to the subject to take home at the Baseline visit. The subject will be instructed to 
take the first dose of study drug on the day after the Baseline visit. It is recommended that the 
subject should take the study drug at approximately the same time each day.  
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 
All subjects will receive once daily doses of pimavanserin over 52 weeks of treatment. 
Details of pimavanserin dosing and administration are provided in Section 5.1.3. 
5.1.5 
Blinding 
This is an open-label study. 
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, 
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 used and unused treatment kits, blister cards, and tablets from Study ACP-103-054 and 
Study ACP-103-059 are to be collected by the Investigator as part of the EOT visit of Study 
ACP-103-054 and Study ACP-103-059 before study drug for the present study can be 
dispensed. 
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. Unused study drug and packaging may also be returned to site staff when 


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visiting the subject’s home. 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 
Baseline Assessments 
Subject consent for the present study must be obtained prior to the final procedures being 
performed at the EOT visit of Study ACP-103-054 and Study ACP-103-059 and before any 
new procedures are performed for Study ACP-103-055. Data from the EOT procedures of 
Study ACP-103-054 and Study ACP-103-059 will be carried over to the ACP-103-055 study 
to be included as baseline information for the present study and this visit will be considered 
Baseline (Visit 1). Subject eligibility will be assessed by the site and the Sponsor through an 
eligibility review process. 
6.1.1 
Medical History, Medication History, and Demographics 
Relevant information collected from Study ACP-103-054 and Study ACP-103-059 will be 
rolled over to the present study; any updates to this information should be collected during 
the Baseline visit of the present study. Any new medical condition beginning after the 
informed consent form (ICF) has been signed will be captured as an AE.  
6.1.2 
Psychiatric History 
Relevant information collected from Study ACP-103-054 and Study ACP-103-059 will be 
rolled over to the present study; any updates to this information should be collected during 
the Baseline visit of the present study. 


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6.1.3 
Background Antidepressant Adherence 
Review of subject adherence with background antidepressant therapy should be conducted at 
the Baseline visit and all visits. 
6.2 
Exploratory 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 will be used for exploratory efficacy analyses and is to be the first 
scale completed at each visit. 
6.2.2 
Clinical Global Impression–Severity Scale 
The CGI-S (Guy 1976) is a scale 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 
performed at all scheduled visits and will be used for exploratory efficacy analyses. 
6.2.3 
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 exploratory 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 exploratory 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, 


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great effort to keep awake, fighting sleep.” The timeframe for this scale is the past 7 days. 
The KSS will be used for exploratory efficacy analyses. 
6.2.6 
Impact of COVID-19 Pandemic on Exploratory Efficacy Assessments 
Subjects who cannot attend clinic visits due to the COVID-19 pandemic are allowed to 
participate in remote visits via telephone or video, or site staff can visit subjects in their 
homes. 
6.3 
Safety Assessments  
6.3.1 
Physical Examinations 
A general physical examination will be conducted at Baseline and Weeks 28 and 52. 
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 and will be used for 
exploratory safety analyses. 
6.3.3 
Weight and Body Mass Index 
Weight will be measured at all scheduled and unscheduled visits and will be used for 
exploratory safety analyses. The height recorded in Study ACP-103-054 or 
Study ACP-103-059 will be used. 
Body mass index will be calculated using the following formula:  
Weight (kg) / [height (m)]2. 
6.3.4 
Electrocardiograms 
All 12-lead electrocardiograms (ECGs) will be complete, standardized recordings. A single 
12-lead ECG will be completed at all scheduled visits at the investigator site during the 
present study (Table S-1). In the US and UK, a 6-lead ECG device will be given to subjects 
in order to perform ECGs on themselves at home when they cannot go the clinic and site staff 
cannot go to their home. This should be done in discussion with the Medical Monitor. When 
an ECG is performed outside of the investigator site, this should be documented in the source 
record. All ECGs will be centrally read; the interpretation by the central cardiologist is 
considered the official result. If a site performs additional ECGs beyond the single ECG 
prescribed at Baseline, the mean QTcF/QRS values of all the tracings of adequate quality will 
be used to determine eligibility. 


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At Baseline, a subject 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 enrollment 
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.  
For subjects who completed the Baseline/Screening version in Study ACP-103-054 or Study 
ACP-103-059, the Since Last Visit version will be administered at all visits. The C-SSRS 
results for each subject should be reviewed by the Investigator at each visit. If at any time the 
C-SSRS results for a given subject reveal potential suicidality, then the Investigator should 
assess the clinical significance of such results. If a clinically significant risk of suicidality is 
identified for a subject, then the Investigator should discontinue the subject and implement 
appropriate treatment (Section 4.4). 
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 all scheduled and unscheduled visits.  
6.3.7 
Laboratory Evaluations 
Clinical laboratory sample collection 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 


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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), aspartate aminotransferase (AST), 
gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), total 
bilirubin (TBIL), lactate dehydrogenase (LDH) 
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, 
very low density lipoprotein cholesterol 
• 
Pregnancy test 
o A urine pregnancy test should be performed at all designated visits (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 
o Sites will be supplied with instant-read dipstick urine toxicity (drug) screen 
tests to utilize as a tool at the Baseline 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 in the urine toxicity (drug) screen performed by the 
central laboratory for benzodiazepines, opiates, any other controlled 
medication, tetrahydrocannabinol (THC), or illicit substance, 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 A 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 
Tests 
Visit 1 (Baseline) 
CHEM, CBC, UA, urine toxicity (drug) screen, and urine 
pregnancy testa 
Visit 5 (Week 12) and 
Visit 9 (EOT/ET) 
CHEM, CBC, UA, urine toxicity (drug) screen, and urine 
pregnancy testa 
Visits 3, 4, 6, 7, 8 
Urine pregnancy testa 
Abbreviations: CBC=complete blood count; CHEM=clinical chemistry serum tests; EOT=end of treatment; 
ET=early termination; UA=urinalysis 
a 
To be completed only if female is of childbearing potential. If urine cannot be obtained in women of 
childbearing potential, a serum pregnancy test should be done in its place. 
6.3.8 
Impact of COVID-19 Pandemic on Safety Assessments 
Subjects who cannot attend clinic visits due to the COVID-19 pandemic are allowed to 
participate in remote visits via telephone or video, or site staff can visit subjects in their 
homes.  
Some safety assessments may not be able to be performed, or may be 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. 


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6.3.8.1 
Priority Medical Assessments in Remote Visits 
The C-SSRS is to be performed as a priority, along with an assessment of AEs and 
COVID-19 symptoms. Additionally, subjects are 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 be able to be performed because 
the visit has to be conducted remotely. If the visit is remote, the subject may report vitals 
obtained on home devices. If vitals are obtained outside of the investigator site, this should be 
documented in the source record. 
6.3.8.3 
Electrocardiograms 
ECGs may have to be performed by site staff during a home visit after discussion with 
Medical Monitor. In the US and UK, a 6-lead ECG device will be given to subjects in order 
to perform ECGs on themselves at home when they cannot go to the clinic and site staff 
cannot go to their home. This should be done in discussion with the Medical Monitor. When 
an ECG is performed outside of the investigator site, this should be documented in the source 
record. 
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 cannot be performed (e.g., when the visit is performed 
via telephone with no video component) then no scoring of symptoms is to be completed. 
The clinical interview questions are 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 is to be documented in the source record. The clinical significance of any 
symptoms is to be evaluated by the Investigator, and the adverse event page updated when 
new or worsening symptoms are reported. 
6.3.8.6 
Laboratory Evaluations 
If subjects cannot attend clinic visits for laboratory evaluations, they are 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, as well as those who discontinue prematurely from the 


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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 C-SSRS. 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 a subject cannot attend the clinic for an unscheduled visit, this may occur 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 with an onset before the first dose of open-label pimavanserin in the present 
study will be recorded as an AE in the antecedent study. All ongoing AEs from 
Study ACP-103-054 and Study ACP-103-059 will be carried over after informed consent has 
been obtained for the present study and recorded from Baseline for the present study until 
resolution or the follow-up safety assessment. An adverse event occurring after the first dose 
of open-label pimavanserin in the present study will be recorded as an AE in the present 
study. Adverse events for the present study will be recorded from the time of first dose of 
open-label pimavanserin 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 of 
the present study. 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. 


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All AEs, serious and not serious, will be recorded on the AE eCRF page using appropriate 
medical terminology. Severity and relationship to study drug will be assessed by the 
Investigator. 
When possible, clinical AEs should be described by diagnosis and not by symptoms 
(e.g., “cold” or “seasonal allergies” instead of “runny nose”). 
All AEs, whether or not related to the study drug, must be fully and completely documented 
on the AE eCRF and in the subject’s notes. 
7.4.2 
Serious Adverse Event Reporting 
The reporting of SAEs by the Sponsor or designee to the regulatory authorities is a regulatory 
requirement. Each regulatory authority has established a timetable for reporting SAEs based 
upon established criteria. 
Serious AEs must be reported within 24 hours of discovery to the Sponsor or its designee; 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. 


