A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled, Study to Evaluate the Efficacy and Safety of Adjunctive Pimavanserin in Major Depressive Disorder
Phase: PHASE2
Conditions: Adjunctive Treatment of Major Depressive Disorder
Sponsor: ACADIA Pharmaceuticals Inc.

Official Title: A Phase 2, multicenter, randomized, double-blind, placebo-controlled, 
study to evaluate the efficacy and safety of adjunctive pimavanserin in major 
depressive disorder 
NCT Number: NCT03018340 
Date of IRB Approval: 26 April 2017 

 
 
 
ACADIA Pharmaceuticals Inc. 
 
 
Clinical Study Protocol  
UNMASKED PROTOCOL FOR DISTRIBUTION TO ETHICS 
COMMITTEES AND REGULATORY AUTHORITIES ONLY 
 
A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled, 
Study to Evaluate the Efficacy and Safety of Adjunctive Pimavanserin in 
Major Depressive Disorder 
 
Protocol No. ACP-103-042 
 
Original Protocol Date: 09 September 2016 
Protocol Amendment 1 Date:  26 April 2017 
 
Confidentiality Statement 
This protocol amendment is the confidential information of ACADIA Pharmaceuticals Inc. 
and is intended solely for the guidance of the clinical investigation.  This protocol 
amendment may not be disclosed to parties not associated with the clinical investigation or 
used for any purpose without the prior written consent of ACADIA Pharmaceuticals Inc. 
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PROTOCOL SYNOPSIS 
Protocol Number ACP-103-042 
Title 
A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled, 
Study to Evaluate the Efficacy and Safety of Adjunctive Pimavanserin in 
Major Depressive Disorder 
Phase of 
Development 
2 
Name of Drug 
Pimavanserin 
Indication 
Adjunctive Treatment of Major Depressive Disorder 
ACADIA 
ACADIA Pharmaceuticals Inc. 
 
 
 
Medical Monitor 
 
 
 
 
 
Test Product, 
Dose, and Mode 
of 
Administration 
Pimavanserin 34 mg (provided as 2×17 mg tablets), and matching 
placebo (2×placebo tablets); oral administration as a single dose once 
daily (QD).  17 mg of the active moiety is dosed as 20 mg of the salt 
pimavanserin tartrate. 
Concurrent 
Control 
Placebo 
Objectives 
Primary Objective 
To assess the efficacy of pimavanserin compared to placebo when given 
adjunctively to a selective serotonin reuptake inhibitor (SSRI)/serotonin-
norepinephrine reuptake inhibitor (SNRI) antidepressant as treatment of 
patients with Major Depressive Disorder (MDD) and an inadequate 
response to antidepressant therapy 
Secondary Objectives 
To evaluate the efficacy of pimavanserin compared with placebo for the 
following: 
• patient disability 
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• clinician’s global assessment of treatment benefit 
• quality of life 
• drug attitude 
• sleep 
• sexual functioning 
• impulsivity 
• irritability 
To assess the safety and tolerability of adjunctive pimavanserin compared 
to placebo 
To characterize the pharmacokinetics (PK) of pimavanserin administered 
as adjunct to SSRI/SNRI antidepressants in MDD patients 
To assess the pharmacokinetics/pharmacodynamics (PK/PD) using 
measures of safety, efficacy, and sleep parameters 
Study Design 
Multicenter, randomized, double-blind, placebo-controlled, 2-stage 
Sequential Parallel Comparison Design (SPCD) study in patients with 
MDD and an inadequate response to antidepressant therapy with 
concurrent SSRI/SNRI.  MDD and Major Depressive Episode (MDE) are 
defined by the Diagnostic and Statistical Manual of Mental Disorders, 
Fifth Edition (DSM-5), confirmed by the Structured Clinical Interview 
for DSM-5, Clinical Trials Version (SCID-5-CT).  Inadequate treatment 
response will be determined through the administration of the 
Massachusetts General Hospital Antidepressant Treatment Questionnaire 
(MGH ATRQ). 
Study Periods 
• Screening (8-21 days) 
• Stage 1 Double-blind treatment  (5 weeks) 
• Stage 2 Double-blind treatment  (5 weeks) 
• Safety follow-up period (approximately 30 days) 
Screening Period 
During the Screening phase, subjects will be assessed for study 
eligibility.  The Screening phase will be 8 to 21 days in duration.  All 
prohibited medications should be discontinued during the Screening 
phase and prior to the Baseline visit. 
Stage 1 Double-blind Treatment Period 
Subjects who meet the criteria for study eligibility will continue to 
receive their SSRI/SNRI antidepressant at a stable dose for the duration 
of the study and will be randomly assigned (1:3) to pimavanserin 
34 mg/day or placebo. 
Clinic visits occurring after Baseline will be conducted at Weeks 1, 2, 3, 
4, and 5 (End-of-Stage 1). 
Stage 2 Double-blind Treatment Period 
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At the end of Stage 1 (Week 5), subjects initially randomized to placebo 
and who have met the criteria for a non-responder (i.e., Hamilton 
Depression Scale [17-Items] [HAMD-17] total score at Week 5 >14 and a 
percent-reduction from baseline in HAMD-17 total score of <50%) will 
be randomly assigned (1:1) to pimavanserin 34 mg/day or placebo.  The 
determination of the subject’s status and eligibility for randomization in 
Stage 2 will be made in a double-blind manner via the interactive 
response technology (IRT) system.  Subjects who do not meet criteria for 
randomization into Stage 2 will continue with the assigned treatment 
from Stage 1 for an additional 5-week period (until the end of the study 
double-blind treatment).  Clinic visits will be conducted at Weeks 6, 7, 8, 
9, and 10 (End of-Stage 2/End of the study double-blind treatment). 
All study subjects and site study personnel will be blinded to the 
randomization into Stage 2 of the study or continuation of the treatment.  
From the perspective of study subjects and Investigators, the study will 
be conducted as a seamless 10-week double-blind treatment period.  
During Stage 2 of double-blind treatment, all patients will continue to 
receive their SSRI/SNRI antidepressant at a stable dose for the duration 
of the study. 
Safety Follow-up 
Upon completion of the double-blind treatment period, subjects should 
return to standard of care treatment.  A safety follow-up phone call will 
occur approximately 30 days after the last dose of study drug. 
Study Sites 
Multicenter; up to approximately 30 study sites will participate in this 
study. 
Number of 
Subjects Planned 
Approximately 188 adult male and female subjects with MDD 
Study Population Patients must meet all of the following inclusion and none of the 
exclusion criteria to be eligible for participation in the study. 
Inclusion Criteria 
1. Is a male or female ≥18 years of age at time of Screening. 
2. Is able to understand and provide signed informed consent, and is able 
to sign and date a Health Insurance Portability and Accountability Act 
(HIPAA) authorization form or subject privacy form, if appropriate. 
3. Is able to understand the nature of the trial and follow protocol 
requirements (in the opinion of the Investigator), and is willing to 
comply with study drug administration requirements and discontinue 
prohibited concomitant medications (including sedative hypnotic 
agents). 
4. Is able to complete subject-reported outcome measures and can be 
reliably rated on assessment scales (in the opinion of the Investigator). 
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5. Has a DSM-5 primary diagnosis of an MDE as part of MDD 
(confirmed using the SCID-5-CT). 
6. Is being treated with only one of the following SSRI or SNRI 
antidepressants at a dose within the US Food and Drug Administration 
(FDA)-approved dose range.  Subjects who are currently taking a 
second antidepressant or antidepressant augmentation agent are not 
eligible for the study. 
a. Citalopram 
b. Escitalopram 
c. Paroxetine 
d. Fluoxetine 
e. Sertraline 
f. Duloxetine 
g. Venlafaxine 
h. Desvenlafaxine 
i. Venlafaxine XR 
7. Has been treated with SSRI/SNRI monotherapy during the current 
MDE for at least 8 weeks, with the same adequate dose over the last 
4 weeks, and the dose level is expected to remain stable throughout 
the study. 
8. Has a history of inadequate response during the entire current MDE to 
1 or 2 adequate antidepressant treatments, including current treatment, 
as confirmed by the MGH ATRQ through the SAFER interview. 
9. Has a history of MDD diagnosis ≥1 year prior to Screening.  To 
satisfy this criterion, the current MDE either represents a recurrent 
episode and the MDD was diagnosed >1 year ago, OR, if this is the 
first episode, its duration must be of greater length than 1 year. 
10. Was medically stable within the month prior to Screening (in the 
opinion of the Investigator). 
11. Has a Montgomery-Asberg Depression Rating Scale (MADRS) total 
score >20 at both Screening and Baseline. 
12. Has a Clinical Global Impression – Severity (CGI-S) score ≥4 
(moderately ill or worse) at both Screening and Baseline. 
13. Is not actively suicidal (including, on the Columbia Suicide Severity 
Rating Scale [C-SSRS], an answer of “no” to question 4 or 5 [current 
or over the last 6 months]) and has not attempted suicide in the 
2 years prior to Screening. 
14. If the subject is a female, she must 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 throughout the study and for 1 month 
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following study completion.  Clinically acceptable methods of 
contraception include oral, injectable, transdermal, or implantable 
contraception, an intrauterine device (IUD), and a condom, 
diaphragm, cervical cap, or sponge with spermicide.  Only one of the 
two clinically acceptable methods can be a hormonal method. 
15. If the subject is a female of childbearing potential, she must have a 
negative serum pregnancy test at Screening and a negative urine 
pregnancy test at Baseline. 
16. Must have a detectable blood level of SSRI/SNRI monotherapy 
identified at Screening. 
 
Exclusion Criteria 
1. Is inappropriate for the study (in the opinion of the Investigator or the 
Medical Monitor). 
2. Has any condition that would interfere with the ability to comply with 
study instructions or might confound the interpretation of the study 
results or put the subject at undue risk (in the opinion of the 
Investigator). 
3. Has a body mass index (BMI) <19 or >35 at Screening. 
4. Has clinically significant laboratory abnormalities that would 
jeopardize the safe participation of the subject in the study (in the 
opinion of the Investigator). 
5. Has current evidence, or a history within the previous 3 months prior 
to Screening, of a serious and/or unstable neurologic, cardiovascular, 
respiratory, gastrointestinal, renal, hepatic, hematologic, or other 
medical disorder, including cancer, that would jeopardize the safe 
participation of the subject in the study (in the opinion of the 
Investigator). 
6. Has a known history of a positive hepatitis C virus (HCV) or human 
immunodeficiency virus (HIV) test. 
7. Has laboratory evidence of hypothyroidism at Screening, as measured 
by thyroid-stimulating hormone (TSH) and reflex free thyroxine (T4).  
If TSH is abnormal and the reflex free T4 is normal, the subject may 
be enrolled. 
8. Has current unstable diabetes or glycosylated hemoglobin (HbA1c) 
>8% at Screening. 
9. Has a history of delirium, dementia, amnestic disorder, cognitive 
disorder, schizophrenia or other psychotic disorder, or bipolar I or II 
disorder.  Subjects who are currently being treated for eating disorder, 
obsessive-compulsive disorder (OCD), attention deficit hyperactivity 
disorder (ADHD), panic disorder, acute stress disorder, or 
posttraumatic stress disorder (PTSD), according to DSM-5 criteria, are 
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also not eligible. 
10. Has a current primary diagnosis of borderline, antisocial, paranoid, 
schizoid, schizotypal, or histrionic personality disorder, according to 
DSM-5 criteria. 
11. Has met DSM-5 criteria for substance use disorders within the last 
6 months prior to Screening, except for disorders related to the use of 
caffeine or nicotine. 
12. Has a positive test for an illicit drug or cannabis at Screening or 
Baseline.  Subjects who test positive for a controlled substance and 
who have a valid prescription may be retested if they agree to abstain 
from the medication for the length of their participation in the study.  
The repeat test, and any other tests, must be negative for them to 
participate in the study. 
13. Has a history of seizure disorder or of neuroleptic malignant 
syndrome/serotonin syndrome.  Single, absence, or febrile seizures 
are not exclusionary. 
14. Is experiencing hallucinations, delusions, or any psychotic 
symptomatology in the current MDE. 
15. Has received new-onset psychotherapy or has had a change in the 
intensity of psychotherapy within the 8 weeks prior to Screening. 
16. Has received electroconvulsive therapy (ECT) during the current 
MDE. 
17. Has a known history of long QT syndrome or family history of 
sudden cardiac death. 
18. Has a Screening or Baseline ECG with a QTcF >450 ms when the 
QRS duration is <120 ms or has a Screening or Baseline ECG with a 
QTcF >470 ms when the QRS duration is ≥120 ms.  (The ECG may 
be repeated once at Screening or Baseline in consultation with the 
Medical Monitor.) 
19. Has a significant sensitivity or allergic reaction to pimavanserin or its 
excipients. 
20. Has previously been randomized in any prior clinical study with 
pimavanserin, and/or has received any other investigational (either 
approved or unapproved) drug within 30 days or 5 half-lives 
(whichever is longer) prior to Screening. 
21. Has participated in >2 clinical research trials utilizing an 
investigational product within the previous 2 years. 
22. Is an employee of ACADIA Pharmaceuticals Inc. or is a family 
member of an employee of ACADIA Pharmaceuticals Inc. 
23. Has a history of minimal or non-response to adjunctive 
antipsychotics, such as quetiapine or aripiprazole, for prior MDEs, as 
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clinically assessed by the Investigator. 
24. Has a history of myocardial infarction, unstable angina, acute 
coronary syndrome, or cerebrovascular accident (CVA) within the last 
4 months.  Has greater than NYHA Class 2 congestive heart failure or 
Class 2 angina pectoris, sustained ventricular tachycardia (VT), 
ventricular fibrillation, torsade de pointes, or syncope due to an 
arrhythmia. 
 