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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. 
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 11.2. 
Clinical site monitoring is conducted to ensure that the rights and well-being of human 
subjects are protected, that the reported study data are accurate, complete, and verifiable, and 
that the conduct of the study is in compliance with the currently approved protocol and 
amendment(s) as applicable, with GCP, and with applicable regulatory requirements. Details 
of the study site monitoring process are described in a separate clinical monitoring plan 
document. 


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9 STATISTICAL METHODS AND DATA ANALYSIS 
9.1 
Statistical and Analytical Plans 
Statistical methods will be documented in detail in a statistical analysis plan (SAP) to be 
approved by the Sponsor prior to database lock. 
9.2 
Statistical Hypotheses 
No formal testing of hypotheses is planned. All outcomes will be summarized descriptively. 
9.3 
Sample Size Determination 
It is estimated that approximately 420 subjects from Study ACP-103-054 and Study 
ACP-103-059 will be eligible to enter this study. The sample size for this study is not based 
on statistical power, but will depend on the number of subjects who transition into this 
open-label extension study from the antecedent studies, Study ACP-103-054 and 
Study ACP-103-059. 
9.4 
Subject Populations for Analysis 
The Safety Analysis Set will consist of all enrolled subjects who have taken at least one dose 
of study drug. The Safety Analysis Set will be used for all analyses. 
9.5 
Statistical Analyses 
All endpoints will be summarized for the Safety Analysis Set. Additional summaries by prior 
treatment may be included.  
Continuous measurement results will be reported using the number of subjects with data 
values, mean, standard error of the mean, median, standard deviation, minimum, and 
maximum. For each categorical outcome, the frequency and percentage of subjects in each 
category will be reported. 
9.5.1 
Primary Analyses 
All 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. 


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9.5.2 
Exploratory Analyses 
For the C-SSRS, the number and percentage of subjects with suicidal ideation or suicidal 
behavior during this study will be tabulated. 
Descriptive summary statistics for ESRS-A observed values and change from Baseline will 
be provided by timepoint. 
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. 
Vital sign measurements and body weight, including changes from Baseline, will be 
summarized by timepoint using descriptive statistics. The number and percentage of subjects 
with changes from Baseline (increases and decreases separately) in body weight of ≥7% will 
also be provided by timepoint. 
Clinical laboratory parameters, including changes from Baseline, will be summarized by 
timepoint using descriptive statistics. For selected parameters, the number and percentage of 
subjects with potentially clinically important post-baseline laboratory values will be 
summarized by timepoint as well as across all post-baseline timepoints. The criteria for 
potentially important values will be specified in the SAP. 
Descriptive summary statistics for HAMD-17, CGI-S, SDS, CSFQ-14, and KSS observed 
values, and change from Baseline will be provided by timepoint. 
Treatment responder rate and treatment remission rate will be summarized by timepoint. 
9.5.3 
Other Safety Analyses 
9.5.3.1 
Exposure to Study Drug 
For each subject, the duration of exposure to study drug will be calculated as the number of 
days from first dose date to last dose date inclusive. Descriptive statistics will be tabulated. A 
categorical summary will also be provided using categories defined in the SAP. 
In addition, the maximum dose, final dose, and mean daily dose will be determined for each 
subject and summarized. 
9.5.3.2 
Electrocardiograms 
ECG parameters, including changes from Baseline, will be summarized by timepoint using 
descriptive statistics. Additionally, categorical analyses will be conducted on the incidence of 
subjects with prolonged QTc intervals and changes in QTc intervals in accordance with ICH 
guidelines and Food and Drug Administration (FDA) E14 guidance document. 


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9.5.3.3 
Physical Examinations 
The results of the physical examinations will be tabulated by timepoint. 
9.5.4 
Subgroup Analyses 
Selected subgroup analyses may be performed. Details will be provided in the SAP. 
9.6 
Interim Analyses 
One or more interim analyses may be conducted prior to study completion if required for 
regulatory reporting. 
9.7 
Measures to Minimize Bias 
Not applicable. The present study is open-label. 
9.8 
Breaking the Study Blind/Subject Code 
Not applicable. The present study is open-label. 
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 
notes captured by site personnel as well as laboratory reports, ECG reports, and electronic 
source data. 


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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. 
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. 


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Protocol waivers for eligibility will not be granted by the Sponsor under any circumstances. 
If, during the course of a subject’s post-enrollment participation in the trial it is discovered 
that the subject did not meet all eligibility criteria, this will be reported as a major protocol 
deviation and not a waiver. In this situation, the subject will be discontinued, unless the 
discontinuation presents an unacceptable medical risk. The justification to allow the subject 
to continue in the trial will be made by the Sponsor, with medical input from the Investigator, 
and will be documented. All follow-up safety assessments must be completed and 
documented as outlined in the protocol (Section 6.4). 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:  
• 
Risk Identification: risks to critical trial processes, governing systems, investigational 
product, trial design, data collection, and recording are identified. 


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• 
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 may also be 
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. 
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 


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


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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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Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
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15 LITERATURE REFERENCES 
ACADIA Pharmaceuticals Inc. NUPLAZID® [package insert]. San Diego, CA, May 2019. 
Akerstedt T, Gillberg M. Subjective and objective sleepiness in the active individual. Int J 
Neurosci. 1990;52(1-2):29-37. 
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 
depressive episode. BMC Med. 2011;9:90. 
Chen YW, Dilsaver SC. Lifetime rates of suicide attempts among subjects with bipolar and 
unipolar disorders relative to subjects with other Axis I disorders. Biol Psychiatry. 
1996;39(10):896-899. 
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. 
1997;33:731-745. 
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. 
Murray CJ, Lopez AD. Evidence-based health policy: lessons from the Global Burden of 
Disease Study. Science. 1996;274(5288):740-743. 


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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. 
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. 
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. 


Study: ACP-103-055 
 
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Clinical Study Protocol Amendment 4 
 
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16 APPENDICES 
Appendix A Prohibited and Restricted Medications 
Subjects taking prohibited medications at study entry will not be eligible for the study.  
Subjects who require current treatment with a prohibited medication will be withdrawn from 
the study. 
Subjects who have previously taken a prohibited medication during the study will be 
withdrawn from the study unless:  
• the prohibited medication has been discontinued AND  
• withdrawal from the study presents an unacceptable medical risk to the subject 
The justification to allow the subject to continue in the trial will be made by the 
Sponsor/Medical Monitor with medical input from the Investigator, and will be documented. 
If allowed to remain in the trial, this will be reported as a major protocol deviation and not a 
waiver. 
The table below lists prohibitions and restrictions by medication class, including 
representative medications within class. A prohibited medication is not allowed. A restricted 
medication is allowed only under certain conditions. 
Medication Class 
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 


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Medication Class 
Medicationa 
Prohibition/restrictions 
Antidepressants 
other than 
background therapy 
PROHIBITED 
• 
mirtazapine 
• 
nefazadone 
• 
fluvoxamine 
• 
mianserin 
• 
trazodone 
• 
amitriptyline 
• 
nortriptyline 
• 
imipramine 
• 
trimipramine 
• 
desipramine 
• 
clomipramine 
• 
bupropion 
• 
levomilnacipran 
• 
vilazodone 
• 
vortioxetine 
• 
ketamine 
• 
esketamine 
• 
Prohibited throughout the study 
• 
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 State versus trait, Assessability, 
Face validity, Ecological validity, and 
Rule of three Ps (pervasive, persistent, 
and pathological) (SAFER) Remote 
Interview for 054/059 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 


Study: ACP-103-055 
 
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Medication Class 
Medicationa 
Prohibition/restrictions 
treatment of allergies and as 
antihistamine-decongestant for colds 
only 
• 
First generation antihistamines should 
not be used within 12 hours of an 
efficacy assessment 
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 
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 
• 
Prohibited at study entry and throughout 
the study 


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Medication Class 
Medicationa 
Prohibition/restrictions 
• 
bretylium 
• 
disopyramide 
• 
dofetilide 
• 
dronedarone 
• 
flecainide 
• 
ibutilide 
• 
procainamide 
• 
propafenone 
• 
quinidine 
• 
sotalol, d-sotalol 
Opioids 
PROHIBITED 
• 
methadone 
• 
hydrocodone 
• 
oxycodone 
• 
codeine 
• 
morphine 
• 
Prohibited at study entry and throughout 
the study 
• 
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. 


Study: ACP-103-055 
 
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Date: 11 August 2020 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
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Appendix B Prohibited and Restricted Concomitant Medications: Inhibitors and 
Inducers of Cytochrome P450 Enzyme 3A4 
The information presented here is intended to provide guidance and does not constitute an 
exhaustive list of strong CYP 3A4 enzyme (CYP3A4) inhibitors and inducers. Any questions 
should be discussed with the Medical Monitor or appropriate designee.  
Subjects who require current treatment with a prohibited medication will be withdrawn from 
the study. 
Subjects who have previously taken a prohibited medication during the study will be 
withdrawn from the study unless:  
• the prohibited medication has been discontinued AND  
• withdrawal from the study presents an unacceptable medical risk to the subject 
The justification to allow the subject to continue in the study will be made by the 
Sponsor/Medical Monitor with medical input from the Investigator, and will be documented. 
If allowed to remain in the study, this will be reported as a major protocol deviation and not a 
waiver. 
The metabolism of pimavanserin is affected by strong CYP3A4 inhibitors, resulting in an 
increase in maximum (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. 
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®) 
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®) 


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quinupristin (Synercid®) 
ritonavir (Norvir®, part of Viekira 
Pak™) 
saquinavir (Invirase®) 
telaprevir (Incivek®) 
telithromycin (Ketek®) 
voriconazole (Vfend®) 
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). 


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SAP_001.pdf: 
Official Title: A 52-Week Open-Label Extension Study of Pimavanserin in Subjects 
With Major Depressive Disorder and Inadequate Response to Antidepressant 
Treatment 
NCT Numbers: NCT04000009 
Document Date: 11 Feb 2021 
 


Protocol ACP-103-055 
Version 1.0 
Statistical Analysis Plan 
11 February 2021 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc. 
Page 1 of 36 
 
 
STATISTICAL ANALYSIS PLAN 
 
Protocol No.: 
ACP-103-055 
Protocol Title: 
A 52-Week Open-Label Extension Study of 
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, 11 February 2021 
 
 
 


Protocol ACP-103-055 
Version 1.0 
Statistical Analysis Plan 
11 February 2021 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc. 
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SIGNATURE/APPROVAL PAGE 
AUTHOR 
See appended electronic signature page 
_____________________________________________ 
____________ 
 
 Date 
Consultant, Biostatistics  
Acadia Pharmaceuticals Inc. 
 
 
APPROVERS 
See appended electronic signature page 
_____________________________________________ 
____________ 
                                                                                           Date 
Executive Director, Clinical Research  
Acadia Pharmaceuticals Inc. 
See appended electronic signature page 
_____________________________________________ 
____________ 
  
 Date 
Executive Director, Biostatistics 
Acadia Pharmaceuticals Inc. 
 
 
 
 
 


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Signature Page for ACP-103-055 SAP
Approve
ics
11-Feb-2021 20:57:31 GMT+0000
Approve
stics
11-Feb-2021 20:58:00 GMT+0000
Approve
11-Feb-2021 21:07:41 GMT+0000


Protocol ACP-103-055 
Version 1.0 
Statistical Analysis Plan 
11 February 2021 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc. 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ........................................................................................................... 4 
LIST OF TABLES ..................................................................................................................... 7 
LIST OF FIGURES ................................................................................................................... 7 
ABBREVIATIONS .................................................................................................................... 8 
1 INTRODUCTION ............................................................................................................... 9 
2 OBJECTIVES ...................................................................................................................... 9 
2.1 
Primary Objective ............................................................................................................ 9 
2.2 
Exploratory Objectives .................................................................................................... 9 
3 STUDY DESIGN ................................................................................................................. 9 
3.1 
General Study Design ...................................................................................................... 9 
3.2 
Schedule of Assessments ............................................................................................... 10 
3.3 
Randomization ............................................................................................................... 11 
3.4 
Blinding ......................................................................................................................... 11 
3.5 
Determination of Sample Size ....................................................................................... 11 
3.6 
Coronavirus Disease 2019 ............................................................................................. 11 
4 ANALYSIS SETS .............................................................................................................. 11 
5 DATA HANDLING CONVENTIONS .............................................................................. 12 
5.1 
General Data Reporting Conventions ............................................................................ 12 
5.2 
Derived Variables........................................................................................................... 13 
5.2.1 
Columbia-Suicide Severity Rating Scale (C-SSRS) ................................................. 13 
5.2.2 
Extrapyramidal Symptom Rating Scale–Abbreviated (ESRS-A) ............................. 13 
5.2.3 
Changes in Sexual Functioning Questionnaire Short Form (CSFQ-14) ................... 14 
5.2.4 
Clinical Global Impressions Scale – Severity (CGI-S) ............................................. 14 
5.2.5 
Hamilton Rating Scale for Depression – 17 Items .................................................... 14 
5.2.6 
Sheehan Disability Scale (SDS) ................................................................................ 15 
5.2.7 
Karolinska Sleepiness Scale (KSS) ........................................................................... 15 
5.3 
Analysis Visit Windows ................................................................................................. 15 
5.3.1 
Unscheduled Assessments ......................................................................................... 16 
5.3.2 
Multiple Measurements within Visit Windows ......................................................... 16 
5.4 
Data Handling Conventions........................................................................................... 17 
5.4.1 
Missing or Incomplete Date for Last Dose of Study Drug ........................................ 17 
5.4.2 
Missing or Incomplete Dates for Concomitant or Post-Treatment Medications ....... 17 


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Statistical Analysis Plan 
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5.4.3 
Missing or Incomplete Dates for Adverse Events ..................................................... 17 
5.4.4 
Missing Severity Assessment for Adverse Events ..................................................... 17 
5.4.5 
Missing Relationship to Study Drug for Adverse Events .......................................... 18 
5.4.6 
Character Values of Clinical Laboratory Variables.................................................... 18 
6 SUBJECT DISPOSITION ................................................................................................. 18 
7 PROTOCOL DEVIATIONS .............................................................................................. 18 
8 DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS .......................... 19 
9 MEDICAL HISTORY ....................................................................................................... 19 
10 EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE ................................... 20 
10.1 Exposure to Study Drug ................................................................................................ 20 
10.1.1 
Exposure to Open-label Pimavanserin ...................................................................... 20 
10.1.2 
Total Exposure to Pimavanserin Across the Double-blind and Open-label Periods . 20 
10.2 Measurement of Treatment Compliance ........................................................................ 21 
11 CONCOMITANT AND POST-TREATMENT MEDICATION ....................................... 21 
12 EFFICACY ANALYSES ................................................................................................... 22 
12.1 Efficacy Variables .......................................................................................................... 22 
12.2 Adjustment for Covariates ............................................................................................. 22 
12.3 Handling of Missing Data .............................................................................................. 22 
12.4 Multiple Comparisons / Multiplicity ............................................................................. 22 
12.5 Examination of Subgroups ............................................................................................ 23 
13 METHODS OF EFFICACY ANALYSES ........................................................................ 23 
14 SAFETY ANALYSES ....................................................................................................... 23 
14.1 Adverse Events .............................................................................................................. 23 
14.2 Clinical Laboratory Variables ........................................................................................ 24 
14.3 Vital Signs ...................................................................................................................... 28 
14.4 Electrocardiogram (ECG) .............................................................................................. 29 
14.5 Physical Examination .................................................................................................... 30 
14.6 Other Safety Variables ................................................................................................... 31 
14.6.1 
Suicidality Based on C-SSRS .................................................................................... 31 
14.6.2 
CGI-S Score Based on ESRS-A ................................................................................ 31 
14.6.3 
Sexual Dysfunction Based on CSFQ-14 ................................................................... 31 
15 CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES ........ 31 


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16 INTERIM ANALYSIS ....................................................................................................... 31 
17 DATA MONITORING/REVIEW COMMITTEE ............................................................. 31 
18 COMPUTER METHODS ................................................................................................. 31 
19 CHANGES TO ANALYSES SPECIFIED IN PROTOCOL ............................................. 32 
20 REFERENCES .................................................................................................................. 32 
21 APPENDICES ................................................................................................................... 33 
Appendix A 
Schedule of Events and Assessments .............................................................. 33 
Appendix B 
Summary of Version Changes ......................................................................... 36 
 


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LIST OF TABLES 
Table 1 
Analysis Visit Windows ................................................................................... 16 
Table 2 
Criteria for Potentially Clinically Important Laboratory Values – 
Hematology and Chemistry ............................................................................. 27 
Table 3 
Criteria for Potentially Clinically Important Laboratory Values - 
Urinalysis ......................................................................................................... 28 
Table 4 
Criteria for Potentially Clinically Important Vital Signs ................................. 29 
Table 5 
Criteria for Potentially Clinically Important ECG Values ............................... 30 
 
LIST OF FIGURES 
Figure 1 
Schematic of Study Design .............................................................................. 10 
 


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ABBREVIATIONS 
AE 
adverse event 
ATC 
Anatomical Therapeutic Chemical 
BMI 
body mass index 
CGI-S 
Clinical Global Impression scale – Severity 
COVID-19 
Coronavirus disease 2019 
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 
GSD 
Guidance for Site Documentation and Data Management Querying of 
Data Impacted by COVID-19 
HAMD-17 
Hamilton Depression Scale (17 items)  
MedDRA 
Medical Dictionary for Regulatory Activities 
msec 
milliseconds 
OL 
open-label 
PCI 
potentially clinically important 
QTcB 
QT interval corrected for heart rate using Bazett’s formula 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS® 
Statistical Analysis System 
SD 
standard deviation 
SE 
standard error 
SOC 
system organ class 
TEAE   
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 


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1 INTRODUCTION 
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the 
statistical analyses of safety and efficacy data as described in the study protocol Amendment 
4 dated 11 August 2020. Specifications for tables, figures, and listings are contained in a 
separate document. 
2 OBJECTIVES 
2.1 
Primary Objective 
• To assess the safety and tolerability of long-term pimavanserin treatment in subjects 
with major depressive disorder and inadequate response to antidepressant treatment 
2.2 
Exploratory Objectives 
• To explore the safety and tolerability of long-term pimavanserin treatment in subjects 
with major depressive disorder and inadequate response to antidepressant treatment 
on the following: 
o suicidality 
o extrapyramidal symptoms 
o general health assessments 
• To explore the benefits of long-term pimavanserin treatment in subjects with major 
depressive disorder and inadequate response to antidepressant treatment on the 
following: 
o improvement of depression symptoms 
o clinical global impression of severity of depressive symptoms 
o functional impairment 
o sexual functioning 
3 STUDY DESIGN 
3.1 
General Study Design 
This study is an open-label extension study to evaluate the long-term safety and tolerability 
of pimavanserin in subjects with major depressive disorder and inadequate response to 
antidepressant treatment. This study will be conducted as a 52-week extension of Studies 
ACP-103-054, and -059. 