Duration per 
Subject 
Approximately 17 weeks total consisting of a Screening Period of 8-21 
days, a 10-week Treatment Period divided into 2 stages of equal 5-week 
durations, and a Safety Follow-up period of approximately 30 days. 
Subject 
Assignment 
Eligible subjects will be randomized to receive: 
• Placebo + antidepressant (SSRI or SNRI) 
Pimavanserin (34 mg) + antidepressant (SSRI or SNRI) 
Stage 1: Randomization ratio 1:3 (pimavanserin 34 mg vs. placebo) 
Stage 2: Re-randomization ratio of placebo non-responders 1:1 
(pimavanserin 34 mg vs. placebo) 
Sample Size 
Calculations 
A total sample size of 168 evaluable subjects was estimated to provide at 
least 80% power at a two-sided significance level of 0.05 assuming a 
mean change in HAMD-17 total score of –7.8 (SD=8.0) and -10.0 
(SD=8) in Stage 1, and -2.8 (SD=6) and -6.0 (SD=6) in Stage 2 for the 
placebo and pimavanserin groups, respectively. 
For the above calculation, the weight for each double-blind treatment 
stage is equal to 0.5 and it is assumed that approximately 70% of placebo 
subjects will be non-responders at the end of Stage 1. 
Adjusting for a potential non-evaluable rate of up to 10%, approximately 
188 subjects will be randomized into Stage 1 (47 to pimavanserin and 
141 to placebo).  It is anticipated that approximately 98 subjects will be 
randomized into Stage 2 (49 to pimavanserin and 49 to placebo).  
Criteria for 
Efficacy 
Evaluation 
Primary Endpoint 
• Change from Baseline to Week 5 in HAMD-17 total score 
Secondary Endpoints 
Key Secondary Endpoint 
• Change from baseline to Week 5 in Sheehan Disability Scale (SDS) 
score 
Other Secondary Endpoints 
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• Treatment responder and remission rates at the end of 5-week 
treatment period 
• Change from Baseline to Week 5 in Clinical Global Impression – 
Severity (CGI-S) total score 
• Clinical Global Impression – Improvement (CGI-I) score at Week 5 
• Change from Baseline to Week 5 in 12-Item Short Form Health 
Survey (SF-12) score 
• Change from Baseline to Week 5 in Drug Attitude Inventory (DAI-10) 
score 
• Change from Baseline to Week 5 in Karolinska Sleepiness Scale 
(KSS) score 
• Change from Baseline to Week 5 in Massachusetts General Hospital 
Sexual Functioning Inventory (MGH-SFI) score 
• Change from Baseline to Week 5 in Barratt Impulsiveness Scale (BIS-
11) score 
• Change from Baseline to Week 5 in Sheehan Irritability Scale (SIS) 
score 
Treatment response is defined as a reduction from Baseline in HAMD-17 
total score of 50% or more.  Remission is defined as a HAMD-17 total 
score less than or equal to 7. 
Safety 
Assessments 
• Physical examinations 
• Clinical laboratory tests to include hematology, serum chemistry 
including metabolic parameters, prolactin levels, and urinalysis 
• Vital sign measurements 
• 12-lead ECG 
• Adverse event reporting 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
• Barnes Akathisia Rating Scale (BARS) 
• Abnormal Involuntary Movement Scale (AIMS) 
• Simpson-Angus Scale (SAS) 
• Demographics, medical history, and medication history 
• Height and weight 
Pharmacokinetic 
Assessments 
• At Screening, blood samples for the analysis of only the concomitant 
SSRI/SNRI antidepressants will be collected. At Baseline (pre-dose) 
and at Weeks 1, 3, 5, 6, 8, and 10 blood samples will be collected for 
the analysis of concomitant SSRI/SNRI antidepressant concentrations, 
as well as pimavanserin and the metabolite, AC-279. 
• When possible, blood samples for pimavanserin, AC-279, and the 
concomitant SSRI/SNRI antidepressant will be collected from 
subjects experiencing a serious adverse event (SAE) or an AE leading 
to discontinuation. 
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Interim Analysis 
No interim analyses are planned. 
Statistical 
Methods 
Analysis Sets 
The full analysis set includes all randomized subjects who received at 
least one dose of blinded study drug and who have both a Baseline value 
and at least one post-Baseline value for the HAMD-17 total score.  The 
full analysis set will be used for the analysis of all efficacy endpoints.  
For efficacy analyses that only use Stage 2 data from placebo non-
responders from Stage 1, a subset of the full analysis set will be used, 
consisting of subjects who were re-randomized at Week 5, received at 
least one dose of study drug after re-randomization, and have at least one 
value for the HAMD-17 total score after re-randomization. 
The per-protocol (PP) analysis set will be defined prior to unblinding the 
study for the final analysis.  Subjects will be analyzed based on their 
randomized treatment assignment.  The PP analysis set will be used for 
sensitivity analyses of selected efficacy endpoints. 
Safety analyses will be conducted using the Safety analysis set, which is 
defined as all subjects who received at least one dose of blinded study 
drug. 
Any other analysis groups, if necessary, will be defined in the Statistical 
Analysis Plan (SAP). 
Subgroup Analysis 
Selected analyses will be performed in subgroups to be defined in the 
SAP. 
Descriptive Statistics 
For continuous variables the following summary statistics will be 
provided: number of subjects, mean, standard error of the mean, standard 
deviation, minimum, maximum, and median.  For categorical variables, 
summaries will include the number and percentage of subjects in each 
category, using the number of subjects with non-missing values as the 
denominator for the percentages (unless otherwise specified). 
Missing Data 
Handling of missing values will be described in detail in the SAP. 
Efficacy Analyses 
The primary efficacy endpoint, HAMD-17 total score change from 
baseline to the end of the 5-week treatment period in both stages, will be 
evaluated using the weighted combination of statistics from the stage-
specific mixed models for repeated measures (MMRM).  The models will 
include effects for treatment group, visit, treatment-by-visit interaction, 
baseline HAMD-17 total score, and the baseline HAMD-17 total score-
by-visit interaction.  An unstructured covariance matrix will be used and 
the Kenward-Roger approximation will be used to adjust the denominator 
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degrees of freedom. 
The treatment effect will be assessed as the differences in least-squares 
mean change from baseline to Week 5 for the pimavanserin and placebo 
groups, combined across Stages 1 and 2 using prespecified 0.5/0.5 
weighting for Stage 1/Stage 2. 
Inference will be conducted using the following weighted linear 
combination of stage-wise treatment effects: 
𝑤𝑤𝜃𝜃෠1 + (1 −𝑤𝑤)𝜃𝜃෠2
ට𝑤𝑤2𝑉𝑉𝑉𝑉𝑉𝑉൫𝜃𝜃෠1൯+ (1 −𝑤𝑤)2𝑉𝑉𝑉𝑉𝑉𝑉൫𝜃𝜃෠2൯
 
In the above formula, w = 0.5 and 𝜃𝜃෠1 and 𝜃𝜃෠2 are the differences in least 
squares means between pimavanserin and placebo at week 5, for stages 1 
and 2 respectively. 
Similar statistical methods will be used to analyze other continuous 
endpoints.  For CGI-I, baseline CGI-S score will be used as the covariate.  
For the SF-12, DAI-10, and MGH-SFI, which are assessed only at 
Baseline and at Week 5 of each stage, an analysis of covariance model 
with effects for treatment group and baseline score will be used instead of 
the MMRM model. 
Safety Analyses 
Safety results will be summarized by treatment group using descriptive 
statistics.  AEs will be classified into standard terminology using the 
Medical Dictionary for Regulatory Activities (MedDRA).  All AEs will 
be coded using the MedDRA coding dictionary.  All AEs will be listed 
and treatment-emergent adverse events (TEAEs) will be summarized by 
system organ class and preferred term.  A treatment-emergent adverse 
event is defined as an AE that started after the first dose of study drug.  
Summaries by maximum severity and by relationship will also be 
provided.  Serious TEAEs, fatal TEAEs, and TEAEs leading to 
discontinuation will also be summarized.  Other TEAEs of special 
interest may also be summarized. 
The serum clinical chemistry, hematology, and urinalysis results at 
baseline and at Weeks 5 and 10 will be summarized by treatment group.  
Change from baseline values will also be summarized. 
The number and percentage of subjects with markedly abnormal post-
baseline laboratory values will be summarized by treatment group at each 
post-baseline visit and overall post-baseline for selected parameters.  The 
markedly abnormal criteria will be specified in the SAP. 
Vital signs and body weight at baseline and each post-baseline visit will 
be summarized by treatment group.  Change from baseline values will 
also be summarized.  The number and percentage of subjects with 
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changes from baseline (increases and decreases separately) in body 
weight of 7% or more will also be provided. 
The results of the physical examinations at each visit (Screening and 
Weeks 5 and 10 visits) will be tabulated by treatment group. 
ECG parameters at baseline and at Weeks 1, 5, 6, and 10 will be 
summarized by treatment group.  Change from baseline values will also 
be summarized.  Categorical analyses will be conducted on the incidence 
of subjects with prolonged QTc intervals and changes in QTc intervals in 
accordance with International Conference on Harmonisation (ICH) 
guidelines and based on the FDA E14 Guidance Document. 
For the C-SSRS, the number and percentage of subjects with suicidal 
ideation or suicidal behavior during the study will be tabulated. 
Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analyses 
Plasma concentration data for pimavanserin, AC-279 (active metabolite) 
and SSRIs/SNRIs will be listed and summarized using descriptive 
statistics. 
If data allow, results will be used for other analyses (e.g., PopPK and 
PK/PD) which will be presented in a separate report. 
If data allow, graphical depictions of the concentration-versus-time 
profiles for the concomitant SSRIs/SNRIs will be generated.  The 
measured plasma concentrations of the SSRIs/SNRIs will be overlaid on 
the respective representative graph to assess actual versus expected 
plasma concentrations.  The results will be presented in a separate report. 
Date 
26 April 2017 
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Figure 1 
Schematic of Study Design 
 
 
 
 
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STUDY CONTACTS 
Medical Monitor 
 
 
 
 
 
 
 
 
 
 
 
 
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PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
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 FDA GCP Regulations (US CFR 21 parts 45, 50, 54, 56, and 312), as well as 
ICH GCP Guidelines (E6) and clinical safety data management (E2A). 
 
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) 
 
 
 
 
 
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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ............................................................................................... 2 
PROTOCOL SYNOPSIS ........................................................................................................... 3 
STUDY CONTACTS .............................................................................................................. 15 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE ............................................................. 16 
TABLE OF CONTENTS ......................................................................................................... 17 
LIST OF TABLES ................................................................................................................... 22 
LIST OF FIGURES ................................................................................................................. 22 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................. 23 
1 
INTRODUCTION ......................................................................................................... 26 
1.1 
Background Information ................................................................................................ 26 
1.1.1 
Investigational Drug .................................................................................................. 26 
1.1.2 
Previous Clinical Experience ..................................................................................... 27 
1.2 
Study Rationale.............................................................................................................. 28 
1.3 
Potential Risks and Benefits .......................................................................................... 29 
1.3.1 
Known Potential Risks .............................................................................................. 29 
1.3.2 
Potential Benefits ....................................................................................................... 30 
2 
STUDY OBJECTIVE AND PURPOSE ........................................................................ 31 
2.1 
Primary Objective .......................................................................................................... 31 
2.2 
Secondary Objectives .................................................................................................... 31 
3 
STUDY DESIGN AND ENDPOINTS .......................................................................... 32 
3.1 
Description of the Study Design .................................................................................... 32 
3.1.1 
Study Duration ........................................................................................................... 32 
3.1.2 
Study Sites and Number of Subjects Planned ........................................................... 32 
3.2 
Study Endpoints ............................................................................................................. 33 
3.2.1 
Primary Endpoint ....................................................................................................... 33 
3.2.2 
Secondary Endpoints ................................................................................................. 33 
3.2.2.1 
Key Secondary Endpoint ....................................................................................... 33 
3.2.2.2 
Other Secondary Endpoints ................................................................................... 33 
4 
STUDY ENROLLMENT AND WITHDRAWAL ........................................................ 34 
4.1 
Subject Inclusion Criteria .............................................................................................. 34 
4.2 
Subject Exclusion Criteria ............................................................................................. 35 
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4.3 
Strategies for Recruitment and Retention ...................................................................... 37 
4.4 
Subject Withdrawal or Termination ............................................................................... 38 
4.5 
Premature Termination or Suspension of Study ............................................................ 39 
5 
INVESTIGATIONAL PRODUCT ................................................................................ 39 
5.1 
Investigational Product Description .............................................................................. 39 
5.1.1 
Formulation, Appearance, Packaging, and Labeling ................................................. 39 
5.1.2 
Product Storage and Stability .................................................................................... 40 
5.1.3 
Dosing and Administration ........................................................................................ 40 
5.1.4 
Ongoing Antidepressant Therapy .............................................................................. 40 
5.1.5 
Dose Adjustments/Modifications/Delays .................................................................. 40 
5.1.6 
Overdose .................................................................................................................... 40 
5.2 
Investigational Product Accountability Procedures ....................................................... 41 
6 
STUDY PROCEDURES ............................................................................................... 41 
6.1 
Diagnostic Scales ........................................................................................................... 46 
6.1.1 
Structured Clinical Interview for DSM-5, Clinical Trials Version ............................ 46 
6.1.2 
Massachusetts General Hospital Antidepressant Treatment Response 
Questionnaire ............................................................................................................. 46 
6.2 
Efficacy Scales............................................................................................................... 46 
6.2.1 
Hamilton Rating Scale for Depression – 17 items .................................................... 46 
6.2.2 
Montgomery-Asberg Depression Rating Scale ......................................................... 46 
6.2.3 
Clinical Global Impressions–Severity and Clinical Global 
Impressions-Improvement Scales .............................................................................. 46 
6.2.4 
Sheehan Disability Scale ........................................................................................... 47 
6.2.5 
Barratt Impulsiveness Scale ....................................................................................... 47 
6.2.6 
Drug Attitude Inventory ............................................................................................. 47 
6.2.7 
Karolinska Sleepiness Scale ...................................................................................... 47 
6.2.8 
Massachusetts General Hospital Sexual Functioning Index ...................................... 47 
6.2.9 
12-Item Short Form Health Survey ........................................................................... 47 
6.2.10 
Sheehan Irritability Scale ........................................................................................... 48 
6.3 
Safety Assessments ........................................................................................................ 48 
6.3.1 
Columbia Suicide Severity Rating Scale ................................................................... 48 
6.3.2 
Barnes Akathisia Rating Scale ................................................................................... 49 
6.3.3 
Abnormal Involuntary Movement Scale ................................................................... 49 
6.3.4 
Simpson Angus Scale ................................................................................................ 49 
6.3.5 
Demographics, Medical History, and Medication History ........................................ 49 
6.3.6 
Physical Examinations ............................................................................................... 49 
6.3.7 
Vital Signs .................................................................................................................. 50 
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6.3.8 
Height, Weight and Body Mass Index ....................................................................... 50 
6.3.9 
Electrocardiograms .................................................................................................... 50 
6.3.10 
Laboratory Evaluations .............................................................................................. 50 
6.3.11 
Adverse Event Reporting ........................................................................................... 52 
6.4 
Pharmacokinetic Assessments ....................................................................................... 52 
6.5 
Study Schedule .............................................................................................................. 53 
6.5.1 
Screening ................................................................................................................... 53 
6.5.1.1 
Screening Visits (Day -21 to Day -8) ..................................................................... 53 
6.5.1.2 
SAFER Interview ................................................................................................... 54 
6.5.2 
Baseline (Week 0) ...................................................................................................... 54 
6.5.3 
Week 1 ....................................................................................................................... 55 
6.5.4 
Week 2 ....................................................................................................................... 55 
6.5.5 
Week 3 ....................................................................................................................... 56 
6.5.6 
Week 4 ....................................................................................................................... 56 
6.5.7 
Week 5 ....................................................................................................................... 56 
6.5.8 
Week 6 ....................................................................................................................... 57 
6.5.9 
Week 7 ....................................................................................................................... 57 
6.5.10 
Week 8 ....................................................................................................................... 58 
6.5.11 
Week 9 ....................................................................................................................... 58 
6.5.12 
Week 10/Early Termination Visit ............................................................................... 59 
6.5.13 
30 Day Follow-Up Visit ............................................................................................. 59 
6.5.14 
Early Termination Visit .............................................................................................. 59 
6.5.15 
Unscheduled Visit ...................................................................................................... 59 
6.6 
Precautionary Medications, Treatments, and Procedures .............................................. 60 
6.7 
Concomitant Medications, Treatments, and Procedures ............................................... 60 
6.8 
Prohibited Medications, Treatments, and Procedures ................................................... 60 
7 
ASSESSMENTS OF SAFETY ..................................................................................... 60 
7.1 
Specification of Safety Parameters ................................................................................ 60 
7.1.1 
Definition of Adverse Event ...................................................................................... 60 
7.1.2 
Definition of Serious Adverse Event ......................................................................... 61 
7.2 
Classification of an Adverse Event ................................................................................ 62 
7.2.1 
Severity of Event ....................................................................................................... 62 
7.2.2 
Relationship to Study Drug ....................................................................................... 62 
7.2.2.1 
Duration ................................................................................................................. 63 
7.2.2.2 
Frequency ............................................................................................................... 63 
7.2.2.3 
Action Taken with Study Drug .............................................................................. 63 
7.2.2.4 
Therapy .................................................................................................................. 63 
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7.2.2.5 
Outcome ................................................................................................................. 63 
7.2.2.6 
Seriousness ............................................................................................................. 63 
7.2.3 
Definition of Unexpectedness ................................................................................... 64 
7.3 
Time Period and Frequency for Event Assessment and Follow-up ............................... 64 
7.4 
Reporting Procedures .................................................................................................... 64 
7.4.1 
Adverse Event Reporting ........................................................................................... 64 
7.4.2 
Serious Adverse Event Reporting .............................................................................. 64 
7.4.3 
Reporting of Pregnancy ............................................................................................. 65 
7.4.4 
Reporting of Overdose ............................................................................................... 66 
8 
CLINICAL MONITORING .......................................................................................... 66 
9 
STATISTICAL CONSIDERATIONS ............................................................................ 66 
9.1 
Statistical and Analytical Plans...................................................................................... 66 
9.2 
Statistical Hypotheses .................................................................................................... 66 
9.3 
Analysis Datasets ........................................................................................................... 66 
9.4 
Description of Statistical Methods ................................................................................ 67 
9.4.1 
General Approach ...................................................................................................... 67 
9.4.2 
Analysis of the Primary Efficacy Endpoint ............................................................... 67 
9.4.3 
Analysis of the Secondary Endpoints ........................................................................ 68 
9.4.4 
Safety Analyses .......................................................................................................... 68 
9.4.4.1 
Adverse Events ...................................................................................................... 68 
9.4.4.2 
Clinical Laboratory Values..................................................................................... 69 
9.4.4.3 
Vital Signs and Body Weight ................................................................................. 69 
9.4.4.4 
Electrocardiogram .................................................................................................. 69 
9.4.4.5 
Physical Examinations ........................................................................................... 69 
9.4.4.6 
Columbia Suicide Severity Rating ......................................................................... 69 
9.4.5 
Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analyses ....................... 69 
9.4.6 
Adherence and Retention Analyses ........................................................................... 70 
9.4.7 
Baseline Descriptive Statistics ................................................................................... 70 
9.4.8 
Planned Interim Analyses .......................................................................................... 70 
9.4.9 
Additional Sub-group Analyses ................................................................................. 70 
9.4.10 
Multiple Comparison/Multiplicity ............................................................................. 70 
9.4.11 
Tabulation of Individual Response Data.................................................................... 70 
9.4.12 
Exploratory Analyses ................................................................................................. 70 
9.5 
Sample Size ................................................................................................................... 71 
9.6 
Measures to Minimize Bias ........................................................................................... 71 
9.6.1 
Masking Procedures .................................................................................................. 71 
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9.6.2 
Randomization Procedures ........................................................................................ 72 
9.6.2.1 
Stage 1 Double-blind Treatment Period ................................................................. 72 
9.6.2.2 
Stage 2 Double-blind Treatment Period ................................................................. 72 
9.6.3 
Breaking the Study Blind/Subject Code .................................................................... 72 
10 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ........ 72 
10.1 Case Report Forms and Data Verification ..................................................................... 72 
10.2 Source Documentation .................................................................................................. 73 
11 
QUALITY ASSURANCE AND QUALITY CONTROL ............................................. 73 
12 
ETHICS/PROTECTION OF HUMAN SUBJECTS ..................................................... 74 
12.1 Ethical Standard ............................................................................................................. 74 
12.2 Institutional Review Board/Independent Ethics Committee ......................................... 74 
12.3 Informed Consent Process ............................................................................................. 74 
12.3.1 
Consent/Assent and Other Informational Documents Provided to Subjects ............. 75 
12.3.2 
Consent Procedures and Documentation ................................................................... 75 
12.4 Subject and Data Confidentiality ................................................................................... 75 
12.5 Research Use of Stored Human Samples ...................................................................... 75 
12.6 Future Use of Stored Specimens ................................................................................... 75 
13 
DATA HANDLING AND RECORD KEEPING .......................................................... 76 
13.1 Data Collection and Management Responsibilities ....................................................... 76 
13.2 Study Records Retention ............................................................................................... 76 
13.3 Protocol Changes ........................................................................................................... 76 
13.3.1 
Protocol Amendments ................................................................................................ 76 
13.3.2 
Protocol Exceptions and Deviations .......................................................................... 77 
13.4 Publication and Data Sharing Policy ............................................................................. 77 
14 
CONFLICT OF INTEREST POLICY .......................................................................... 77 
14.1 Finance, Insurance, and Indemnity ................................................................................ 77 
15 
LITERATURE REFERENCES ..................................................................................... 78 
16 
APPENDICES ............................................................................................................... 82 
Appendix A:  Prohibited and Restricted Medications ............................................................. 83 
Appendix B:  Prohibited and Restricted Concomitant Medications:  Inhibitors and Inducers of 
Cytochrome P450 Enzyme 3A4 .............................................................................................. 86 
Appendix C:  Sample Assessment Scales ................................................................................ 88 
 