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Subjects who have completed Studies ACP-103-054, or -059, who continue to meet entry 
criteria, and who may continue to benefit from adjunctive pimavanserin treatment based on 
the Investigator’s judgment will be included in this long-term extension study.  
All subjects will receive pimavanserin once-daily dosing at 34 mg over 52 weeks of 
treatment. During the treatment period, clinic visits will be conducted at Baseline and 
Weeks 2, 4, 8, 12, 16, 28, 40, and 52 (EOT), or upon early termination (ET) from the study. 
Study drug will be dispensed to the subject to take home at the Baseline visit and at Weeks 4, 
8, 12, 16, 28, and 40. The subject will be instructed to take the first dose of study drug on the 
day after the Baseline visit. It is recommended that the subject should take the study drug at 
approximately the same time each day. 
A 30-day safety follow-up telephone contact is to be completed for subjects who complete 
the treatment period of the study, as well as those who discontinue prematurely from the 
study. 
Figure 1 illustrates the study design. 
 
Figure 1 
Schematic of Study Design 
 
Abbreviation: QD=once daily 
Note: The antecedent study is either Study ACP-103-054 or Study ACP-103-059. 
 
3.2 
Schedule of Assessments 
Schedule of events and assessments can be found in Appendix A.


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3.3 
Randomization 
Not applicable. 
3.4 
Blinding 
Not applicable. 
3.5 
Determination of Sample Size 
It is estimated that approximately 420 subjects from Study ACP-103-054 and 
Study ACP-103-059 will be eligible to enter this study. The sample size for this study is not 
based on statistical power, but will depend on the number of subjects who transition into this 
open-label extension study from the antecedent studies, Study ACP-103-054 and 
Study ACP-103-059. 
ACP-103-054, -059 and -055 were stopped early; the estimated number of subjects will be 
less than originally estimated. 
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] in 
the Data Management Plan).  
Screening and enrollment into studies ACP-103-054 and ACP-103-059 were closed and 
enrollment into ACP-103-055 was allowed to continue. The impact of COVID-19 on the 
statistical analysis is discussed in each of the relevant sections of this SAP. 
Subjects who remained in this study who could not attend clinic visits were allowed to 
participate in remote visits via telephone or video, or site staff conducted the visit in a 
subject’s home. Sites were required to document details of all visits that are administered 
remotely. 
Afterwards, ACP-103-055 was stopped early and the remaining subjects were discontinued in 
the study. 
4 ANALYSIS SETS 
The Safety Analysis Set will consist of all enrolled subjects who have taken at least one dose 
of open-label study drug. The Safety Analysis Set will be used for all analyses. 


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5 DATA HANDLING CONVENTIONS 
All data collected in the study will be listed. 
5.1 
General Data Reporting Conventions 
For continuous variables, the following summary statistics will be provided: number of 
subjects, mean, standard error of the mean (SE), standard deviation (SD), minimum, 
maximum, and median. Unless specified otherwise, means, and medians will be presented to 
one more decimal place than the raw data, and the SDs and SEs will be presented to 2 more 
decimal places than the raw data. 
For categorical variables, summaries will include the number and percentage of subjects in 
each category, using the number of subjects with non-missing values as the denominator for 
the percentages (unless otherwise specified). Categories with zero counts will not have zero 
percentages displayed. Percentages will be presented to 1 decimal place.  
When converting number of days to months, it will be calculated as the number of days 
divided by 365.25 and then multiplied by 12. When converting number of days to years, it 
will be calculated as the number of days divided by 365.25. 
No hypothesis testing is planned. Descriptive summaries of all safety and efficacy endpoints 
will be provided.  
All safety and efficacy endpoints will be summarized for the Safety Analysis Set. In addition, 
summaries by treatment group according to the original double–blinded treatment actually 
received in the antecedent study (placebo or pimavanserin) will also be provided.  
For each continuous measure in safety and efficacy analyses, change from Baseline results 
will be presented in two ways: 
1. Main analysis: using the Baseline from Study ACP-103-055 and reporting the 
changes across Study ACP-103-055 timepoints 
2. Exploratory analysis: using the Baseline from the antecedent study (ACP-103-054 or 
ACP-103-059), and reporting the changes across Study ACP-103-055 timepoints 
For the treatment responder rate, the summary will also be presented in two ways: 
1. Main analysis: using the Baseline from Study ACP-103-055 and reporting the rate 
across Study ACP-103-055 timepoints 
2. Exploratory analysis: using the Baseline from the antecedent study (ACP-103-054 or 
ACP-103-059), and reporting the rate across Study ACP-103-055 timepoints 


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The treatment remission rate and the percentage of subjects with sexual dysfunction will 
also be summarized across Study ACP-103-055 timepoints using the Baseline from 
Study ACP-103-055 and the Baseline from the antecedent double-blind studies as reference 
points. 
5.2 
Derived Variables 
In general, the assessment scale total scores and subscores will be derived within the analysis 
datasets. In the event that total scores and/or subscores are also collected on the electronic 
case report form (eCRF), the derived values will be used for all analyses. Both the raw and 
derived scores will be presented in listings. 
5.2.1 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is assessed at Baseline, Weeks 2, 4, 8, 12, 16, 28, 40, and 52 (EOT/ET). 
C-SSRS is a safety assessment and subjects rolled over from all antecedent studies will be 
assessed. 
The C-SSRS version assessing information since the last visit will be completed at all 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, this subject will be counted as having suicidal ideation. 
There are 5 questions about suicidal behavior, representing 5 types of suicidal behavior: 
preparatory acts or behavior; aborted attempt; interrupted attempt; actual attempt; suicide. If 
a subject answers “yes” to any of these 5 questions, this subject will be counted as having 
suicidal behavior. 
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. 
Missing C-SSRS item scores will not be imputed. 
5.2.2 
Extrapyramidal Symptom Rating Scale–Abbreviated (ESRS-A) 
The ESRS-A is assessed at Baseline, Weeks 2, 4, 8, 12, 16, 28, 40, and 52 (EOT/ET). 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 


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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. 
5.2.3 
Changes in Sexual Functioning Questionnaire Short Form (CSFQ-14) 
The CSFQ-14 is assessed at Baseline, Weeks 2, 4, 8, 12, 16, 28, 40, and 52 (EOT/ET). 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. 
5.2.4 
Clinical Global Impressions Scale – Severity (CGI-S)  
The CGI-S is assessed at Baseline, Weeks 2, 4, 8, 12, 16, 28, 40, and 52 (EOT/ET). The 
CGI-S is the scale used by the Investigator or designee to rate the severity of the disorder. 
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  
Higher CGI-S scores denote more severe depression. Missing CGI-S scores will not be 
imputed. 
5.2.5 
Hamilton Rating Scale for Depression – 17 Items  
The HAMD-17 is assessed at Baseline, Weeks 2, 4, 8, 12, 16, 28, 40, and 52 (EOT/ET). 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 


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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. 
5.2.6 
Sheehan Disability Scale (SDS) 
The SDS is assessed at Baseline, Weeks 4, 12, 28, and 52 (EOT/ET). 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. 
5.2.7 
Karolinska Sleepiness Scale (KSS) 
The KSS is assessed at Baseline, Weeks 2, 4, 8, 12, 16, 28, 40, and 52 (EOT/ET). 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. 
5.3 
Analysis Visit Windows  
In general, the open-label Baseline assessment will be defined as the last non-missing 
assessment, including those from repeated and unscheduled measurements, before or on the 
first open-label dose date. Exceptions to this definition will be handled on a case by case 
basis. 