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LIST OF TABLES 
Table 1 
Receptor profiles of Pimavanserin and compounds with antidepressant 
activity ............................................................................................................. 29 
Table 2 
Schedule of Assessments ................................................................................. 43 
Table 3 
Safety Laboratory Evaluations......................................................................... 52 
LIST OF FIGURES 
Figure 1 
Schematic of Study Design .............................................................................. 14 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
5-HT 
5-hydroxytryptamine  
5-HT2A 
5-hydroxytryptamine 2A 
AE 
adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
BARS 
Barnes Akathisia Rating Scale 
BIS-11 
Barratt Impulsiveness Scale 
BMI 
body mass index 
CFR 
Code of Federal Regulations 
CGI-I 
Clinical Global Impression – Improvement scale 
CGI-S 
Clinical Global Impression – Severity scale 
CNS 
central nervous system 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CVA 
cerebrovascular accident 
DAI-10 
Drug Attitude Inventory 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
ECG 
electrocardiogram 
ECT 
electroconvulsive therapy 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOS 
End-of-Study 
ET 
Early Termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HAMD-17 
Hamilton Depression Scale (17 Items) 
HbA1c 
glycosylated hemoglobin 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS (Continued) 
HIV 
human immunodeficiency virus 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IUD 
intrauterine device 
KSS 
Karolinska Sleepiness Scale 
MADRS 
Montgomery Asberg Depression Scale 
MDD 
Major Depressive Disorder 
MDE 
Major Depressive Episode 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGH ATRQ 
Massachusetts General Hospital Antidepressant Treatment Questionnaire 
MGH CTNI 
Massachusetts General Hospital Clinical Trial Network and Institute 
MGH SFI 
Massachusetts General Hospital Sexual Functioning Index 
ms 
milliseconds 
NYHA 
New York Heart Association 
PD 
pharmacodynamic(s) 
PDP 
Parkinson’s disease psychosis 
PK 
pharmacokinetic(s) 
PP 
per protocol 
PSP 
Personal and Social Performance 
QD 
once daily 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
SAE 
serious adverse event 
SAFER 
State versus trait, Assessability, Face validity, Ecological validity, and 
Rule of three Ps (pervasive, persistent, and pathological) 
SAP 
Statistical Analysis Plan 
SAS 
Simpson-Angus Scale 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS (Continued) 
SAS® 
Statistical Analysis System® 
SCID-5-CT 
Structured Clinical Interview for DSM-5, Clinical Trials Version 
SDS 
Sheehan Disability Scale 
SF-12 
12-Item Short Form Health Survey 
SIS 
Sheehan Irritability Scale 
SNRI 
serotonin-norepinephrine reuptake inhibitors 
SPCD 
Sequential Parallel Comparison Design 
SSRI 
selective serotonin reuptake inhibitors 
T4 
thyroxine 
T4, free 
free thyroxine 
TCA 
tricyclic antipsychotic 
TEAE 
treatment-emergent adverse event 
TSH 
thyroid-stimulating hormone 
US 
United States 
VT 
ventricular tachycardia 
 
 
 
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1 INTRODUCTION 
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-IV 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, there is a clear need for efficacious and well-tolerated agents to 
treat patients with an inadequate response to standard antidepressant therapies, and current 
research continues to investigate novel molecular and cellular mechanisms of augmentation 
of antidepressant therapies. 
1.1.1 
Investigational Drug 
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), is a novel small molecule designed to specifically block 
serotoninergic neurotransmission mediated by the 5-hydroxytryptamine2A (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 (Peretti et al., 1997, 
Mehta et al., 2004, Saeedi et al., 2006) currently used as adjunctive treatment for depression.  
Given the putative antidepressant role of 5-HT2A antagonists (Artigas 2015), it is also quite 
possible that pimavanserin may be an effective augmentation strategy for patients with an 
inadequate response to antidepressant therapy. 
Pimavanserin demonstrates dose-proportional pharmacokinetics after single oral doses from 
17 to 255 mg.  The mean plasma half-lives for pimavanserin and the active metabolite 
(N-desmethylated metabolite) are approximately 57 hours and 200 hours, respectively.  
Pimavanserin is predominantly metabolized by CYP3A4 and CYP3A5 and to a lesser extent 
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by CYP2J2, CYP2D6, and various other CYP and FMO enzymes.  CYP3A4 is the major 
enzyme responsible for the formation of its major active metabolite (AC-279).  Pimavanserin 
does not cause clinically significant CYP inhibition or induction of CYP3A4.  Based on in 
vitro data, pimavanserin is not an irreversible inhibitor of any of the major hepatic and 
intestinal human CYP enzymes involved in drug metabolism (CYP1A2, 2B6, 2C8, 2C9, 
2C19, 2D6, and 3A4). 
1.1.2 
Previous Clinical Experience 
Pimavanserin was approved by the US Food and Drug Administration (FDA) on 
29 April 2016 for the treatment of hallucinations and delusions associated with Parkinson’s 
disease psychosis (PDP).  The full PDP clinical development program is described in the 
Investigator’s Brochure.  This is the first clinical study of pimavanserin in MDD.   
Pimavanserin is considered to be generally safe and well tolerated.  In single and multiple 
dose studies in healthy volunteers, the highest doses administered were 255 mg and 136 mg, 
respectively.  Across all clinical studies of pimavanserin, the most frequently reported 
treatment-emergent AEs (TEAEs) were in the central nervous system (CNS), gastrointestinal, 
and psychiatric systems.  Most events were mild to moderate in intensity.  The most common 
CNS events included dizziness (including postural), headache, and somnolence (drowsiness).  
Common GI disturbances included dyspepsia, nausea, constipation, and vomiting; severe 
nausea and vomiting were dose limiting in a few cases.  Reported psychiatric conditions 
included such events as agitation, insomnia, and confusional state.   
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 
were urinary tract infection (UTI) (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, the most frequent adverse events (AEs) include fall (29.3%), UTI (18.5%), 
hallucination (14.5%), decreased weight (12.4%), and confusional state (11.0%).  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. 
Pimavanserin increases QT interval.  The magnitude of effect in humans has been assessed in 
a thorough QT study with doses of pimavanserin ranging from 17 to 68 mg and in the Phase 
3 PDP program with a clinical dose of 34 mg.  An average prolongation of approximately 
5-8 milliseconds was observed.  No clinically significant patterns have been observed in 
serious adverse events (SAEs) and there has been no evidence of pimavanserin-related 
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laboratory abnormalities.  As of 30 October 2015, 67 subjects have died during study 
participation 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 10 mg pimavanserin, and 3 subjects received 34 mg 
pimavanserin), and 62 deaths occurred in the multi-year, long-term open-label extension 
studies where the majority of subjects have been treated with pimavanserin for greater than 
2 years. 
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 Investigator’s Brochure. 
1.2 
Study Rationale 
The rationale for the use of pimavanserin as adjunctive treatment for MDD is based on the 
following: 
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 co-administered with selective serotonin reuptake 
inhibitors (SSRIs; see Table 1).  These compounds include volinanserin, pruvanserin, 
ketanserin, ritanserin, mirtazapine, mianserin and trazodone (see Table 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. 
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Table 1 
Receptor profiles of Pimavanserin and compounds with 
antidepressant activity 
Values rep
nity (Ki) in nM of the indicated ligands and transporters/receptors.  For “Other Noteworthy Targets”, Ki 
values provided in parentheses.  "na" denotes not available.  Low denotes Ki >1000 nM.  Legend:  PIM, Pimavanserin; RIT, 
ritanserin; VOL, volinanserin; PRUV, pruvanserin; PIP, pipamperone; KET, ketanserin; MIRT, mirtazepine; MIAN, 
mianserin; TRAZ, trazodone; SERT, serotonin transporter; NET, norepinephrine transporter; DAT, dopamine transporter; 
α1, alpha1 adrenergic receptor; α2, alpha2 adrenergic receptor; H1, histamine 1 receptor.  Data on file except pipamperone 
(Schotte et al. 1996); trazodone and mianserin (PDSP Ki database, see Roth et al. 2000); mirtazepine (Brayfield, 2014); and 
(Wikström et al., 2002). 
1.3 
Potential Risks and Benefits 
This study will potentially help individuals with inadequate response to antidepressant 
treatment.  If the study shows that adjunctive treatment with pimavanserin is effective, the 
results could lead to a further clinical development of this treatment for adjunctive treatment 
of depression. Because of the tremendous public health impact of depression, if pimavanserin 
is shown to be effective, it could reduce the burden of depression-related morbidity and 
mortality. 
The treatment has been selected with consideration of safety in mind.  Adequate protections 
are in place to carefully monitor the medical wellbeing of subjects.  This is an adjunctive 
study, and subjects remain on their prescribed antidepressant therapy throughout the study.  In 
contrast, the high morbidity and mortality associated with inadequately treated depression are 
well known given the long-term disability associated with MDD. 
1.3.1 
Known Potential Risks 
The Prescribing Information for NUPLAZID® (pimavanserin) tablets for oral use (ACADIA 
Pharmaceuticals Inc., 2017) indicates the following contraindication and includes the 
following Boxed Warnings: 
• Contraindication: NUPLAZID is contraindicated in patients with a history of 
hypersensitivity reaction to pimavanserin or any of its components.  Reactions have 
included rash, urticaria, tongue swelling, circumoral edema, and throat tightness. 
Target
RIT
VOL
PRUV
PIP
KET
MIRT
MIAN
TRAZ
SERT
Low
Low
Low
na
Low
Low
Low
350
NET
Low
Low
Low
na
Low
Low
70
Low
DAT
Low
Low
Low
na
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
α2 (35)
H1 (1)
H1 (1)
α2 (4-20)
5-HT1A (100)
D4 (5)
None
None
None
α1 (15-20)
α2 (15-20)
Other 
noteworthy 
targets
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• Boxed Warnings: 
– Increased mortality in elderly patients with dementia-related psychosis; elderly 
patients with dementia-related psychosis treated with antipsychotic drugs are at an 
increased risk of death 
– Not approved for the treatment of patients with dementia-related psychosis 
unrelated to the hallucinations and delusions associated with Parkinson’s disease 
psychosis 
The increased mortality in elderly patients is based on information regarding antipsychotic 
drugs generally, rather than on specific pimavanserin data.  Antipsychotic drugs increase the 
all-cause risk of death in elderly patients with dementia-related psychosis.  Analyses of 17 
dementia-related psychosis placebo-controlled trials (modal duration of 10 weeks and largely 
in patients taking atypical antipsychotic drugs) revealed a risk of death in the drug-treated 
patients of between 1.6- to 1.7-times that in placebo-treated patients.  Over the course of a 
typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, 
compared to a rate of about 2.6% in placebo-treated patients.  Although the causes of death 
were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, 
sudden death) or infectious (e.g., pneumonia) in nature. 
The Warnings and Precautions section of the Prescribing Information for pimavanserin also 
includes QT interval prolongation.  Pimavanserin prolongs the 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 a Phase 3 Parkinson's Disease psychosis program with a 
clinical dose of 34 mg.  An average prolongation of approximately 5-8 ms was observed. 
The use of pimavanserin should be avoided in patients with known QT prolongation or in 
combination with other drugs known to prolong QT interval including Class 1A 
antiarrhythmics (e.g., quinidine, procainamide) or Class 3 antiarrhythmics (e.g., amiodarone, 
sotalol), certain antipsychotic medications (e.g., ziprasidone, chlorpromazine, thioridazine), 
and certain antibiotics (e.g., gatifloxacin, moxifloxacin).  Pimavanserin should also be 
avoided in patients with a history of cardiac arrhythmias, as well as other circumstances that 
may increase the risk of the occurrence of torsade de pointes and/or sudden death, including 
symptomatic bradycardia, hypokalemia or hypomagnesemia, and the presence of congenital 
prolongation of the QT interval. 
1.3.2 
Potential Benefits 
Because SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs) elevate synaptic 
levels of 5-HT, they indirectly activate both 5-HT1A and 5-HT2A receptors.  Efficacy of SSRIs 
is thought to be primarily mediated through activation of 5-HT1A serotonin receptors 
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(Samuels et al., 2015).  Preclinical studies have shown that activation of 5-HT2A receptors has 
many depressogenic effects which are blocked by selective 5-HT2A antagonists/inverse 
agonists (Rajkumar et al., 2009; Hemrick-Luecke and Evans, 2002; Vaidya et al., 1997).  In 
essence, 5-HT1A and 5-HT2A receptors appear to have functionally opposing roles with 
respect to resolution or exacerbation of depression.  Consistent with this notion, compounds 
with approximately equal 5-HT1 and 5-HT2 receptor antagonist activity (methysergide and 
metergoline) were inactive in the Differential Reinforcement of Low Rate–72 sec 
Responding (DRL-72s-R) test, suggesting functionally opposing effects of 5-HT1 and 5-HT2 
receptors in this assay.  Conversely, the direct 5-HT1A agonists 8-hydroxy-2-
(di-n-propylamino) tetralin and 5-methoxy-N,N-dimethyltryptamine were found to be active 
(Marek et al., 1989). Similarly, it has been shown that 5-HT1A and 5-HT2A receptors have 
functionally opposing effects on neuronal excitability.  The activation of 5-HT1A receptors 
increases potassium conductance, thus hyperpolarizing the neuronal membrane and reducing 
the firing rate of serotonergic and pyramidal neurons in the cortex and hippocampus 
(Celada et al., 2004).  In contrast, 5-HT2A receptors are mainly expressed postsynaptically, 
and cause neuronal depolarization when activated (Araneda and Andrade 1991; 
Ashby et al., 1994).  Therefore, blocking 5-HT2A receptors with co-administration of 5-HT2A 
antagonists/inverse agonists may augment efficacy of SSRIs in a synergistic manner 
(Marek et al., 2003). 
In summary, compounds sharing potent antagonist/inverse agonist activity at 5-HT2A 
receptors, exhibit antidepressant properties in a variety of animal models of depression.  In 
addition, co-administration of 5-HT2A receptor antagonists/inverse agonists augments the 
efficacy of antidepressants, including SSRIs.  Thus, selective 5-HT2A receptor 
antagonists/inverse agonists hold promise for treating MDD. 
2 STUDY OBJECTIVE AND PURPOSE 
2.1 
Primary Objective 
The primary objective of this study is to assess the efficacy of pimavanserin compared to 
placebo when given adjunctively to an SSRI/SNRI antidepressant as treatment of patients 
with MDD and an inadequate response to antidepressant therapy. 
2.2 
Secondary Objectives 
Secondary objectives of this study are to evaluate the efficacy of pimavanserin compared 
with placebo for the following: 
• patient disability 
• clinician’s global assessment of treatment benefit 
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• quality of life 
• drug attitude 
• sleep 
• sexual functioning 
• impulsivity 
• irritability 
Other secondary objectives of this study are as follows: 
• To assess the safety and tolerability of adjunctive pimavanserin compared to placebo 
• To characterize the pharmacokinetics (PK) of pimavanserin administered as adjunct to 
an SSRI/SNRI antidepressant in MDD patients 
• To assess the PK/pharmacodynamics (PD) using measures of safety, efficacy, and 
sleep parameters 
3 STUDY DESIGN AND ENDPOINTS 
3.1 
Description of the Study Design 
This study is a multicenter, randomized, double-blind, placebo-controlled, 2-stage Sequential 
Parallel Comparison Design (SPCD) study in patients with MDD and an inadequate response 
to antidepressant therapy with concurrent SSRI/SNRI.  MDD and Major Depressive Episode 
(MDE) are defined according to the Diagnostic and Statistical Manual of Mental Disorders, 
Fifth Edition (DSM-5), as confirmed by the Structured Clinical Interview for DSM-5, 
Clinical Trials Version (SCID-5-CT).  Inadequate treatment response will be determined 
through the administration of the Massachusetts General Hospital Antidepressant Treatment 
Questionnaire (MGH ATRQ). 
3.1.1 
Study Duration 
Approximately 17 weeks total consisting of a Screening Period of 8-21 days, a 10-week 
Treatment Period divided into 2 stages of equal 5-week durations, and a Safety Follow-up 
period of approximately 30 days. 
3.1.2 
Study Sites and Number of Subjects Planned 
The study will be a multicenter study with up to 30 study sites participating.  Approximately 
188 adult male and female patients with MDD are expected to participate in this study (see 
Section 9.5). 
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3.2 
Study Endpoints 
Of note, “Baseline to Week 5” refers to the Baseline and Week 5 visits in each double-blind 
treatment phase, whether Stage 1 or Stage 2. 
3.2.1 
Primary Endpoint 
The primary endpoint, which is an efficacy endpoint, is the following: 
• Change from Baseline to Week 5 in Hamilton Depression Rating Scale (17 Items) 
(HAMD-17) total score 
3.2.2 
Secondary Endpoints 
The secondary endpoints, which are efficacy endpoints, include the key secondary endpoint 
and the other secondary endpoints. 
3.2.2.1 
Key Secondary Endpoint 
The key secondary endpoint, which is an efficacy endpoint, is the following: 
• Change from baseline to Week 5 in Sheehan Disability Scale (SDS) score 
3.2.2.2 
Other Secondary Endpoints 
Other secondary endpoints are the following: 
• Treatment responder and remission rates at the end of 5-week treatment period  
• Change from Baseline to Week 5 in Clinical Global Impression – Severity (CGI-S) 
total score 
• Clinical Global Impression – Improvement (CGI-I) score at Week 5 
• Change from Baseline to Week 5 in 12-Item Short Form Health Survey (SF-12) score  
• Change from Baseline to Week 5 in Drug Attitude Inventory (DAI-10) score 
• Change from Baseline to Week 5 in Karolinska Sleepiness Scale (KSS) score 
• Change from Baseline to Week 5 in Massachusetts General Hospital Sexual 
Functioning Inventory (MGH-SFI) score 
• Change from Baseline to Week 5 in Barratt Impulsiveness Scale (BIS-11) score 
• Change from Baseline to Week 5 in Sheehan Irritability Scale (SIS) score 
Treatment response is defined as a reduction from Baseline in HAMD-17 total score of 50% 
or more.  Remission is defined as a HAMD-17 total score less than or equal to 7. 
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4 STUDY ENROLLMENT AND WITHDRAWAL 
Subjects must meet all of the following inclusion and none of the exclusion criteria 
(Section 4.2) to be eligible for participation in the study. 
Protocol waivers for eligibility will not be granted by ACADIA Pharmaceuticals Inc. 
(hereafter referred to as ACADIA) under any circumstances.  If, during the course of a 
subject’s post-randomization participation in the study, it is discovered that the subject did 
not meet all eligibility criteria, she or he will be discontinued, unless the discontinuation 
presents an unacceptable medical risk.  The justification to allow the subject to continue in 
the study will be made by ACADIA, with medical input from the Investigator, and will be 
documented.  If the subject is allowed to remain in the study, this will be reported as a major 
protocol deviation and not a waiver.  
4.1 
Subject Inclusion Criteria 
A subject must meet all of the following inclusion criteria to be eligible for participation in 
the study: 
1. Is a male or female ≥18 years of age at time of Screening. 
2. Is able to understand and provide signed informed consent, and is able to sign and date 
a Health Insurance Portability and Accountability Act (HIPAA) authorization form or 
subject privacy form, if appropriate. 
3. Is able to understand the nature of the trial and follow protocol requirements (in the 
opinion of the Investigator), and is willing to comply with study drug administration 
requirements and discontinue prohibited concomitant medications (including sedative 
hypnotic agents). 
4. Is able to complete subject-reported outcome measures and can be reliably rated on 
assessment scales (in the opinion of the Investigator). 
5. Has a DSM-5 primary diagnosis of an MDE as part of MDD (confirmed using the 
SCID-5-CT). 
6. Is being treated with only one of the following SSRI or SNRI antidepressants at a dose 
within the FDA-approved dose range.  Subjects who are currently taking a second 
antidepressant or antidepressant augmentation agent are not eligible for the study. 
a. Citalopram 
b. Escitalopram 
c. Paroxetine 
d. Fluoxetine 
e. Sertraline 
f. Duloxetine 
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g. Venlafaxine 
h. Desvenlafaxine 
i. Venlafaxine XR 
7. Has been treated with SSRI/SNRI monotherapy during the current MDE for at least 
8 weeks, with the same adequate dose over the last 4 weeks, and the dose level is 
expected to remain stable throughout the study. 
8. Has a history of inadequate response during the entire current MDE to 1 or 2 adequate 
antidepressant treatments, including current treatment, as confirmed by the MGH 
ATRQ through the SAFER interview. 
9. Has a history of MDD diagnosis ≥1 year prior to Screening.  To satisfy this criterion, 
the current MDE either represents a recurrent episode and the MDD was diagnosed >1 
year ago, OR, if this is the first episode, its duration must be of greater length than 
1 year. 
10. Was medically stable within the month prior to Screening (in the opinion of the 
Investigator). 
11. Has a Montgomery-Asberg Depression Rating Scale (MADRS) total score >20 at both 
Screening and Baseline. 
12. Has a Clinical Global Impression – Severity (CGI-S) score ≥4 (moderately ill or 
worse) at both Screening and Baseline. 
13. Is not actively suicidal (including, on the Columbia Suicide Severity Rating Scale 
[C-SSRS], an answer of “no” to question 4 or 5 [current or over the last 6 months]) 
and has not attempted suicide in the 2 years prior to Screening. 
14. If the subject is a female, she must 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 throughout the study and for 1 month 
following study completion.  Clinically acceptable methods of contraception include 
oral, injectable, transdermal, or implantable contraception, an intrauterine device 
(IUD), and a condom, diaphragm, cervical cap, or sponge with spermicide.  Only one 
of the two clinically acceptable methods can be a hormonal method. 
15. If the subject is a female of childbearing potential, she must have a negative serum 
pregnancy test at Screening and a negative urine pregnancy test at Baseline. 
16. Must have a detectable blood level of SSRI/SNRI monotherapy identified at 
Screening. 
4.2 
Subject Exclusion Criteria 
A subject must meet none of the following exclusion criteria to be eligible for the study: 
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1. Is inappropriate for the study (in the opinion of the Investigator or the Medical 
Monitor). 
2. Has any condition that would interfere with the ability to comply with study 
instructions or might confound the interpretation of the study results or put the subject 
at undue risk (in the opinion of the Investigator). 
3. Has a body mass index (BMI) <19 or >35 at Screening. 
4. Has clinically significant laboratory abnormalities that would jeopardize the safe 
participation of the subject in the study (in the opinion of the Investigator). 
5. Has current evidence, or a history within the previous 3 months prior to Screening, of 
a serious and/or unstable neurologic, cardiovascular, respiratory, gastrointestinal, renal, 
hepatic, hematologic, or other medical disorder, including cancer, that would 
jeopardize the safe participation of the subject in the study (in the opinion of the 
Investigator). 
6. Has a known history of a positive hepatitis C virus (HCV) or human 
immunodeficiency virus (HIV) test. 
7. Has laboratory evidence of hypothyroidism at Screening, as measured by thyroid-
stimulating hormone (TSH) and reflex free thyroxine (T4).  If TSH is abnormal and 
the reflex free T4 is normal, the subject may be enrolled. 
8. Has current unstable diabetes or glycosylated hemoglobin (HbA1c) >8% at Screening. 
9. Has a history of delirium, dementia, amnestic disorder, cognitive disorder, 
schizophrenia or other psychotic disorder, or bipolar I or II disorder.  Subjects who are 
currently being treated for eating disorder, obsessive-compulsive disorder (OCD), 
attention deficit hyperactivity disorder (ADHD), panic disorder, acute stress disorder, 
or posttraumatic stress disorder (PTSD), according to DSM-5 criteria, are also not 
eligible. 
10. Has a current primary diagnosis of borderline, antisocial, paranoid, schizoid, 
schizotypal, or histrionic personality disorder, according to DSM-5 criteria. 
11. Has met DSM-5 criteria for substance use disorders within the last 6 months prior to 
Screening, except for disorders related to the use of caffeine or nicotine. 
12. Has a positive test for an illicit drug or cannabis at Screening or Baseline.  Subjects 
who test positive for a controlled substance and who have a valid prescription may be 
retested if they agree to abstain from the medication for the length of their 
participation in the study.  The repeat test, and any other tests, must be negative for 
them to participate in the study. 
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13. Has a history of seizure disorder or of neuroleptic malignant syndrome/serotonin 
syndrome.  Single, absence, or febrile seizures are not exclusionary. 
14. Is experiencing hallucinations, delusions, or any psychotic symptomatology in the 
current MDE. 
15. Has received new-onset psychotherapy or has had a change in the intensity of 
psychotherapy within the 8 weeks prior to Screening. 
16. Has received electroconvulsive therapy (ECT) during the current MDE. 
17. Has a known history of long QT syndrome or family history of sudden cardiac death. 
18. Has a Screening or Baseline ECG with a QTcF >450 ms when the QRS duration is 
<120 ms or has a Screening or Baseline ECG with a QTcF >470 ms when the QRS 
duration is ≥120 ms.  (The ECG may be repeated once at Screening or Baseline in 
consultation with the Medical Monitor.) 
19. Has a significant sensitivity or allergic reaction to pimavanserin or its excipients. 
20. Has previously been randomized in any prior clinical study with pimavanserin, and/or 
has received any other investigational (either approved or unapproved) drug within 
30 days or 5 half-lives (whichever is longer) prior to Screening. 
21. Has participated in >2 clinical research trials utilizing an investigational product 
within the previous 2 years. 
22. Is an employee of ACADIA Pharmaceuticals Inc. or is a family member of an 
employee of ACADIA Pharmaceuticals Inc. 
23. Has a history of minimal or non-response to adjunctive antipsychotics, such as 
quetiapine or aripiprazole, for prior MDEs, as clinically assessed by the Investigator. 
24. Has a history of myocardial infarction, unstable angina, acute coronary syndrome, or 
cerebrovascular accident (CVA) within the last 4 months.  Has greater than NYHA 
Class 2 congestive heart failure or Class 2 angina pectoris, sustained ventricular 
tachycardia (VT), ventricular fibrillation, torsade de pointes, or syncope due to an 
arrhythmia. 
 
4.3 
Strategies for Recruitment and Retention 
Subjects will be recruited through clinician referral and self-referral as well as through 
advertisement. 
Potentially eligible subjects will be scheduled for a screening visit with one of the study 
physicians at the sites.  Based on clinical and human subject protection considerations, a 
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potential subject will, under no circumstance, be advised to taper or change his/her current 
medication regimen prior to the screening visit. 
Participants will also be recruited through physician referral.  Each site will recruit subjects 
via referral from primary care and specialty clinics from the communities surrounding each 
study site. Each site will utilize the experience of the
 
o conduct outreach activities to community 
organizations, colleges and other resources.  Sites will regularly collaborate on strategies to 
recruit women and minorities, and sites will employ strategies specific to their local 
community, in ways that are culturally sensitive and specific to the local minority population.  
Retention will be enhanced with fair reimbursement (as deemed appropriate by the local 
IRB) for a subject's time. 
4.4 
Subject Withdrawal or Termination 
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. 
Subjects may be discontinued or withdrawn from the study for a number of reasons, 
including but not limited to those listed below: 
• AE(s) (SAE or non-serious)  
• Death 
• Lack of efficacy 
• Lost to follow-up 
• Non-compliance (with study drug or study procedures) 
• Physician decision 
• Pregnancy 
• Protocol violation 
• Study terminated by sponsor 
• Subject withdrew consent 
• Other, specify 
Every effort should be made to complete the Week 10/ET visit should a subject discontinue 
prematurely from the study. 
If a subject is lost to follow-up, every effort should be made to phone the subject 
approximately 30 days after last known contact with the subject in order to assess the 
subject’s current status.  All phone contact with the subject should be documented. 
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For subjects who continue to be followed for safety, SAEs should continue to be reported as 
described in Section 7. 
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. 
If a subject is discontinued from the study due to pregnancy, every reasonable attempt should 
be made to follow the subject through the first well-baby visit and to document that 
follow-up. 
All SAEs will continue to be followed until such events have resolved or the Investigator 
deems them to be chronic or stable. 
4.5 
Premature Termination or Suspension of Study 
ACADIA 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 or ethical reasons affecting the continued performance of the study 
• Business reasons 
Regulatory Authorities also have the right to terminate the conduct of the study in their 
region for any reason. 
5 INVESTIGATIONAL PRODUCT 
5.1 
Investigational Product Description 
The Investigational Product (IP) will be pimavanserin 34 mg (provided as 2×17 mg tablets), 
and matching placebo (2×placebo tablets); oral administration as a single dose once daily 
(QD).  17 mg of the active moiety is dosed as 20 mg of the salt pimavanserin tartrate. 
5.1.1 
Formulation, Appearance, Packaging, and Labeling  
ACADIA will supply pimavanserin 17 mg strength tablets and matching placebo tablets. 
Pimavanserin tartrate is a white to off-white powder.  Pimavanserin tablets include the active 
compound (pimavanserin) and the following
 
.  The 
drug product is formulated with standard pharmaceutical excipients at 17 mg strength (20 mg 
of pimavanserin tartrate).  Pimavanserin treatment consists of 2 tablets once-daily for oral 
administration. 
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Placebo tablets contain all of the same excipients as pimavanserin 17 mg tablets, but do not 
contain any pimavanserin. 
Pimavanserin and placebo used for the tablets are manufactured under current Good 
Manufacturing Practice compliance by
 