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Efficacy and safety assessments will be summarized by analysis visit as presented in Table 1 
below. 
Table 1 
Analysis Visit Windows 
Open-label (OL) Analysis 
Visit Name 
Target Study Day1 
Study Day Interval 
OL Baseline  
1  
≤1 (based on the first OL 
dose date) 
 
OL Week 2 
15 
2 to 21 
OL Week 4 
29 
22 to 42 
OL Week 8 
57 
43 to 70 
OL Week 12 
85 
71 to 98 
OL Week 16 
113 
99 to 154 
OL Week 28 
197 
155 to 238 
OL Week 40 
281 
239 to 322 
OL Week 52 
365 
323 to 379 
OL Follow-up 
395 
380 – maximum 
1 
If the assessment date ≥ first OL dose date, study day = assessment date - first OL dose date + 1, 
otherwise study day = assessment date – first OL dose. Study day 1 is the first OL dose date. 
5.3.1 
Unscheduled Assessments 
Both scheduled and unscheduled assessments, including early termination visits and remote 
visits, will be considered for planned timepoint summaries. All assessments will be presented 
in data listings. 
5.3.2 
Multiple Measurements within Visit Windows 
If more than one assessment falls within a given window then the assessment closest to the 
target study day will be selected for the by-visit summaries. If two assessments are 
equidistant from the target day then the chronologically last assessment will be used for 
summary. 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 summaries where the most extreme values should be selected, e.g. overall post-
baseline minimum, overall post-baseline maximum, and potentially clinically important 
values for overall post-Baseline summaries, all non-missing post-Baseline values should be 
considered, regardless of whether the value is selected for the by-visit summaries. All results 
will be presented in data listings. 


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5.4 
Data Handling Conventions 
5.4.1 
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 or  EOT/ET date, whichever occurs 
earlier. The last expected dosing date will be calculated as the last drug dispense date plus the 
expected dosing interval days. For the incomplete last dose date of the 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. 
For the data summarization before final database lock, if a subject is still ongoing, then this 
subject’s last dose date will be imputed using the database extract date.  
5.4.2 
Missing or Incomplete Dates for Concomitant or Post-Treatment Medications 
Missing or incomplete medication start or end dates will be imputed for the purpose of 
determining whether the medications are taken concomitantly (see Section 11 for definition). 
When the chronological order of medication use relative to the study drug treatment period is 
unclear due to missing or incomplete date(s), the medication will be considered as 
concomitant. The imputation algorithms will be detailed in the analysis dataset specification 
document. The missing or incomplete dates will be displayed in the data listings as reported 
on the eCRF rather than the imputed dates. 
5.4.3 
Missing or Incomplete Dates for Adverse Events  
Missing or incomplete adverse event (AE) start dates will be imputed for the purpose of 
determining whether the AEs are treatment-emergent (see Section 14.1 for definition). When 
the chronological order of an AE onset relative to the study drug treatment period is unclear 
due to missing or incomplete date(s), the AE will be considered as treatment-emergent. The 
imputation algorithms will be 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. 
5.4.4 
Missing Severity Assessment for Adverse Events 
If the severity is missing for a treatment-emergent AE, a severity of “Severe” will be 
assigned. The imputed values for severity assessment will be used for incidence summaries, 
and the actual values will be presented in data listings. 


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5.4.5 
Missing Relationship to Study Drug for Adverse Events 
If the relationship to study drug is missing for a treatment-emergent AE, a causality of 
“Related” will be assigned. The imputed values for relationship to study drug will be used for 
incidence summaries, and the actual values will be presented in data listings. 
5.4.6 
Character Values of Clinical Laboratory Variables  
If the reported value of a clinical laboratory variable cannot be used in a summary due to, for 
example, a character string reported for a numeric variable, an appropriately determined 
coded value will be used in the summary. 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. 
6 SUBJECT DISPOSITION 
The number of sites that evaluated at least one subject for enrollment and number of subjects 
enrolled will be summarized by study (ACP-103-054 and ACP-103-059) and overall. 
Enrolled subjects are subjects who signed informed consent for Study ACP-103-055 and not 
recorded as “rollover failure” on eCRF. 
For enrolled subjects, number and percentage of subjects in the Safety Analysis Set will be 
summarized. A listing will be provided displaying all subjects excluded from the Safety 
Analysis Set (if any), and will include reason(s) for exclusion.  
The number and percentage of subjects in the Safety Analysis Set who completed the study 
or discontinued (all discontinued and by discontinuation reasons including the reasons due to 
COVID-19) will also be summarized. Summaries by study (ACP-103-054 and ACP-103-059) 
will also be presented. 
7 PROTOCOL DEVIATIONS 
Protocol deviations that occurred during the extension study period 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. 
For enrolled subjects, a summary of the number and percentage of subjects with major 
protocol deviations for each deviation category will be presented in three ways: all protocol 
deviations, COVID-19 related protocol deviations, and non COVID-19 related protocol 
deviations. 


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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. 
8 DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
Demographics and open-label Baseline characteristics will be summarized for the Safety 
Analysis Set using descriptive statistics. Summaries by study (ACP-103-054 and 
ACP-103-059) will also be presented. Variables include age, age group (18-40 years and 
>40 years), sex, primary race, ethnicity, height, weight, body mass index (BMI), antecedent 
study (ACP-103-054 and ACP-103-059), Baseline HAMD-17 total score, Baseline 
HAMD-17 total score <24 and ≥24, Baseline CGI-S, Baseline SDS mean score, Baseline 
CSFQ-14 total score, Baseline KSS score, and antidepressant (SSRI and SNRI). 
Race will also be categorized by White vs. Non-White. The eCRF reported age reflects a 
subject’s age at the open-label Baseline visit date. Baseline CGI-S will be summarized as 
both a continuous variable and a categorical variable. 
Depression history will be summarized for Safety Analysis Set 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 open-label 
Baseline visit date) 
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. 
9 MEDICAL HISTORY 
Medical history data will be coded using Medical Dictionary for Regulatory activities 
(MedDRA) version 23.0. The subject incidence will be summarized for each system organ 
class (SOC) and preferred term for the Safety Analysis Set. A subject will be counted only 
once per SOC or per preferred term for the summary. 


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A listing of the SOC, preferred term, body system, verbatim term for the medical history 
condition/event, start and stop dates (when available), and an indicator for whether or not the 
condition is ongoing will be provided. 
10 EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE 
Summaries of exposure and compliance to study drug will be provided for the Safety 
Analysis Set. 
10.1 Exposure to Study Drug  
10.1.1 Exposure to Open-label Pimavanserin 
For each subject, the duration of exposure to open-label pimavanserin (open-label last dose 
date – open-label first dose date + 1) will be calculated and summarized. The number and 
percentage of subjects within each of the following exposure levels in terms of duration of 
exposure will also be tabulated: <2 week (1 to 13 days), 2 to <4 weeks (14 to 27 days), 4 to 
<8 weeks (28 to 55 days), 8 to <12 weeks (56 to 83 days), 12 to <16 weeks (84 to 111 days), 
16 to <28 weeks (112 to 195 days), 28 to <40 weeks (196 to 279 days), 40 to <52 weeks 
(280 to 363 days), ≥52 weeks (≥364 days). 
In addition, the maximum dose in the open-label period, final dose in open-label period, and 
the mean daily dose during open-label period will be determined for each subject and 
summarized. The mean daily dose will be calculated as the number of pimavanserin tablets 
taken in the open label period multiplied by 17 (mg) divided by the duration of total exposure 
in the open-label period in days. 
10.1.2 Total Exposure to Pimavanserin Across the Double-blind and Open-label 
Periods  
For subjects who received pimavanserin in the antecedent studies, the total duration of 
exposure (in days) to pimavanserin will be calculated as the sum of the exposure durations in 
the double-blind and open-label periods:  
[(date of last double-blind dose) – (date of first double-blind dose) + 1] + [(date of last open-
label dose) – (date of first open-label dose) + 1]. 
In case that a subject whose last dose date in the antecedent study is equal the first dose date 
in the extension study, the total duration of exposure (in days) to pimavanserin will be the 
exposure durations in the double-blind and open-label periods minus one (i.e. the above 
formula minus one). For subjects who received placebo in the antecedent studies, the total 
duration of exposure to pimavanserin across the double-blind and open-label periods will be 
the same as the values calculated for the open-label study period alone. Duration of total 
exposure across the double-blind and open-label periods will be summarized descriptively. 