During the treatment period, study drug will be supplied in Treatment Kits.  Each Treatment 
Kit which will contain one (1) Blister Card.  Each Blister Card contains 20 tablets.  Each 
Treatment Kit contains 10 days of treatment (7 days treatment + 3 days extra). 
5.1.2 
Product Storage and Stability 
Investigational Product must be stored at 15°C to 30°C (59°F to 86°F) (see USP Controlled 
Room Temperature) in a secure area with restricted access and according to local and national 
regulations. 
5.1.3 
Dosing and Administration 
The first dose of study drug will be administered at the clinic during the Baseline visit; study 
drug kits will then be dispensed to the subject to take home.  On the second day, patients 
should take the study drug at the time that they plan to usually take it.  Each daily dose 
consists of 2 individual tablets that should be taken together.  Subjects should be instructed to 
take 2 tablets, orally, once each day, at approximately the same time.  The tablets may be 
taken with or without food. 
5.1.4 
Ongoing Antidepressant Therapy 
Subjects will be instructed to maintain their current antidepressant treatment regimen 
throughout the study. 
5.1.5 
Dose Adjustments/Modifications/Delays 
If a subject misses 1 dose of Investigational Product (IP), he or she should not take an extra 
dose the next day.  Subjects who miss more than 2 consecutive doses, or 4 doses in a 2-week 
period, will be discontinued from the study. 
5.1.6 
Overdose 
An overdose is a deliberate or inadvertent administration of a treatment at a dose higher than 
specified in the protocol.  It must be reported, irrespective of outcome even if toxic effects 
were not observed.  An overdose is considered an AE only if there are symptoms associated 
with the event.  All events of overdose are to be captured as protocol deviations. 
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5.2 
Investigational Product Accountability Procedures  
The Investigator or designee will keep current and accurate records of the study drug product 
dispensed, used, and returned for each subject to assure the health authority and ACADIA 
that the study drug is being handled appropriately.  Subjects should be instructed to return all 
used/empty kits, blister cards and unused tablets to the Investigator at regularly scheduled 
clinic visits and at the end-of-study (EOS)/early termination (ET) visit. 
At appropriate intervals during the study, study drug reconciliation will be performed by the 
ACADIA representative 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 
ACADIA.  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 ACADIA 
and the Sponsor’s designee. 
The Investigator and/or study staff is responsible for taking an inventory of each shipment of 
study drug received and comparing it with the accompanying drug accountability 
report/material shipping form.  The Investigator or study staff member will verify the 
accuracy of the information on the form, sign and date it, and provide a copy of the form to 
ACADIA or designee.  All study drug supplied is for use in this study only and should not be 
used for any other purpose. 
6 STUDY PROCEDURES 
Study specific procedures are detailed in Table 2. 
The Screening period will range from a minimum of 8 days to a maximum of 21 days.  The 
Screening period (between the Screening and Baseline visit) can be extended under certain 
circumstances described below.  The Screening period begins when the informed consent is 
signed.  Only the Investigator or designee will perform the informed consent procedures.  
Once subjects agree to participate in the study by signing the informed consent document, a 
full medical and psychiatric history will be taken and a physical and laboratory examination 
will be performed, as outlined in Table 2. 
Only subjects currently on a stable dose of one antidepressant will be eligible for the study.  
Subjects that are taking a second antidepressant and/or an antidepressant augmentation agent 
are not eligible.  During screening Investigators must document history of inadequate 
response during the current episode to at least 1 and not more than 2 courses of 
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antidepressant treatment of adequate dose and duration, as specified by the MGH ATRQ 
(Fava and Davidson 1996; Fava 2003; Chandler et al., 2010).  Such determination will be 
confirmed by the remote, independent
 raters during the SAFER interview. 
The Screening period is also designed to allow the gradual taper and discontinuation of any 
ongoing, excluded psychotropic or hypnotic drugs, including all sleep aids so that any 
prohibited medications are washed out under supervision of a study physician. (See 
Appendix A: Prohibited and Restricted Medications.)  The Investigator (or designee) should 
maintain ongoing contact with the subject, as deemed medically necessary, during the 
washout period in order to ensure subject safety during this time.  Subjects will discontinue 
the above-referenced prohibited drugs during the screening phase to allow proper wash-out at 
the baseline/randomization visit (e.g., at least 5 half-lives of the drug). 
When prohibited medication is discontinued during the screening period the subject should 
be advised to inform the treating physician that prohibited medication has been discontinued 
to ensure continuity of care.  This may also be done by the investigator with appropriate 
subject consent.  A subject who declines to inform the treating physician may continue in the 
study.  The investigator’s discussion with the subject should be described in the source 
record. 
The Investigator (or designee) will determine whether a patient meets eligibility criteria and 
will collect the demographic and medical data permitting full characterization of subjects.
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Table 2 
Schedule of Assessments 
Visit 
Double-blind Treatment Period 
~30-Day 
Follow-Upa
Screening 
1 
Baseline 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
(Day -21 
to -8) 
Week 0 Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Week 7 Week 8 Week 9 
Week 
10/ET 
Visit window (days) 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
+7 
Informed consent and if 
applicable, privacy forms 
X 
Inclusion/exclusion criteria 
X 
X 
Medical history, medication 
history, and demographics 
X 
Psychiatric history 
X 
MGH ATRQ 
X 
SAFER remote interview 
X 
SCID-5-CT 
X 
Physical examination 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height and weightb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGc 
X 
X 
X 
X 
X 
X 
Clinical laboratory testsd,e 
X 
X 
X 
X 
Pregnancy testf 
X 
X 
X 
X 
PK blood drawsg 
X 
X 
X 
X 
X 
X 
X 
X 
Urine toxicity screen 
X 
X 
X 
MADRS 
X 
X 
HAMD-17 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-S 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGI-I 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SF-12 
X 
X 
X 
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Visit 
Double-blind Treatment Period 
~30-Day 
Follow-Upa
Screening 
1 
Baseline 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
(Day -21 
to -8) 
Week 0 Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Week 7 Week 8 Week 9 
Week 
10/ET 
Visit window (days) 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
+7 
SDS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DAI-10 
X 
X 
X 
MGH-SFI 
X 
X 
X 
KSS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BIS-11 
X 
X 
X 
X 
X 
X 
X 
SIS 
X 
X 
X 
X 
X 
X 
X 
C-SSRSh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AIMS 
X 
X 
X 
X 
X 
BARS 
X 
X 
X 
X 
X 
SAS 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of adverse 
events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense study drug 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug accountability 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations:  AIMS=Abnormal Involuntary Movement Scale; BARS=Barnes Akathisia Rating Scale; BIS-11=Barratt Impulsiveness Scale; CGI-I=Clinical Global Impression-
Improvement; CGI-S=Clinical Global Impression-Severity; C-SSRS=Columbia Suicide Severity Rating Scale; DAI-10=Drug Attitude Inventory; ECG=electrocardiogram; 
EOS=end of study; ET=early termination; HAMD-17=17-Item Hamilton Depression Rating Scale; KSS=Karolinska Sleepiness Scale; MADRS=Montgomery Asberg Depression 
Rating Scale; MGH ATRQ=Massachusetts General Hospital Antidepressant Treatment Questionnaire; MGH-SFI=Massachusetts General Hospital Sexual Functioning Inventory; 
PK=pharmacokinetic; SAS=Simpson-Angus Scale; SCID-5-CT=Structured Clinical Interview for DSM-5, Clinical Trials Version; SF-12=12-Item Short Form Health Survey; 
SIS=Sheehan Irritability Scale 
aSafety follow-up (telephone call) will occur approximately 30 days after the last dose of study drug. 
bHeight will only be measured at the Screening visit. 
cA single 12-lead ECG can be performed any time before blood sampling or at least 30 minutes after blood sampling during clinic visits.  At Screening or Baseline, ECG can be 
repeated once in consultation with the Medical Monitor. 
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dTo include hematology, serum chemistry, prolactin levels, and urinalysis; TSH and reflex free T4 will be done at Screening only. 
eClinical labs (including HbA1c at Screening only) are encouraged, but not required to be completed under fasting conditions. 
fFor female study subjects of childbearing potential, a serum pregnancy test will be completed at the Screening visit; serum and urine pregnancy tests will be completed at all other 
scheduled time-points. 
gPK blood draw at the Screening visit will be for the concomitant SSRI/SNRI level only. At Baseline and Weeks 1, 3, 5, 6, 8, & 10 visits pimavanserin, AC-279, and the 
concomitant SSRI/SNRI antidepressant levels will be evaluated; at Baseline, the PK blood draw should be completed pre-dose (see Section 6.4).  When possible, PK blood 
samples will also be collected from subjects experiencing a serious adverse event or an adverse event leading to discontinuation, in order to assess levels of pimavanserin and the 
concomitant SSRI/SNRI.  For all Pk samples (scheduled and unscheduled), the date and time of the last 3 doses of study drug and the concomitant SSRI/SNRI, as well as the date 
and time that the blood sample was drawn, should be recorded on the source document and the eCRF. 
hAt Screening, the timeframe for the C-SSRS assessment should be lifetime and the past 6 months for Suicidal Ideation, and lifetime and the past 2 years for Suicidal Behavior. At 
all other visits, the timeframe for C-SSRS should be since the previous visit.  The relevant C-SSRS versions should be used to capture these timeframes. 
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6.1 
Diagnostic Scales 
6.1.1 
Structured Clinical Interview for DSM-5, Clinical Trials Version 
The SCID-5-CT, administered by the Investigator or designee, includes targeted modules 
aimed at diagnosing possible Axis I disorders. Questions here are asked exactly as written, 
and each is based on the diagnostic criteria from DSM-5. 
6.1.2 
Massachusetts General Hospital Antidepressant Treatment Response 
Questionnaire 
The MGH ATRQ (Fava and Davidson 1996; Fava 2003) is a clinician-assisted questionnaire 
that examines a patient’s antidepressant treatment history using specific anchor points to 
define the adequacy of both the dose and duration of each antidepressant course, as well as 
the degree of symptomatic improvement obtained with each course.  This validated 
questionnaire allows for the determination of inadequate response to antidepressant therapy 
in MDD (Chandler et al., 2010). 
6.2 
Efficacy Scales 
6.2.1 
Hamilton Rating Scale for Depression – 17 items 
The HAMD-17 (Hamilton 1960) is completed with a structured interview guide developed by 
Bech and colleagues (Bech et al., 1986) by the Investigator or designee based on an 
assessment of a patient’s symptoms.  This structured interview has been validated in the 
Danish University Antidepressant Group (DUAG) studies (Gram 2008) for use with time 
frames shorter than 1 week.  The time frame for this scale is the past 7 days. 
6.2.2 
Montgomery-Asberg Depression Rating Scale 
The MADRS (Montgomery and Asberg 1979) is a 10-item, clinician-rated instrument 
measuring depression severity.  It will be administered by the Investigator or designee with a 
structured interview guide developed by the MGH CTNI.  The time frame for this scale is the 
past 7 days. 
6.2.3 
Clinical Global Impressions–Severity and Clinical Global 
Impressions-Improvement Scales 
The CGI-S and CGI-I (Guy 1976) are scales used by the Investigator or designee to rate the 
severity of the disorder and the global improvement since beginning of the study.  The CGI-S 
rates the severity of a patient’s depression over the past 7 days.  The CGI-I rates the change in 
a patient's depression over the past 7 days relative to the patient’s symptoms at Baseline. 
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6.2.4 
Sheehan Disability Scale 
The SDS (Sheehan et al., 1996) is a 3-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. 
6.2.5 
Barratt Impulsiveness Scale 
The BIS-11 (Patton et al., 1995) is a questionnaire designed to assess the 
personality/behavioral construct of impulsiveness.  It is composed of 30 items describing 
common impulsive or non-impulsive (for reverse scored items) behaviors and preferences.  
Items are scored on the following 4-point scale:  Rarely/Never = 1; Occasionally = 2; 
Often = 3; Almost Always/Always = 4. 
6.2.6 
Drug Attitude Inventory 
The DAI-10 (Hogan et al., 1983) is a 6-item patient-facing questionnaire (with true/false 
responses) used to evaluate a patient's perceptions and experiences of treatment.  The DAI-10 
contains 6 items that a patient who is fully adherent to prescribed medication would answer 
as "True," and 4 items that a patient who is fully adherent would rate as “False.”  Scores are 
allocated to each answer and the total score is calculated.  A positive total score indicates a 
positive subjective response (adherent) and a negative total score indicates a negative 
subjective response (nonadherent). 
6.2.7 
Karolinska Sleepiness Scale 
The KSS (Akerstedt and Gilberg 1990) is a patient-facing scale that measures the patient's 
drowsiness and is frequently used in studies measuring subjective sleepiness.  Scoring is 
based on a 9-point verbally anchored scale ranging from "extremely alert" to "very sleepy, 
great effort to keep awake, fighting sleep."  The time frame for this scale is the past 7 days. 
6.2.8 
Massachusetts General Hospital Sexual Functioning Index 
Sexual functioning will be assessed using the MGH-SFI (Labbate 2001).  This is a patient-
facing questionnaire that quantifies sexual dysfunction into 5 functional domains (“interest in 
sex,” “sexual arousal,” “ability to achieve orgasm,” “ability to maintain erection” [males 
only], and “sexual satisfaction”).  Patients rate each item using a 6-point scale ranging from 1 
(good function) to 6 (poor function).  The time frame for this scale is the past month. 
6.2.9 
12-Item Short Form Health Survey 
The SF-12v2 (Ware et al., 1996) is a patient-reported outcome measure that addresses the 
same 8 domains as identified in the SF-36v2.  However, due to brevity of the assessment, the 
only 2 scores obtained from this assessment are composite scores representing physical 
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health and mental health composite summaries, PCS and MCS, respectively.  The 8 domains 
that are measured include Physical functioning (PF), Role – physical (RP), Bodily pain (BP), 
General health perceptions (GH), Vitality (V), Social functioning (SF), Role – emotional 
(RE), and Mental health (MH).  Composite scores are obtained for the PCS and MCS.  An 
algorithm is used to generate the PCS and MCS for comparison to normative data.  In 
normative data, the mean score is set to 50; thus, scores >50 indicate better physical or 
mental health than the mean and scores <50 indicate worse health.  The time frame for this 
scale is the past 4 weeks. 
6.2.10 
Sheehan Irritability Scale 
The SIS (Mannix et al., 2016) is a 7-item patient-reported outcome measure that was 
developed to measure the frequency, severity, and impairment associated with irritability in 
psychiatric patients.  It includes items on: irritability, frustration, 
edginess/impatience/overreaction, moodiness, anger with self, anger with others, and temper.  
The recall period is the past 7 days.  Items are answered on an 11-point rating scale where 
higher scores indicate greater severity (0=not at all, 10=extremely).  Item responses are 
summed into a total score (range=0-70).  The time frame for this scale is the past week. 
6.3 
Safety Assessments 
6.3.1 
Columbia Suicide Severity Rating Scale 
The C-SSRS (Posner et al., 2011) is a low-burden measure of the spectrum of suicidal 
ideation and behavior that was developed in the National Institute of Mental Health 
Treatment of Adolescent Suicide Attempters Study to assess severity and track suicidal 
events through any treatment.  It is a clinical interview providing a summary of both ideation 
and behavior that can be administered during any evaluation or risk assessment to identify the 
level and type of suicidality present.  The C-SSRS can also be used during treatment to 
monitor for clinical worsening.  The C-SSRS will be performed to assess suicidal ideation 
and behavior.  The C-SSRS tool was first developed for a prospective national study of 
treatment for adolescent suicide attempts. C-SSRS was developed by reliance on evidence 
stemming from 2 decades of research.  It includes a 5-point rating scale for suicidal ideation 
of increasing severity (from a "wish list to die" to an "active thought of killing oneself with 
plan and intent").  At Screening, the timeframe for the C-SSRS assessments is lifetime and 
the past 6 months for Suicidal Ideation, and lifetime and the past 2 years for Suicidal 
Behavior.  At all other visits, the timeframe for the C-SSRS is since the previous visit.  The 
relevant C-SSRS versions should be used to capture these timeframes. 
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6.3.2 
Barnes Akathisia Rating Scale 
The Barnes Akathisia Scale (BARS) (Barnes 1989) is a clinician-rated scale to assess drug-
induced akathisia and classify it as absent, mild, moderate, or severe.  It comprises items for 
rating the observable, restless movements which characterize the condition, the subjective 
awareness of restlessness, and any distress associated with the akathisia.  In addition, there is 
an item for rating global severity.  It is the scale used most commonly in trials comparing 
incidence and severity of akathisia between antipsychotic medications and placebo.  The time 
frame is “at this time.”  With trained raters, the BARS has demonstrated strong inter-rater 
reliability (Kappa= 0.74-0.95) (Barnes 2003). 
6.3.3 
Abnormal Involuntary Movement Scale 
The Abnormal Involuntary Movement Scale (AIMS) (Guy 1976) is a rating scale that was 
designed in the 1970s to measure involuntary movements known as tardive dyskinesia.  The 
AIMS has a total of 12 items rating involuntary movements of various areas of the patient's 
body.  These items are rated on a 5-point scale of severity.  The scale is rated from 0 (none), 1 
(minimal), 2 (mild), 3 (moderate), 4 (severe).  Two of the 12 items refer to dental care.  The 
remaining 10 items refer to body movements themselves. 
6.3.4 
Simpson Angus Scale 
The Simpson Angus Scale (SAS) (Simpson and Angus 1970) is composed of 10 items and is 
used to assess pseudoparkinsonism.  The grade of severity of each item is rated using a 
5-point scale.  Total SAS scores can range from 0-40.  Signs assessed include gait, arm-
dropping, shoulder shaking, elbow rigidity, wrist rigidity, leg pendulousness, head dropping, 
glabella tap, tremor, and salivation.  In more than 1 randomized controlled trial of bipolar I 
disorder (Tohen et al., 2004), treatment-emergent parkinsonism was defined as a SAS score 
of greater than 3 at any time following a score of 3 or less. 
6.3.5 
Demographics, Medical History, and Medication History 
A complete medical and psychiatric history will be obtained from each potential subject at 
the visits indicated in Table 2.  Demographic information, including date of birth, gender, 
race, and ethnicity will be recorded as well.  Any new medical condition reported after the 
informed consent form (ICF) has been signed will be captured as an AE.  In addition, a 
history of the medications that the subject has taken for the current depressive episode should 
be obtained.  Subjects may be asked to provide pharmacy or medical records to substantiate 
the medication history. 
6.3.6 
Physical Examinations 
A general physical examination will be conducted at the visits indicated in Table 2. 
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6.3.7 
Vital Signs 
Vital signs will be collected at the visits indicated in Table 2. 
Vital signs will include resting respiration rate, sitting systolic and diastolic blood pressure 
(BP), pulse rate, and temperature.  The sitting BP should be measured after the subject has 
been sitting for ≥3 minutes. 
6.3.8 
Height, Weight and Body Mass Index 
Height (in cm) will be measured at the Screening visit only. 
Body weight (in kg) will be measured at the visits indicated in Table 2. 
Body Mass Index (BMI) will be calculated and recorded at the visits indicated in Table 2 
using the following formula:  Weight (kg) / [height (m)]2. 
6.3.9 
Electrocardiograms 
All 12-lead ECGs will be complete, standardized recordings performed at the visits indicated 
in Table 2.  The subject must rest in a supine position 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, RR, QRS, QT, QTcF and QTcB intervals) will be 
included and summarized in the subject's study records. 
6.3.10 
Laboratory Evaluations 
The laboratory evaluations will include, but are not be limited to, the following: 
• 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/SGPT), aspartate aminotransferase (AST/SGOT), 
gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), total bilirubin 
(TBIL), lactate dehydrogenase (LDH), thyroid stimulating hormone (TSH).  (The 
TSH will only be done at Screening; if the TSH level is outside of the laboratory 
reference range, a reflex free T4 test will automatically be performed by the central 
lab.) 
o HbA1c (Screening only) 
o Glucose 
o Albumin (ALB), total protein 
o Prolactin 
o Creatine kinase (CK)/creatine phosphokinase (CPK) 
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o Lipid panel 
- Total cholesterol, HDL-cholesterol, triglycerides, LDL-cholesterol, 
Cholesterol/HDL ratio, Non-HDL cholesterol 
• Serum pregnancy test for women of child-bearing potential 
• Urine pregnancy test for women of child-bearing potential 
• 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 
• Urine toxicity screen 
o The following controlled substances will be tested with a urine toxicity screen 
according to the schedule presented in Table 3: amphetamine, barbiturates, 
benzodiazepines, cocaine, methadone, morphine/opiates, methamphetamine, 
marijuana (THC), phencyclidine (PCP), ecstasy (MDMA).  Negative drug screens 
are required for study eligibility. 
o Subjects who test positive and have a valid prescription for a controlled substance 
may be retested if they agree to abstain from the medication for the length of their 
participation in the study.  The repeat test, and any other tests, must be negative for 
them to participate in the study. 
Laboratory evaluations will be completed according to the schedule presented in Table 3 and 
procedures detailed in the laboratory Manual of Procedures (MOP).  Additional safety testing 
may be performed at the discretion of the Investigator or designee. 
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Table 3 
Safety Laboratory Evaluations 
Visit 
Tests 
Screening (initial visit) CHEM, TSH, reflex free T4, CBC, UA, urine toxicity screen, and 
serum pregnancy test 
Baseline (Week 0) 
CHEM, CBC, UA, urine toxicity screen, and serum and urine 
pregnancy tests 
Week 5 
CHEM, CBC, UA, urine toxicity screen, and serum and urine 
pregnancy tests 
Week 10 
CHEM, CBC, UA, and serum and urine pregnancy tests 
CBC=complete blood count; CHEM=clinical chemistry serum tests; UA=urinalysis 
 
6.3.11 
Adverse Event Reporting 
Adverse event reporting is described in Section 7. 
6.4 
Pharmacokinetic Assessments 
At Screening, blood samples will be collected for the measurement of the subject’s 
SSRI/SNRI antidepressant plasma concentrations.  The results will be provided to the 
investigator to assess the subject’s eligibility for the study.   
 
At Baseline (pre-dose) and at Weeks 1, 3, 5, 6, 8, and 10 blood samples will be collected for 
the measurement of plasma concentrations of pimavanserin, the metabolite AC-279, and the 
concomitant SSRI/SNRI antidepressant.  These data will remain blinded until the clinical 
database is unlocked at the end of the study. 
 
The dates and times of the administration of the last 3 doses of study drug, and the 
concomitant SSRI/SNRI antidepressant, as well as the date and time the blood sample was 
drawn, will be recorded in source documents and the eCRF at each of the above study visits. 
 
When possible, PK samples for pimavanserin, AC-279, and the concomitant SSRI/SNRI 
antidepressant should also be collected from subjects experiencing a serious adverse event 
(SAE) or AE leading to discontinuation.  The dates and times of administration of the last 
3 doses of both study drug and the concomitant SSRI/SNRI antidepressant prior to the SAE 
or AE leading to discontinuation, as well as date and time the blood sample was drawn, 
should also be recorded in source documents and in the eCRF.  These data will remain 
blinded until the clinical database is unlocked at the end of the study. 
 
Additional information for specimen preparation, handling, storage, and shipping can be 
found in the laboratory MOP. 
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6.5 
Study Schedule 
A schedule of the required study procedures and evaluations are outlined in Table 2.  Every 
effort should be made to complete the required procedures and evaluations at the designated 
visits and times. 
6.5.1 
Screening 
6.5.1.1 
Screening Visits (Day -21 to Day -8) 
Subjects will report to the clinical research unit for eligibility screening within 21 to 8 days 
prior to the Baseline Visit (Week 0).  Before any study specific procedures are conducted, the 
subject must sign a written ICF. 
During this visit, the following study procedures will be performed: 
• Signing of informed consent and if applicable, privacy forms 
• Evaluation of inclusion and exclusion criteria 
• Evaluation of medical and medication history 
• Collection of demographic information 
• Evaluation of psychiatric history 
• MGH ATRQ 
• Schedule SAFER remote interview 
• SCID-5-CT 
• Routine physical examination 
• Urine toxicity screen (done by central lab) 
• Serum pregnancy (for all female subjects of childbearing potential) 
• Height (cm) 
• Weight (kg) 
• Body mass index (BMI) 
• Oral body temperature (°C) 
• Blood pressure (seated) 
• Clinical laboratory tests  
• PK blood draw for concomitant SSRI/SNRI level 
• 12-lead ECG (single recording; before blood sampling or at least 30 minutes after 
blood sampling).  May be repeated once in consultation with the medical monitor. 
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• Columbia Suicide Severity Rating Scale (C-SSRS) for the following time frames: 
○ Suicidal Ideation: Lifetime and past 6 months 
○ Suicidal Behavior: Lifetime and past 2 years 
• 
HAMD-17 
• 
MADRS 
• 
CGI-S 
• 
Assessment of concomitant medications 
• 
Assessment of AEs 
6.5.1.2 
SAFER Interview  
To ensure that appropriate subjects are entered into the study, a remote interview will be 
conducted by
 raters.  The assessments administered will be the SAFER 
Interview, which will include the MADRS, the CGI-S, and the MGH ATRQ.  The interview 
will be performed remotely by the 
 rater, and the subject will be contacted at his 
or her home or other off-site location between the Screening and Baseline visits, during 
which call the above assessments will be performed.  Sites will be notified of the results 
within 24 hours of the interview.   
6.5.2 
Baseline (Week 0) 
At Baseline, after Screening procedures are completed and reviewed (e.g., acceptable clinical 
laboratory tests), the subject will be evaluated for continued eligibility and if qualified, may 
enter the treatment phase and receive the first dose study drug.  Subjects will complete the 
following procedures at Baseline: 
• Physical examination 
• Vital signs (pre-dose; sitting [at least 3 minutes] BP, pulse, respiratory rate, and 
temperature) 
• Weight 
• 12-lead ECG (single recording; before blood sampling or at least 30 minutes after 
blood sampling).  May be repeated once in consultation with the medical monitor. 
• Clinical laboratory tests 
• Serum and urine pregnancy tests for women of childbearing potential   
• Urine toxicity screen (done by central lab) 
• PK blood draw (pre-dose) for pimavanserin, AC-279, and concomitant SSRI/SNRI 
concentrations 
• Assessment of concomitant medications 
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• Assessment of AEs 
• Scales listed in Table 2 (MADRS, HAMD-17, CGI-S, SF-12, SDS, DAI-10, 
MGH-SFI, KSS, BIS-11, SIS, C-SSRS, AIMS, BARS, and SAS). 
o The C-SSRS time frame is since last visit. 
• Randomization 
• Dispense and administer first dose of study drug 
o Each subject will be assigned study drug according to the randomization schedule.  
The first dose will be administered at the clinic; study drug kits will then be 
dispensed to the subject to take home.  It is recommended that the subject take the 
study drug at approximately the same time each day. 
6.5.3 
Week 1 
Subjects will complete the following procedures: 
• Vital signs (sitting [at least 3 minutes] BP, pulse, respiratory rate, and temperature) 
• Weight 
• 12-lead ECG (single recording; before blood sampling or at least 30 minutes after 
blood sampling) 
• PK blood draw for pimavanserin, AC-279, and concomitant SSRI/SNRI levels 
• Assessment of concomitant medications 
• Assessment of AEs 
• Scales listed in Table 2 (HAMD-17, CGI-S and I, SDS, KSS, BIS-11, SIS, C-SSRS, 
AIMS, BARS, and SAS) 
o The C-SSRS time frame is since last visit 
• Study drug accountability 
• Dispense study drug 
6.5.4 
Week 2 
Subjects will complete the following procedures: 
• Vital signs (sitting [at least 3 minutes] BP, pulse, respiratory rate, and temperature) 
• Weight 
• Assessment of concomitant medications 
• Assessment of AEs 
• Scales listed in Table 2 (HAMD-17, CGI-S and I, SDS, KSS, C-SSRS) 
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o The C-SSRS time frame is since last visit 
• Study drug accountability 
• Dispense study drug 
6.5.5 
Week 3 
Subjects will complete the following procedures: 
• Vital signs (sitting [at least 3 minutes] BP, pulse, respiratory rate, and temperature) 
• Weight 
• PK blood draw for pimavanserin, AC-279, and concomitant SSRI/SNRI levels 
• Assessment of concomitant medications 
• Assessment of AEs 
• Scales listed in Table 2 (HAMD-17, CGI-S and I, SDS, KSS, BIS-11, SIS, C-SSRS) 
o The C-SSRS time frame is since last visit 
• Study drug accountability 
• Dispense study drug 
6.5.6 
Week 4 
Subjects will complete the following procedures: 
• Vital signs (sitting [at least 3 minutes] BP, pulse, respiratory rate, and temperature) 
• Weight 
• Assessment of concomitant medications 
• Assessment of AEs 
• Scales listed in Table 2 (HAMD-17, CGI-S and I, SDS, KSS, C-SSRS) 
o The C-SSRS time frame is since last visit 
• Study drug accountability 
• Dispense study drug 
6.5.7 
Week 5 
Subjects will complete the following procedures: 
• Physical examination 
• Vital signs (sitting [at least 3 minutes] BP, pulse, respiratory rate, and temperature) 
• Weight 
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• 12-lead ECG (single recording; before blood sampling or at least 30 minutes after 
blood sampling) 
• Clinical laboratory tests 
• Serum and urine pregnancy tests for women of childbearing potential 
• Urine toxicity screen (done by central lab) 
• PK blood draw for pimavanserin, AC-279, and concomitant SSRI/SNRI levels 
• Assessment of concomitant medications 
• Assessment of AEs 
• Scales listed in Table 2 (HAMD-17, CGI-S and I, SF-12, SDS, DAI-10, MGH-SFI, 
KSS, BIS-11, SIS, C-SSRS, AIMS, BARS, and SAS) 
o The C-SSRS time frame is since last visit 
• Study drug accountability 
• Re-randomization (see Section 9.6.2.2) 
• Dispense study drug 
6.5.8 
Week 6 
Subjects will complete the following procedures: 
• Vital signs (sitting [at least 3 minutes] BP, pulse, respiratory rate, and temperature) 
• Weight 
• 12-lead ECG (single recording; before blood sampling or at least 30 minutes after 
blood sampling) 
• PK blood draw for pimavanserin, AC-279, and concomitant SSRI/SNRI levels 
• Assessment of concomitant medications 
• Assessment of AEs 
• Scales listed in Table 2 (HAMD-17, CGI-S and I, SDS, KSS, BIS-11, SIS, C-SSRS, 
AIMS, BARS, and SAS) 
o The C-SSRS time frame is since last visit 
• Study drug accountability 
• Dispense study drug 
6.5.9 
Week 7 
Subjects will complete the following procedures: 
• Vital signs (sitting [at least 3 minutes] BP, pulse, respiratory rate, and temperature) 
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• Weight 
• Assessment of concomitant medications 
• Assessment of AEs 
• Scales listed in Table 2 (HAMD-17, CGI-S and I, SDS, KSS, C-SSRS) 
o The C-SSRS time frame is since last visit 
• Study Drug Accountability 
• Dispense study drug 
6.5.10 
Week 8 
Subjects will complete the following procedures: 
• Vital signs (sitting [at least 3 minutes] BP, pulse, respiratory rate, and temperature) 
• Weight 
• PK blood draw for pimavanserin, AC 279, and concomitant SSRI/SNRI levels 
• Assessment of concomitant medications 
• Assessment of AEs 
• Scales listed in Table 2 (HAMD-17, CGI-S and I, SDS, KSS, BIS-11, SIS, C-SSRS) 
o The C-SSRS time frame is since last visit 
• Study drug accountability 
• Dispense study drug 
6.5.11 
Week 9 
Subjects will complete the following procedures: 
• Vital signs (sitting [at least 3 minutes] BP, pulse, respiratory rate, and temperature) 
• Weight 
• Assessment of concomitant medications 
• Assessment of AEs 
• Scales listed in Table 2 (HAMD-17, CGI-S and I, SDS, KSS, C-SSRS) 
o The C-SSRS time frame is since last visit 
• Study drug accountability 
• Dispense study drug 
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6.5.12 
Week 10/Early Termination Visit 
Subjects will have the following procedures completed: 
•
Physical examination
•
Vital signs (sitting [at least 3 minutes] BP, pulse, respiratory rate, and temperature)
•
Weight
•
12-lead ECG  (single recording; before blood sampling or at least 30 minutes after
blood sampling)
•
Clinical laboratory tests
•
Serum and urine pregnancy tests for all  women of childbearing potential
•
PK blood draw for pimavanserin, AC-279, and concomitant SSRI/SNRI levels
•
Assessment of concomitant medications
•
Assessment of AEs
•
Scales listed in Table 2 (HAMD-17, CGI-S and I, SF-12, SDS, DAI-10, MGH-SFI,
KSS, BIS-11, SIS, C-SSRS, AIMS, BARS, and SAS)
o
The C-SSRS time frame is since last visit
•
Study drug accountability
6.5.13 
 30 Day Follow-Up Visit 
Subjects will have the following procedures completed approximately 30 days following 
Week 10/Early Termination: 
•
Assessment of concomitant medications
•
Assessment of AEs
These assessments will be performed through a telephone contact with the subject, and 
should be completed for subjects that complete all study visits and those who discontinue 
prematurely from the study. 
6.5.14 
Early Termination Visit 
Every reasonable effort should be made to complete assessments as outlined in Section 6.5.12 
for subjects who discontinue prematurely from the study.  A 30-day safety follow-up is to be 
completed for all study subjects. 
6.5.15 
Unscheduled Visit 
Unscheduled visits may occur as determined by the Investigator. 
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6.6 
Precautionary Medications, Treatments, and Procedures 
See below for restrictions for concomitant medications. 
6.7 
Concomitant Medications, Treatments, and Procedures 
All medications used up to 4 weeks prior to Baseline (Week 0) through the 30-day Follow-up 
Visit should be recorded. 
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.  ACADIA and the 
Investigator, or designee, will confer to determine whether it is appropriate to continue such a 
subject in the study if a prohibited medication is prescribed. 
6.8 
Prohibited Medications, Treatments, and Procedures 
Subjects should be instructed to refrain from taking the medications listed in Appendix A, 
that doing so will result in discontinuation from the study, and to consult the Investigator 
before taking any medications not listed in Appendix A as well.  These include prescribed, 
over-the-counter, and herbal medications. 
7 ASSESSMENTS OF SAFETY 
7.1 
Specification of Safety Parameters 
7.1.1 
Definition of Adverse Event 
An AE is defined as “any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related” (CDER, 2012).  
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 either study drug (see Section 5.1.6) or 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 
Adverse events will be recorded from the time informed consent is obtained through the 
duration of the study.  All AEs must be either resolved or stable at end of study.  If ongoing at 
the end of the study the subject should be referred for appropriate treatment. 
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 ACADIA 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) 
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Outpatient surgery 
Preplanned or elective procedures 
Protocol procedures 
Social hospitalization, defined as admission to the hospital as a result of inadequate family 
support or care at the subject’s primary residence  
Definition of Disability or Permanent Damage 
Disability is defined as a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions. 
Definition of Medically Significant 
Important medical events (medically significant events) that may not result in death, be life 
threatening, or require hospitalization may be considered to be an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject or may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition.  Examples of 
such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias, 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). 
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Consider the following when assessing causality: 
Temporal associations between the agent and the event 
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 related to AE 
Unknown:  Unknown 
7.2.2.6 
Seriousness 
Not serious 
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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 
In the event that a subject is withdrawn from the study because of an AE, the subject should 
be followed and treated by the Investigator until the AE has resolved, stabilized, or a new 
chronic baseline has been established.  
7.4 
 Reporting Procedures 
7.4.1 
Adverse Event Reporting 
The Investigator must record all observed AEs and all reported AEs.  At each visit, the 
Investigator should ask the subject a nonspecific question (e.g., “Have you noticed anything 
different since your last visit?”) to assess whether any AEs have been experienced since the 
last report or visit. 
Note that any use of medication (and specifically any newly prescribed medication) during 
the course of a study may indicate the occurrence of an AE that may need to be recorded on 
both the AE and the concomitant medication page.  
All AEs, serious and not serious, will be recorded on the AE eCRF page using appropriate 
medical terminology.  Severity and relationship to study drug will be assessed by the 
Investigator as described above. 
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 ACADIA 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 and other reportable information must be reported within 24 hours of discovery 
to ACADIA or its designee.  The SAE (initial and/or follow-up), pregnancy, or overdose of 
study drug (i.e., any amount more than the prescribed 2 tablets in a given day) must be 
reported within 24 hours by completing the SAE, Overdose, and/or pregnancy forms, as 
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appropriate (details on how to report SAEs are provided in a separate study reference 
manual). 
At a minimum, events identified by ACADIA to require expedited reporting as serious, 
unexpected, and related to study drug must be brought to the attention of the responsible 
IRB/EC.  These will be provided by ACADIA after their assessment.  For European Union 
member states, ACADIA 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.  
For this study, sites will complete the paper SAE, Pregnancy and/or Overdose form (for 
initial and/or follow-up information) including available supporting documentation relevant 
to the event and fax or email (within 24 hours of discovery) to the following: 
 