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Duration of total exposure will also be tabulated as a categorical variable: <2 week (1 to 13 
days), 2 to <4 weeks (14 to 27 days), 4 to <8 weeks (28 to 55 days), 8 to <12 weeks (56 to 83 
days), 12 to <16 weeks (84 to 111 days), 16 to <28 weeks (112 to 195 days), 28 to <40 weeks 
(196 to 279 days), 40 to <52 weeks (280 to 363 days), 52 to <54 weeks (364 to 377 days), 
54 to <56 weeks (378 to 391 days), 56 to <57 weeks (392 to 398 days), and ≥57 weeks (≥399 
days).  
In addition, the maximum dose across the double-blind and open-label periods and the mean 
daily dose across the double-blind and open-label periods will be determined for each subject 
and summarized. The mean daily dose will be calculated as the number of pimavanserin 
tablets taken across the double-blind and open-label periods multiplied by 17 (mg) divided by 
the duration of total exposure across the double-blind and open-label periods in days. 
10.2 Measurement of Treatment Compliance 
Study drug dosing compliance (in percentage) during the open-label study period for a 
subject is defined as: 
(𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡)
(𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑡𝑡𝑡𝑡 𝑏𝑏𝑏𝑏 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡) × 100. 
The total number of tablets actually taken is calculated as: 
(the total number of tablets dispensed) – (the total number of tablets returned). 
The total number of tablets expected to be taken is calculated as:  
(the duration of exposure) × 2. 
For any visit with unreturned drug kits, the total number of tablets actually taken will be 
imputed as the total number of tablets expected to be taken for that visit period. 
Compliance will be summarized as both continuous and categorical variables. For categorical 
presentation, the number and percentage of subjects in each of the following categories will 
be presented: <80%, 80 to 120%, and >120%. 
11 CONCOMITANT AND POST-TREATMENT MEDICATION 
Concomitant medication is defined as any medication with a start date prior to the date of the 
open-label first dose and continuing after the open-label first dose date or with a start date 
between the open-label first dose date and open-label last dose date, inclusive. Any 
medication with a start date after the open-label last dose date will be considered as post-
treatment medication. Concomitant and post-treatment medications will be summarized 
separately. 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 


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summarized by relationship to COVID-19 (Not related to COVID-19 vs. Related to 
COVID-19). 
Medications will be coded using WHO Drug Dictionary March 2020. For concomitant 
medications, the number and percentage of subjects taking each drug class (ATC Level 3) 
and medication preferred term will be tabulated for Safety Analysis Set. A subject will be 
counted only once per drug class or per medication preferred term for the summary. 
12 EFFICACY ANALYSES 
All efficacy analyses will be performed for the Safety Analysis Set. No hypothesis testing is 
planned. Descriptive summaries of all efficacy endpoints will be provided. 
12.1 Efficacy Variables 
Efficacy Endpoints 
• Change from Baseline in Hamilton Depression Scale (17 items) (HAMD-17) total 
score 
• Treatment responder rates. Treatment response is defined as a reduction from 
Baseline in HAMD-17 total score of 50% or more. 
• Treatment remission rates. Treatment remission is defined as a HAMD-17 total score 
≤7. 
• Change from Baseline in Clinical Global Impression–Severity (CGI-S) score for 
depressive symptoms 
• Change from Baseline in Sheehan Disability Scale (SDS) mean score 
• Change from Baseline in the Changes in Sexual Functioning Questionnaire Short 
Form (CSFQ-14) total score 
• Change from Baseline in Karolinska Sleepiness Scale (KSS) score 
12.2 Adjustment for Covariates 
Not applicable. 
12.3 Handling of Missing Data 
Any derived scores (i.e. total, domain, or subscale scores) that are missing, after the 
imputation of individual missing items as described in Section 5.2, will not be imputed. 
12.4 Multiple Comparisons / Multiplicity 
No hypothesis testing is planned. 


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12.5 Examination of Subgroups 
Summaries for below subgroups will be tabulated for the change from Baseline in the 
HAMD-17 total score, the SDS mean score, the CGI-S score, the CSFQ-14 score, and the 
KSS score: 
• age group (18-40 years and >40 years) 
• sex (male and female) 
• background antidepressant type (SSRI [citalopram, escitalopram, paroxetine, fluoxetine, 
or sertraline] and SNRI [duloxetine, venlafaxine, desvenlafaxine, or venlafaxine XR]) 
13 METHODS OF EFFICACY ANALYSES 
Descriptive statistics for all efficacy endpoints listed in Section 12.1 including treatment 
responder and remission rates will be tabulated by the double-blind treatment group in the 
antecedent studies at scheduled timepoints. The summaries of the change from Baseline 
results will be presented in two ways (main analysis and exploratory analysis) as specified in 
Section 5.1. 
14 SAFETY ANALYSES 
The safety summaries will be presented for the Safety Analysis Set using descriptive 
statistics. Safety variables include AEs, clinical laboratory variables, vital signs, body weight, 
BMI, physical examinations, ECG, C-SSRS, ESRS-A, and sexual dysfunction defined as a 
CSFQ-14 total score of ≤47 for men and ≤41 for women. Safety variables will also be 
summarized by the double-blind treatment group in the antecedent studies. For each 
continuous measure in clinical laboratory variables, vital signs, and electrocardiogram, 
change from Baseline results will be presented in two ways (main analysis and exploratory 
analysis) as specified in Section 5.1. 
14.1 Adverse Events  
An AE is considered as treatment-emergent adverse event (TEAE) if it started on or after the 
open-label first study dose date and no later than the open-label last study dose date + 30 
days. 
The event counts and the number and percentage of subjects reporting TEAEs will be 
tabulated by SOC and preferred term; and, by SOC, preferred term, and maximum severity. If 
more than 1 AE occurs with the same preferred term for the same subject, the subject will be 
counted only once for that preferred term using the most severe occurrence for the 
summarization by severity. In addition, the event counts and the number and percentage of 
subjects with TEAEs classified by the Investigators as related to the study drug, with most 


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frequently reported TEAEs (preferred terms reported by ≥5% of subjects in the Safety 
Analysis Set), with treatment-emergent serious AEs (TESAEs), with fatal AEs (i.e. events 
that cause death), and with TEAEs leading to discontinuation of study drug will be 
summarized by SOC and preferred term. The display in these tables will be sorted 
alphabetically by SOC and then by descending subject frequency for the preferred terms 
(based on counts in the Safety Analysis set) within each SOC. 
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 three ways: all TEAE, 
COVID-19 related TEAE, and not COVID-19 related TEAE. 
The event counts and the number and percentage of subjects with any TEAEs will also be 
tabulated by preferred term without SOCs. The display in this table will be sorted by 
descending subject frequency based on counts in the Safety Analysis set. 
An AE listing by subject will display all events, including those which are not treatment-
emergent, and will include the verbatim term in addition to the MedDRA SOC and preferred 
term. This listing will also include all relevant eCRF data associated with the event: e.g. date 
of onset, date resolved, date of the open-label first dose, date of the open-label last dose, dose 
level at AE onset, severity, frequency, outcome, relationship to study drug, action taken with 
study drug, and required therapy. When a date is presented, the study day associated with the 
date will also be displayed. Separate listings will be presented for subjects with SAEs, 
subjects with AEs leading to discontinuation and subjects who died (if any), and subjects 
with all COVID-19 related AEs.  
14.2 Clinical Laboratory Variables 
Clinical laboratory tests are performed at Baseline, Week 12, and Week 52 (EOT/ET).  
In general, laboratory test results are from a central laboratory. Due to COVID-19 disruptions 
it is possible that some test results may be collected from a local laboratory. A separate eCRF 
will capture local laboratory results in order to facilitate medical monitoring of subject safety. 
Local laboratory results will not be included in any summary data analysis; they will, 
however, be included in separate data listings.  All results (central and local)  will be 
displayed in Système International [SI] units. It is encouraged, but not required, that clinical 
labs be completed under fasting conditions. The listings will include date and study day of 
collection. Out of range values will be flagged in the data listings. 
 
 


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• Hematology tests 
o Complete blood count (CBC) including: 
− 
White blood cell (WBC) count 
− 
Complete differential (relative and absolute) 
− 
Hematocrit (Hct), hemoglobin (Hgb), red blood cells (RBC), platelets 
− 
Reticulocyte count 
• Clinical chemistry serum tests 
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), aspartate aminotransferase (AST), gamma-glutamyl 
transpeptidase (GGT), alkaline phosphatase (ALP), total bilirubin (TBIL), lactate 
dehydrogenase (LDH)  
o Glucose 
o Albumin (ALB), total protein 
o Prolactin  
o Creatine kinase (CK)/creatine phosphokinase (CPK) 
o Lipid panel  
– Total cholesterol, high-density lipoprotein (HDL)-cholesterol, triglycerides, 
low-density lipoprotein(LDL)-cholesterol, very low density lipoprotein 
cholesterol 
• Urinalysis 
o Blood, RBCs, WBCs, protein, glucose, ketones, specific gravity, pH  
Clinical laboratory values reported as continuous values for hematology, chemistry and 
urinalysis will be summarized using descriptive statistics at Baseline and scheduled 
post-Baseline visits. The change from Baseline values will also be summarized at scheduled 
post-Baseline visits. The overall minimum, maximum and last 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 scheduled post-Baseline visits, and the denominator 
is the number of subjects with non-missing values for the given parameter and visit. 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 to determine the number and 
percentage of subjects with values classified as below (low), within (normal), or above (high) 
normal ranges at scheduled post-Baseline visits relative to the same classification at the 
Baseline visit. The shifts from Baseline to overall post-Baseline minimum and overall post-
Baseline maximum will also be presented. For the by-visit shift summary, the denominator is 
the number of subjects with non-missing values at Baseline and the given visit for the given 


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parameter. For the summaries of shift from Baseline to the overall post-Baseline minimum or 
maximum, the denominator is the number of subjects with non-missing Baseline and at least 
1 post-Baseline value for the given parameter. 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). 
Number and percentage of subjects with potentially clinically important (PCI) laboratory 
values at scheduled post-Baseline visits and overall post-Baseline will be summarized by 
Baseline status (all or within normal range) for selected parameters. PCI criteria are listed in 
Table 2 and Table 3. For the overall post-Baseline summaries, all post-Baseline values will be 
considered, including unscheduled and out of window values. Subjects with multiple PCI 
values for a given parameter will be counted only once for that parameter. For the by-visit 
summary, the numerator for the percentage is the number of subjects with a post-Baseline 
PCI value for the given parameter and visit, and the denominator is the number of subjects 
with non-missing values for the given parameter and visit. For the overall post-Baseline 
summary, the numerator for the percentage is the number of subjects with at least 1 
post-Baseline PCI value for the given parameter, and the denominator is the number of 
subjects with at least 1 post-Baseline value for the given parameter. For hemoglobin, 
hematocrit, and uric acid, the count and percentage of subjects with PCI values will be 
presented for each gender as well as for both genders combined.  A listing of all PCI values in 
study ACP-103-055 will be provided. This listing will include all observations from study 
ACP-103-055 for those subjects and parameters for which at least one PCI value (including 
OL Baseline) was observed. 