 
Subjects will be followed until Week 10/ET for any SAEs and/or other reportable 
information or until such events have resolved or the Investigator, in conjunction with 
ACADIA, deems them to be chronic or stable. 
In the event of any SAE (other than death), the study subject will be instructed to contact the 
Investigator (or designee) using the telephone number provided in the ICF.  All subjects 
experiencing an SAE will be seen by the Investigator or designee as soon as is feasible 
following the report of the SAE. 
Serious AEs occurring after the study Follow-up Period 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 ACADIA or its designee (see fax numbers and email address in 
Section 7.4.2).  Any female subject who becomes pregnant during the study will be followed 
through the first well-baby visit. 
Any AEs that are the consequence of pregnancy and which meet the criteria for serious 
should also be reported via the SAE forms. 
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7.4.4 
Reporting of Overdose 
An overdose of study drug (i.e., any amount more than the prescribed 2 tablets in a given 
day) must be reported on the Overdose Form within 24 hours of discovery to ACADIA or its 
designee (see fax numbers and email address in Section 7.4.2). 
8 CLINICAL MONITORING 
Routine monitoring of study sites is described in Section 11. 
Clinical site monitoring is conducted to ensure that the rights and well-being of human 
subjects are protected, that the reported trial data are accurate, complete, and verifiable, and 
that the conduct of the trial is in compliance with the currently approved protocol and 
amendment(s) as applicable, with GCP, and with applicable regulatory requirements.  Details 
of the study site monitoring process are described in a separate clinical monitoring plan 
document. 
9 STATISTICAL CONSIDERATIONS 
9.1 
Statistical and Analytical Plans 
Statistical methods will be documented in detail in a Statistical Analysis Plan (SAP) to be 
approved by ACADIA prior to database lock. 
9.2 
Statistical Hypotheses 
Let Δ1 be the difference in the mean change from Baseline to Week 5 in the HAMD-17 total 
score between the pimavanserin and placebo groups in Stage 1.  Let Δ2 be the difference in 
the mean change from Baseline to Week 5 in Stage 2 in the HAMD-17 total score between 
the pimavanserin and placebo groups, in the subjects who are re-randomized in Stage 2 (the 
placebo non-responders from Stage 1). Let w be the weight for Stage 1 and 1-w the weight 
for Stage 2. 
The null hypothesis for the primary endpoint is: 
 𝑤𝑤∆1 + (1 −𝑤𝑤)∆2= 0 
The alternative hypothesis for the primary endpoint is: 
𝑤𝑤∆1 + (1 −𝑤𝑤)∆2≠0 
The hypotheses for the key secondary endpoint are of the same form but with Sheehan 
Disability Scale replacing HAMD-17. 
9.3 
Analysis Datasets 
The full analysis set includes all randomized subjects who received at least one dose of 
blinded study drug and who have both a Baseline value and at least one post-Baseline value 
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for the HamD-17 total score.  The full analysis set will be used for the analysis of all efficacy 
endpoints.  For efficacy analyses that only use Stage 2 data from placebo non-responders 
from Stage 1, a subset of the full analysis set will be used, consisting of subjects who were 
re-randomized at Week 5, received at least one dose of study drug after re-randomization, and 
have at least one value for the HAMD-17 total score after re-randomization. 
The per-protocol (PP) analysis set will be defined prior to unblinding the study for the final 
analysis.  Subjects will be analyzed based on their randomized treatment assignment.  The PP 
analysis set will be used for sensitivity analyses of selected efficacy endpoints. 
Safety analyses will be conducted using the Safety analysis set, which is defined as all 
subjects who received at least one dose of blinded study drug. 
Any other analysis groups, if necessary, will be defined in the SAP. 
9.4 
Description of Statistical Methods 
9.4.1 
General Approach 
For continuous variables the following summary statistics will be provided: number of 
subjects, mean, standard error of the mean, standard deviation, minimum, maximum, and 
median.  For categorical variables, summaries will include the number and percentage of 
subjects in each category, using the number of subjects with non-missing values as the 
denominator for the percentages (unless otherwise specified). 
Separate summaries will be provided for Stage 1 data and for Stage 2 data in subjects who 
are re-randomized in Stage 2.  In addition, summaries covering data from both stages will be 
provided for the subjects who are not eligible for re-randomization in Stage 2 (i.e., for 
placebo responders in Stage 1 and for subjects randomized to the pimavanserin group in 
Stage 1). 
Unless otherwise specified, all reported p-values will be two-sided. All analyses will be 
performed using SAS® V9.3 (SAS Institute, Inc., Cary, North Carolina) or higher.  Validation 
and quality control of the tables, listings and figures containing the results of the statistical 
analyses will follow appropriate standard operating procedures. 
9.4.2 
Analysis of the Primary Efficacy Endpoint 
The primary efficacy endpoint, HAMD-17 total score change from baseline to the end of the 
5-week treatment period in both stages, will be evaluated using the weighted combination of 
statistics from the stage-specific mixed models for repeated measures (MMRM).  The models 
will include effects for treatment group, visit, treatment-by-visit interaction, baseline 
HAMD-17 total score, and the baseline HAMD-17 total score-by-visit interaction.  An 
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unstructured covariance matrix will be used and the Kenward-Roger approximation will be 
used to adjust the denominator degrees of freedom. 
The treatment effect will be assessed as the differences in least-squares mean change from 
baseline to Week 5 for the pimavanserin and placebo groups, combined across Stages 1 and 2 
using prespecified 0.5/0.5 weighting for Stage 1/Stage 2. 
Inference will be conducted using the following weighted linear combination of stage-wise 
treatment effects: 
𝑤𝑤𝜃𝜃෠1 + (1 −𝑤𝑤)𝜃𝜃෠2
ට𝑤𝑤2𝑉𝑉𝑉𝑉𝑉𝑉൫𝜃𝜃෠1൯+ (1 −𝑤𝑤)2𝑉𝑉𝑉𝑉𝑉𝑉൫𝜃𝜃෠2൯
 