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Table 2 
Criteria for Potentially Clinically Important Laboratory Values – 
Hematology and Chemistry 
 
Analyte 
Conventional 
Unit 
Low PCI 
Criteria 
High PCI 
Criteria 
SI Unit 
Low PCI 
Criteria 
High PCI 
Criteria 
Hematology (whole blood) 
Hemoglobin (male) 
g/dL 
<11 
>18 
g/L 
<110 
>180 
Hemoglobin 
(female) 
g/dL 
<10 
>17 
g/L 
<100 
>170 
Hematocrit (male) 
% 
<30 
>55 
L/L 
<0.3 
>0.55 
Hematocrit (female) 
% 
<30 
>50 
L/L 
<0.3 
>0.5 
Leukocyte (White 
Blood Cell Count) 
x 103/uL 
≤2.8 
≥15 
x 109/L 
≤2.8 
≥15 
Neutrophils 
x 103/uL 
≤1.5 
No upper limit 
x 109/L 
≤1.5 
No upper limit 
Platelet Count 
x 103/uL 
≤75 
≥700 
109/L 
≤75 
≥700 
Chemistry (serum or plasma) 
ALT (SGPT) 
U/L 
No lower 
limit  
≥3 X ULN 
U/L 
No lower 
limit  
≥3 X ULN 
AST (SGOT) 
U/L 
No lower 
limit  
≥3 X ULN 
U/L 
No lower 
limit  
≥3 X ULN 
Total Bilirubin 
mg/dL 
No lower 
limit 
≥1.5 ULN 
umol/L 
No lower 
limit 
≥1.5 ULN 
BUN 
mg/dL 
No lower 
limit 
≥30.0 
mmol/L 
No lower 
limit 
≥10.71 
Creatine Kinase 
(CK) 
U/L 
No lower 
limit 
≥3 ULN 
U/L 
No lower 
limit 
≥3 ULN 
Sodium 
mEq/L 
≤125 
≥155 
mmol/L 
≤125 
≥155 
Potassium 
mEq/L 
≤3.0 
≥5.5 
mmol/L 
≤3.0 
≥5.5 
Calcium, total 
mg/dL 
<8.0 
>11.0 
mmol/L 
<2.0 
>2.75 
Lactate 
Dehydrogenase 
(LDH) 
U/L 
No lower 
limit 
≥3 X ULN 
U/L 
No lower 
limit 
≥3 X ULN 
Alkaline 
Phosphatase 
U/L 
No lower 
limit 
≥3 X ULN 
U/L 
No lower 
limit 
≥3 X ULN 
Uric acid (male) 
mg/dL 
No lower 
limit 
≥10.5 
umol/L 
No lower 
limit 
≥624.75 
Uric acid (female) 
mg/dL 
No lower 
limit 
≥8.5 
umol/L 
No lower 
limit 
≥505.75 
Albumin 
g/dL 
≤2.6 
≥6.0 
g/L 
≤26 
≥60 
Total Protein 
g/dL 
≤5.0 
≥10.0 
g/L 
≤50 
≥100 
Chloride 
mEq/L 
≤85 
≥120 
mmol/L 
≤85 
≥120 
Glucose (random) 
mg/dL 
≤45.1 
≥200.0 
mmol/L 
≤2.48 
≥11 
Serum Creatinine 
mg/dL 
Not 
Applicable 
>1.5 ULN 
umol/L 
Not 
Applicable 
>1.5 ULN 
Triglycerides 
mg/dL 
Not 
Applicable 
>300 
mmol/L 
Not 
Applicable 
>3.39 
Gamma-Glutamyl 
Transferase (GGT) 
U/L 
Not 
Applicable 
≥3 ULN 
U/L 
Not 
Applicable 
≥3 ULN 
 


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Table 3 
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 
 
The number and percentage of subjects with the shift from baseline, both double-blind and 
open-label, to weeks 12 and 52 that meet the following criteria in the blood lipid parameters 
and glucose will be summarized by 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. 
14.3 Vital Signs 
Vital signs are assessed at Baseline, Weeks 2, 4, 8, 12, 16, 28, 40, and 52 (EOT/ET).  
Vital signs including weight, height (measured at the screening visit of antecedent studies), 
and the derived BMI will be summarized using descriptive statistics at Baseline and all 
scheduled post-Baseline visits. The change from Baseline values will also be summarized at 
the scheduled post-Baseline visits. 
Vital sign values will be considered PCI if they meet the criteria listed in Table 4. The 
number and percentage of subjects with post-Baseline vital signs that are PCI will be 
summarized at scheduled post-Baseline visits and for overall post-Baseline. For the overall 
post-Baseline summaries, all post-Baseline values will be considered, including unscheduled 
and out of window values. Subjects with multiple PCI values for a given parameter will be 
counted only once for that parameter. For the by-visit summary, the numerator for the 
percentage is the number of subjects with a post-Baseline PCI value for the given parameter 
and visit, and the denominator is the number of subjects with non-missing values for the 
given parameter and visit. For the overall post-Baseline summary, the numerator for the 
percentage is the number of subjects with at least 1 post-Baseline PCI value for the given 
parameter, and the denominator is the number of subjects with at least 1 post-Baseline value 


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for the given parameter.  A listing of all PCI values in study ACP-103-055 will be provided. 
This listing will include all observations from study ACP-103-055 for those subjects and 
parameters for which at least one PCI value (including Baseline) was observed. 
Table 4 
Criteria for Potentially Clinically Important Vital Signs 
 
Vital Sign Parameter 
 
Unit 
Criteriaa 
Observed 
Value 
And/Or 
Change Relative to Baseline 
Systolic blood pressure 
(supine or sitting) 
mmHg 
≥180 
And 
Increase of ≥20 
≤90 
And 
Decrease of ≥20 
Diastolic blood pressure 
(supine or sitting) 
mmHg 
≥105 
And 
Increase of ≥15 
≤50 
And 
Decrease of ≥15 
Pulse (supine or sitting) 
bpm 
≥120 
And 
Increase of ≥15 
≤50 
And 
Decrease of ≥15 
Weight 
kg 
Not Applicable 
Increase of ≥7% 
Decrease of ≥7% 
a 
A post-baseline value is considered as a PCI value if it meets both criteria for observed value and change 
from baseline. 
 
14.4 Electrocardiogram (ECG) 
All tracings will be evaluated by qualified clinicians. At the Baseline visit, the machine-read 
results will also be recorded. All data, including the machine-read Baseline results, will be 
listed.  
Observed values of ECG variables (heart rate, PR interval, RR interval, QRS interval, 
QT interval, and QTc intervals) and the changes from Baseline at scheduled visits will be 
summarized.  
QTc intervals include QTcB (Bazett’s formula) and QTcF (Fridericia’s formula). QTcF will 
also be categorized into the following categories (msec) and the number and percentage of 
subjects in each category will be summarized at scheduled visits and overall post-baseline 
maximum: 
• 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. 
For cardiologist’s interpretations, the number and percentage of subjects with ECG results 


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that are determined as normal or abnormal will be summarized at scheduled visits. The 
overall post-baseline worst interpretation will also be summarized (i.e. if a subject has one or 
more ECG results that is/are considered as abnormal, this subject will be counted in the 
abnormal category). Cardiologist’s interpretations will also be summarized in a shift table to 
determine the number and percentage of subjects with ECG results classified as normal or 
abnormal at scheduled post-Baseline visits relative to the same classification at the Baseline 
visit. The shifts from Baseline to overall post-Baseline worst interpretation will also be 
presented. For the by-visit shift summary, the denominator is the number of subjects with 
non-missing cardiologist’s interpretation at Baseline and the given visit. For the summaries 
of shift from Baseline to the overall post-Baseline worst interpretation, the denominator is the 
number of subjects with non-missing Baseline and at least 1 post-Baseline cardiologist’s 
interpretation.  
Electrocardiogram values will be considered PCI if they meet or exceed the upper limit 
values listed in Table 5. The number and percentage of subjects with PCI values will be 
summarized at scheduled post-Baseline visits and for overall post-Baseline. For the by-visit 
summary, the numerator for the percentage is the number of subjects with a post-Baseline 
PCI value for the given parameter and visit, and the denominator is the number of subjects 
with non-missing values for the given parameter and visit. For the overall post-Baseline 
summary, the numerator for the percentage is the number of subjects with at least 1 post-
Baseline PCI value for the given parameter, and the denominator is the number of subjects 
with at least 1 post-Baseline value for the given parameter. A listing of all PCI values in study 
ACP-103-055 will be provided. This listing will include all observations from study 
ACP-103-055 for those subjects and parameters for which at least one PCI value (including 
OL Baseline) was observed. 
Table 5 
Criteria for Potentially Clinically Important ECG Values 
ECG Parameter 
Unit 
High PCI Criteria 
QRS Interval 
msec 
≥120 
PR Interval 
msec 
≥220 
QTcB or QTcF 
msec 
>500 
QTcB or QTcF: change from baseline 
msec 
>60 
 
14.5 Physical Examination 
Physical examination is performed at Baseline, Week 28, and Week 52(EOT/ET). Physical 
examination results (normal, abnormal, and not done) will be summarized at each visit in a 
frequency table by body system. 


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14.6 Other Safety Variables 
14.6.1 Suicidality Based on C-SSRS 
The event counts and the number and percentage of subjects reporting any post double-blind 
Baseline suicidal ideation, suicidal behavior, or suicidality will be tabulated by the double-
blind treatment group in the antecedent studies across the timepoints of both the antecedent 
study and the open-label Study ACP-103-055. The event counts and the number and 
percentage of subjects reporting any post-Baseline non-suicidal self-injurious behavior will 
also be tabulated. For calculating the percentages, the denominator will be the number of 
subjects in the Safety Analysis Set. In addition, a summary counting of any reports post 
open-label Baseline will be presented. 
14.6.2 CGI-S Score Based on ESRS-A 
Descriptive statistics for ESRS-A CGI-S score will be tabulated by the double-blind 
treatment group in the antecedent studies at scheduled timepoints. The summaries of the 
change from Baseline results will be presented in two ways (main analysis and exploratory 
analysis) as specified in Section 5.1. 
14.6.3 Sexual Dysfunction Based on CSFQ-14 
The number and percentage of subjects with sexual dysfunction defined as a CSFQ-14 total 
score of ≤47 for men and ≤41 for women will be tabulated by the double-blind treatment 
group in the antecedent studies across the antecedent study double-blind baseline visit and 
the open-label Study ACP-103-055 timepoints. For calculating the percentages, the 
denominator will be the number of subjects in the Safety Analysis Set. 
15 CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
Not applicable. 
16 INTERIM ANALYSIS 
One or more interim analyses may be planned in this study to support regulatory 
submissions. 
17 DATA MONITORING/REVIEW COMMITTEE 
There is no data monitoring/review committee in this study. 
18 COMPUTER METHODS  
Statistical analyses will be performed using Version 9.4 (or newer) of SAS (SAS® Institute, 
Inc., Cary, North Carolina) on a suitably qualified and validated environment. 
Validation and quality control of the tables, listings and figures containing the results of the 
statistical analyses will follow appropriate standard operating procedures. 


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19 CHANGES TO ANALYSES SPECIFIED IN PROTOCOL 
None. 
 
20 REFERENCES 
1. FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 
Pandemic, March 2020; updated May 14, 2020. 
2. EMA Guidiance on the Management of Clinical Trials during the COVID-19 
(Coronavirus) pandemic, March 2020. 


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21  APPENDICES 
Appendix A Schedule of Events and Assessments 
Period Baselinec 
Treatment Period 
 
Safety 
Follow-Upm 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
(EOT/ET) 
9 
Unscheduled 
Visitl 
10 
Visit Weeka 
Week 
0 
Week 
2 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
28 
Week 
40 
Week  
52 
Week 
56 
Type of visitb
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Phone call 
Visit window (# days) 
 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
+7 
 
+7 
Informed consent and if applicable, 
privacy formsc 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
Medical history, medication history, and 
demographicsd 
X 
 
 
 
 
 
 
 
 
 
 
Psychiatric historyd 
X 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
X 
 
X 
 
 
Vital signs and weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECGe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Clinical laboratory testsf 
X 
 
 
 
X 
 
 
 
X 
 
 
Pregnancy testg 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Urine drug screen 
X 
 
 
 
X 
 
 
 
X 
 
 
ESRS-A 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRS  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
HAMD-17h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
CGI-S 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
SDS 
X 
 
X 
 
X 
 
X 
 
X 
 
 
CSFQ-14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
KSS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of AEsi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense study drug 
Xj,k 
 
X 
X 
X 
X 
X 
X 
 
Xm 
 


Protocol ACP-103-055 
 
 
   
 
          Version 1.0 
Statistical Analysis Plan 
 
 
 
 
11 February 2021 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc. 
Page 34 of 36 
Period Baselinec 
Treatment Period 
 
Safety 
Follow-Upm 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
(EOT/ET) 
9 
Unscheduled 
Visitl 
10 
Visit Weeka 
Week 
0 
Week 
2 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
28 
Week 
40 
Week  
52 
Week 
56 
Study drug accountability 
Xk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Review of background antidepressant 
adherence  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: AE=adverse event; CGI-S=Clinical Global Impression–Severity; CSFQ-14=Changes in Sexual Functioning Questionnaire Short Form; C-   
SSRS=Columbia–Suicide Severity Rating Scale; ECG=electrocardiogram; 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; SDS=Sheehan Disability Scale 
a 
Study visits are designated by weeks and have a ±3-day window (Visits 2 through 5), or a ±7-day window (Visits 6 through 8), or a +7-day window (Visits 9 
and 10), and are calculated from the Baseline Visit. 
b 
If visit is performed remotely due to the COVID-19 pandemic, please refer to Sections 3.1.3 (impact of COVID-19 pandemic), 6.2.6 (exploratory efficacy 
assessments), 6.3.8 (safety assessments) and 6.5.1 (unscheduled visits) of the protocol for further information. 
c  
Subject consent for the present study must be obtained for entry into the present study prior to the final procedures being performed at the end of treatment 
(EOT) visit in the antecedent study, Study ACP-103-054 or Study ACP-103-059. Data from the EOT visit procedures of Study ACP-103-054 and Study 
ACP-103-059 will be carried over as baseline information in the present study, as applicable. 
d 
Relevant information collected from Study ACP-103-054 and Study ACP-103-059 will be rolled over to the present study; any updates to this information 
should be collected during the Baseline visit of the present study. 
e 
A single 12-lead ECG can be performed any time before blood sampling or at least 30 minutes after blood sampling during clinic visits. ECGs should be 
completed with the subject in a supine position after 5 minutes of rest. 
f 
To include hematology, serum chemistry, prolactin levels, and urinalysis. 
g 
A urine pregnancy test should be performed for female study subjects of childbearing potential. If urine cannot be obtained in women of childbearing 
potential, a serum pregnancy test should be done in its place. 
h 
The HAMD-17 is to be the first scale completed at each visit. 
i 
All ongoing AEs from Study ACP-103-054 and Study ACP-103-059 will be carried over after informed consent has been obtained for the present study and 
recorded from Baseline for the present study until resolution or the follow-up safety assessment. An AE occurring after the completion of procedures at the 
EOT visit in Study ACP-103-054 or Study ACP-103-059 will be recorded as an AE in the present study. 
j 
Study drug will be dispensed to the subject to take home at the Baseline visit. The subject will be instructed to take the first dose of study drug on the 
following day. 
k 
The used and unused treatment kits, blister cards, and tablets from Study ACP-103-054 and Study ACP-103-059 are to be collected by the Investigator as 
part of the EOT visit of Study ACP-103-054 and Study ACP-103-059 before study drug for the present study can be dispensed. 
l 
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. 


Protocol ACP-103-055 
 
 
   
 
          Version 1.0 
Statistical Analysis Plan 
 
 
 
 
11 February 2021 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc. 
Page 35 of 36 
m 
Study drug may be dispensed to the subject at unscheduled visits if needed. 
n 
This visit is a safety follow-up telephone call visit for subjects who discontinue prematurely from the study or who complete the present study. This visit will 
occur at least 30 days after the last dose of study drug. 


Protocol ACP-103-055 
          Version 1.0 
Statistical Analysis Plan 
11 February 2021 
Confidential and Proprietary Information of Acadia Pharmaceuticals Inc. 
Page 36 of 36 
 
Appendix B Summary of Version Changes   
Version No: 
Document History 
Description of Update 
Author(s) 
Version Date 
1.0 
 
 
11 February 2021