In the above formula, w = 0.5 and 𝜃𝜃෠1 and 𝜃𝜃෠2 are the differences in least squares means 
between pimavanserin and placebo at Week 5, for Stages 1 and 2, respectively. 
9.4.3 
Analysis of the Secondary Endpoints 
Continuous secondary efficacy endpoints (CGI-S and I, SF-12, SDS, DAI-10, MGH-SFI, 
KSS, BIS-11, and SIS) will be analyzed using methods similar to those described above for 
the primary efficacy endpoint.  For CGI-I, baseline CGI-S score will be used as the covariate 
in the MMRM model.  For the SF-12, DAI-10, and MGH-SFI, which are assessed only at 
Baseline and at Week 5 of each stage, an analysis of covariance model with fixed effects for 
treatment group and baseline score will be used instead of the MMRM model.  
For the binary secondary endpoints of treatment response and remission, inference will be 
based on a combined treatment effect, using data from both stages.  Details will be provided 
in the SAP. 
9.4.4 
Safety Analyses 
Safety results will be summarized by treatment group using descriptive statistics. 
9.4.4.1 
Adverse Events 
All AEs will be coded using the MedDRA coding dictionary.  All AEs will be listed and 
treatment-emergent adverse events (TEAEs) will be summarized by system organ class and 
preferred term.  A treatment-emergent adverse event is defined as an AE that started after the 
first dose of study drug.  Summaries by maximum severity and by relationship will also be 
provided.  Serious TEAEs, fatal TEAEs, and TEAEs leading to discontinuation will also be 
summarized.  Other TEAEs of special interest may also be summarized. 
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9.4.4.2 
Clinical Laboratory Values 
The serum clinical chemistry, hematology, and urinalysis results at baseline and at Weeks 5 
and 10 will be summarized by treatment group.  Change from baseline values will also be 
summarized. 
The number and percentage of subjects with markedly abnormal post-baseline laboratory 
values will be summarized by treatment group at each post-baseline visit and overall post-
baseline for selected parameters.  The markedly abnormal criteria will be specified in the 
SAP. 
9.4.4.3 
Vital Signs and Body Weight 
Vital signs and body weight at baseline and each post-baseline visit will be summarized by 
treatment group.  Change from baseline values will also be summarized.  The number and 
percentage of subjects with changes from baseline (increases and decreases separately) in 
body weight of 7% or more will also be provided. 
9.4.4.4 
Electrocardiogram 
ECG parameters at baseline and at Weeks 1, 5, 6, and 10 will be summarized by treatment 
group.  Change from baseline values will also be summarized.  Categorical analyses will be 
conducted on the incidence of subjects with prolonged QTc intervals and changes in QTc 
intervals in accordance with International Conference on Harmonisation (ICH) guidelines 
and based on the FDA E14 Guidance Document. 
9.4.4.5 
Physical Examinations 
The results of the physical examinations at each visit (Screening and Weeks 5 and 10 visits) 
will be tabulated by treatment group. 
9.4.4.6 
Columbia Suicide Severity Rating 
For the C-SSRS, the number and percentage of subjects with suicidal ideation or suicidal 
behavior during the study will be tabulated. 
9.4.5 
Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analyses 
Plasma concentration data for pimavanserin, AC-279, and concomitant SSRI/SNRI levels 
will be listed and summarized using descriptive statistics. 
If data allow, population PK and PK/PD analyses will be performed to further characterize 
the PK profile and exposure response relationship of pimavanserin and its metabolite using 
measures of safety, efficacy, and sleep parameters.  The results of population PK and PK/PD 
modeling will be presented in a separate report.  If data allow, graphical depictions of the 
concentration-versus-time profiles for the concomitant SSRIs/SNRIs will be generated from 
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literature.  The measured plasma concentrations of the SSRIs/SNRIs will be overlaid on the 
respective representative graph to assess actual versus expected plasma concentrations.  The 
results will be presented in a separate report. 
Pimavanserin and AC-279 plasma concentration data as well as SSRI/SNRI will remain 
blinded until the unblinding of the clinical database at the end of the study. 
9.4.6 
Adherence and Retention Analyses 
Subject disposition, including the number of subjects screened, randomized, received study 
treatment, discontinued, and completed the study, will be summarized by treatment group. 
Reasons for discontinuation will also be summarized.  A listing will be provided displaying 
all subjects excluded from the full or PP analysis sets, and will include reason(s) for 
exclusion. 
Study medication exposure and compliance will also be summarized by treatment group for 
the safety analysis set. 
9.4.7 
Baseline Descriptive Statistics 
Demographics and Baseline characteristics, including sex, age, race, ethnicity, weight, BMI, 
MDD duration, and duration of the current MDE, will be summarized by treatment group. 
9.4.8 
Planned Interim Analyses 
No interim analyses are planned. 
9.4.9 
Additional Sub-group Analyses 
Selected analyses may be performed in subgroups.  Details will be provided in the SAP. 
9.4.10 
Multiple Comparison/Multiplicity 
A hierarchical testing procedure will be used to control the Type I error rate across the 
primary and key secondary endpoints.  The primary endpoint will be tested at a significance 
level of 0.05 and if this test is significant, the key secondary endpoint will also be tested at a 
significance level of 0.05.  If the primary endpoint test is not significant then the key 
secondary endpoint is also not significant. 
Other secondary endpoints will be tested at a nominal significance level of 0.05 (2-sided). 
9.4.11 
Tabulation of Individual Response Data 
Listings of the individual response data will be provided by measure and time point. 
9.4.12 
Exploratory Analyses 
Additional exploratory analyses may be defined in the SAP. 
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9.5 
Sample Size 
A total sample size of 168 evaluable subjects was estimated to provide at least 80% power at 
a two-sided significance level of 0.05 assuming a mean change in HAMD-17 total score 
of -7.8 (SD=8.0) and -10 (SD=8) in Stage 1, and -2.8 (SD=6) and -6.0 (SD=6) in Stage 2 for 
the placebo and pimavanserin groups, respectively. 
For the above calculation, the weight for each double-blind treatment stage is equal to 0.5 
and it is assumed that approximately 70% of placebo subjects will be non-responders at the 
end of Stage 1. 
Adjusting for a potential non-evaluable rate of up to 10%, approximately188 subjects will be 
randomized into Stage 1 (47 to pimavanserin and 141 to placebo).  It is anticipated that 
approximately 98 subjects will be randomized into Stage 2 (49 to pimavanserin and 49 to 
placebo). 
9.6 
Measures to Minimize Bias 
9.6.1 
Masking Procedures 
This unmasked protocol version provides details of certain study design elements, procedures, 
and statistical methods that are not available in the masked version of the protocol. 
This document is intended for use only by unmasked ACADIA or
 personnel or 
their designated agents or for review only by IRBs, IECs, regulatory authorities, or any other 
entity considered suitable by ACADIA. 
The information contained herein is UNMASKED and CONFIDENTIAL.  Therefore, it must 
NOT be shared with or communicated to any individual at an investigational site or from site 
facing members of the clinical operations team of the CRO except with explicit and fully 
documented authorization from ACADIA. 
Key elements revealed but that are masked in the masked protocol include: 
• The 2-stage Sequential Parallel Comparison Design of the study and related details. 
• The duration and timing of the efficacy period. 
• Full definition of Stage 1 and Stage 2 baseline, admission and non-responder criteria 
and timepoints. 
• Details of the statistical methodology that are specific to the Sequential Parallel 
Comparison Design 
Investigators will receive the masked version of the clinical study protocol. 
Investigators will be informed of the 10-week treatment period but will remain masked to the 
distinction between Stage 1 and Stage 2. 
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In order to maintain the masking of the re-randomization visit, Investigators will enter the 
HAMD-17 total score for the subject at every visit into Interactive Response Technology 
(IRT). 
9.6.2 
Randomization Procedures 
9.6.2.1 
Stage 1 Double-blind Treatment Period 
Subjects who meet the criteria for study eligibility will continue to receive their SSRI/SNRI 
antidepressant at a stable dose for the duration of the study and will be randomly assigned 
(1:3) to pimavanserin 34 mg or placebo. 
9.6.2.2 
Stage 2 Double-blind Treatment Period 
At the end of Stage 1 (Week 5), subjects initially randomized to placebo and who have met 
the predefined non-responder criteria (i.e., HAMD-17 total score at Week 5 >14 and percent-
reduction from the Week 0 (Baseline) HAMD-17 total score of <50%) are randomly assigned 
(1:1) to pimavanserin 34 mg or placebo.  The determination of the subject’s status and 
eligibility for randomization in the Stage 2 will be made in the double-blind manner via the 
IRT system.  Subjects who do not meet criteria for randomization into Stage 2 will continue 
with the assigned treatment from Stage 1 for an additional 5 week period (until the end of the 
study double-blind treatment). 
9.6.3 
Breaking the Study Blind/Subject Code 
For the final analysis, the treatment codes for all subjects will be released to ACADIA after 
all subjects have completed the study and the clinical database is locked. 
Unblinding of individual treatment assignment during the study is discouraged.  The 
Investigator at a site may break the blind for a given subject in the event of a medical 
emergency, where knowledge of the subject’s treatment assignment (pimavanserin or 
placebo) must be known in order to facilitate appropriate emergency medical treatment.  The 
Investigator should attempt to contact the study Medical Monitor before unblinding a 
subject’s treatment identity in order to obtain concurrence that unblinding a subject’s 
treatment assignment is necessary.  Details of the process to be followed are provided in a 
separate IRT Manual. 
10 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
10.1 Case Report Forms and Data Verification 
Subject data required by this protocol are to be recorded in an electronic data capture (EDC) 
system on electronic case report forms (eCRFs).  The Investigator and his/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 
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requested on the eCRFs needs to be supplied, including subject identification date(s), 
assessment values, etc.  Any omission or discrepancy will require explanation.  All 
information on eCRFs must be traceable to source documentation at the site. 
The study monitors will be responsible for reviewing and verifying the data recorded on the 
eCRFs, utilizing the source documentation, and will query discrepant findings.  The 
Investigator and site personnel will be responsible for answering all queries.  The eCRFs will 
be submitted to ACADIA or its designee for quality assurance review and statistical analysis.  
A copy of the final eCRFs will be retained by the Investigator, who must ensure that the copy 
is stored in a secure place. 
10.2 Source Documentation 
All study specific medical information obtained at each study visit must be recorded in the 
subject’s record (source documentation) in real time as it is collected, and then entered into a 
validated 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. 
11 QUALITY ASSURANCE AND QUALITY CONTROL 
ACADIA and/or designee representatives 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 study (e.g., eCRFs and other 
pertinent data) provided that subject confidentiality is respected. 
ACADIA and/or designee 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 ACADIA’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 study conduct and compliance with the protocol, 
ICH Guidance on GCP, and applicable regulatory requirements. 
ACADIA and/or designee representatives, regulatory authority inspectors and IRB/IEC 
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 ETHICS/PROTECTION OF HUMAN SUBJECTS 
12.1 Ethical Standard 
The study will be conducted in compliance with the protocol, the Declaration of Helsinki, 
ICH principles of GCP, and other applicable regulatory requirements. 
The study will be performed in accordance with HIPAA regulations, FDA GCP Regulations 
(US CFR 21 parts 50, 54, 56, and 312), and ICH GCP Guidelines (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 (CSR) will be signed by an Investigator and/or Coordinating Investigator 
who will be designated prior to the writing of the CSR. 
12.2 Institutional Review Board/Independent Ethics Committee 
The Principal Investigator or designee will provide the IRB/IEC 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/IEC provides written 
approval of the protocol and the informed consent and until approved documents have been 
obtained by the Principal Investigator and copies received by the ACADIA.  All amendments 
will be sent to the IRB/IEC for information (minor amendment) or for submission (major 
amendment) before implementation.  The Principal Investigator will supply the IRB/IEC and 
the ACADIA 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 ACADIA. 
12.3 Informed Consent Process 
Properly executed, written informed consent must be obtained from each subject or subject’s 
legally authorized representative prior to initiating screening evaluations required by this 
protocol.  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.  Informed consent 
must be obtained from the subject’s legally authorized representative with the subject’s assent 
if the subject is deemed not competent to provide informed consent. 
A copy of the ICF planned for use will be reviewed by ACADIA (or designee) for 
acceptability and must be submitted by the Investigator, together with the protocol, to the 
appropriate IRB/IEC 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 
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prospective subject.  The Investigator must provide ACADIA (or designee) with a copy of the 
IRB/IEC letter approving the protocol and the ICF(s) 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.  Any revision(s) must be submitted to the appropriate 
IRB/IEC for review and approval in advance of use. 
12.3.1 
Consent/Assent and Other Informational Documents Provided to Subjects 
The subject must be given a copy of the signed informed consent. 
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/IEC-approved 
consent form must be personally signed and dated by the subject and by the person who 
conducted the informed-consent discussion.  The Investigator or appropriate site personnel 
must document the details of obtaining informed consent in the subject’s study documents.  
The subject must be given a copy of the signed informed consent and the original maintained 
in the designated location at the site. 
12.4 Subject and Data Confidentiality 
The Investigator must ensure that each subject’s anonymity is maintained as described below.  
On the eCRFs or other documents submitted to ACADIA and/or designee, subjects must be 
identified by a Subject Identification Number only.  Documents that are not for submission to 
ACADIA and/or designee (e.g., signed ICFs) should be kept in strict confidence by the 
Investigator in compliance with Federal regulations or other applicable laws or ICH 
Guidance on GCP. 
12.5 Research Use of Stored Human Samples 
 Each time that blood samples are drawn for the analysis of plasma concentrations of 
pimavanserin, AC-279, and concomitant SSRI/SSNI antidepressants, two aliquots of plasma 
will be sent to the central lab from the same sample.  One of these aliquots will be used for 
the above analysis, and the second aliquot will be retained at the central lab until the study is 
completed for any repeat testing that may be needed.  All retained plasma samples will be 
destroyed after completion of the clinical study report (CSR). 
12.6 Future Use of Stored Specimens 
Not applicable; see Section 12.5 above. 
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13 DATA HANDLING AND RECORD KEEPING 
13.1 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 ACADIA and regulatory agencies.  
The Investigator and institution must permit authorized representatives of ACADIA and/or 
designee (including monitors and auditors), and the regulatory agency(s) (including 
inspectors), and the IRB/IEC 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. 
13.2 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, subject-related source documentation, and 
adequate records for the receipt and disposition of all investigational drug.  Investigators 
should maintain all essential study documentation, for a period of at least two years following 
the last approval of marketing application in an ICH region (US, Europe, and Japan), or until 
at least two years after the drug investigational program is discontinued, unless a longer 
period is required by applicable law or regulation.  Only ACADIA can notify an Investigator 
or vendor when any records may be discarded.  Investigators should contact ACADIA before 
destroying any files. 
13.3 Protocol Changes 
13.3.1 
Protocol Amendments 
Changes to the protocol may be made only by ACADIA (with or without consultation with 
the Investigator).  All protocol modifications must be submitted to the site IRB/IEC in 
accordance with local requirements and, if required, to the Regulatory Authority, 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 study 
subjects, or when the changes involve only logistical or administrative aspects of the study.  
No approval is required for notifications.  
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13.3.2 
Protocol Exceptions and Deviations 
No prospective entry criteria protocol deviations are allowed; all subjects must meet all 
eligibility criteria in order to participate in the study. 
Protocol waivers for eligibility will not be granted by ACADIA under any circumstances.  If, 
during the course of a subject’s post-randomization participation in the study it is discovered 
that the subject did not meet all eligibility criteria, s/he will be discontinued, unless the 
discontinuation presents an unacceptable medical risk.  The justification to allow the subject 
to continue in the study will be made by ACADIA, 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.  All follow-up safety assessments must be completed and 
documented as outlined in the protocol.  The Investigator must report any protocol deviation 
to ACADIA and, if required, to the IRB/IEC in accordance with local regulations, within 
reasonable time. 
13.4 Publication and Data Sharing Policy 
All publication rights are delineated in the Clinical Study Agreement and/or other separate 
agreements with the Investigator and/or Institution, as applicable. 
14 CONFLICT OF INTEREST POLICY 
14.1 Finance, Insurance, and Indemnity 
Arrangements for finance, insurance and indemnity are delineated in the Clinical Study 
Agreement and/or other separate agreements with the Investigator and/or Institution, as 
applicable. 
 
 
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15 LITERATURE REFERENCES 
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dissociable effects on tests of spatial working memory following the dopamine D2 receptor 
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Tohen M, Chengappa KNR, Suppes T, et al. Relapse prevention in bipolar I disorder: 18-
month comparison of olanzapine plus mood stabilizer vs. mood stabilizer alone. Brit J 
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Vaidya VA, Marek GJ, Aghajanian GK, Duman RS. 5-HT2A receptor-mediated regulation of 
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Vanover KE. Pharmacological and behavioral profile of N-(4-Fluorophenylmethyl)-N-(1-
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agonist. J Pharmacol Exp Ther. 2006;317(2):910-918. 
Ware JE Jr, Kosinski M., Keller, SD. A 12-Item Short-Form Health Survey: construction of 
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Wikström HV, Mensonides-Harsema MM, Cremers TI, Moltzen EK, Arnt J. Synthesis and 
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16 APPENDICES 
Appendix A:  Prohibited and Restricted Medications ............................................................. 83 
Appendix B:  Prohibited and Restricted Concomitant Medications:  Inhibitors and 
Inducers of Cytochrome P450 Enzyme 3A4 ................................................... 86 
Appendix C:  Sample Assessment Scales ................................................................................ 88 
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Appendix A:  Prohibited and Restricted Medications 
Subjects taking prohibited medications at study entry will not be randomized.  Subjects 
taking prohibited medications during the trial 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/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.  Medications within each class include but are not 
limited to the examples listed in this table.  Any questions regarding prohibited and restricted 
medications should be discussed with the Medical Monitor or appropriate designee. 
Medication Class 
Examples 1 
Prohibition/restrictions 
Antipsychotics other than 
pimavanserin  
•
aripiprazole
•
brexpiprazole
•
haloperidol
•
olanzapine
•
risperidone
All antipsychotics are prohibited 
Anticonvulsant and mood 
stabilizers 
•
carbamazepine
•
lamotrigine
•
lithium
•
phenytoin
•
valproate
•
topiramate
•
gabapentin
•
pregabalin
•
Must be washed out prior to Baseline or for
5 half-lives of drug prior to Baseline
•
Prohibited throughout the study
Antidepressants other than 
background therapy (see 
Inclusion Criterion #6) 
•
trazodone
•
TCAs – including those
used for pain, migraines
•
mirtazapine
•
bupropion
Prohibited at Baseline and throughout the 
study 
Anxiolytics 
benzodiazepines 
•
Must be washed out prior to Baseline or
for 5 half-lives of drug prior to Baseline
•
Prohibited throughout the study 
Stimulants 
methylphenidate 
Prohibited at Baseline and throughout the 
study 
Non-stimulant ADHD 
medications  
•
Atomoxetine
•
guanfacine
Prohibited at Baseline and throughout the 
study 
Serotonin antagonists 
•
cyproheptadine
•
fluvoxamine
•
mianserin
•
mirtazepine
•
nefazodone
•
trazodone
•
Prohibited throughout the study
•
Must be discontinued at least 3 weeks prior
to the Baseline visit
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Medication Class 
Examples 1 
Prohibition/restrictions 
Antiarrhythmic drugs  
•
ajmaline
•
amakalant, semantilide
•
amiodarone
•
bretylium
•
disopyramide
•
dofetilide
•
dronedarone
•
flecainide
•
ibutilide
•
procainamide
•
propafenone
•
quinidine
•
sotalol, d-sotalol
Prohibited at Baseline and throughout the 
study 
Antimicrobials, antifungals, 
and antimalarials 
PROHIBITED 
•
azithromycin
•
clarithromycin
•
erythromycin
•
levofloxacin
•
moxifloxacin
•
pentamidine
Clarithromycin, erythromycin, levofloxacin, 
moxifloxacin, and pentamidine are prohibited 
at study entry and throughout the study 
RESTRICTED 
•
artenimol/piperaquine
•
azithromycin
•
bedaquiline
•
ciprofloxacin
•
gemifloxacin
•
norfloxacin
•
ofloxacin
•
quinine
•
roxithromycin
•
Ciprofloxacin and azithromycin are
restricted
•
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 PI.
•
Artenimol/piperaquine, bedaquiline,
gemifloxacin, norfloxacin, ofloxacin,
quinine, roxithromycin are only allowed
under the following conditions:
o
The subject has a Baseline ECG
with a QTcF <425 ms OR
o
The subject has a QTcF <450 ms
at Baseline AND QRS duration
≥120 ms
Hypnotics 
•
doxepine
•
diphenhydramine
•
eszopiclone
•
gabapentin
•
mirtazepine
•
quetiapine
•
ramelteon
•
trazadone
•
zaleplon
•
zolpidem
•
Medications should be washed out during
Screening period
•
Prohibited at Baseline and throughout the
study
•
No sedating antihistamines allowed during
the study
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ACADIA Pharmaceuticals Inc. 
Protocol Amendment 1 Date:  26 April 2017  
Protocol ACP-103-042, Amendment 1 
UNMASKED VERSION 
 
Medication Class 
Examples 1 
Prohibition/restrictions 
Herbal and nutritional 
supplements 
• 
St. John’s wart 
• 
S-adenosylmeththionine 
(SAM-E) 
• 
valerian root 
• 
melatonin 
• 
L-tryptophan 
Prohibited at Baseline and throughout the 
study 
Sedating antihistamines for 
sleep 
• 
diphenhydramine 
• 
dimenhydrinate 
• 
hydroxyzine 
• 
promethazine 
Prohibited at Baseline and throughout the 
study 
Opioid Analgesics 
• 
Codeine 
• 
Oxycodone 
• 
Tramadol 
• 
Morphine 
• 
Methadone 
Prohibited throughout the study 
1Medications within each class include but are not limited to the examples listed in this table. 
 
 
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ACADIA Pharmaceuticals Inc. 
Protocol Amendment 1 Date:  26 April 2017 
Protocol ACP-103-042, Amendment 1 
UNMASKED VERSION 
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 and moderate CYP 3A4 enzyme (CYP3A4) inhibitors and inducers.  
Any questions should be discussed with the Medical Monitor or appropriate designee.  
Subjects who take prohibited concomitant medications during the trial will be discontinued, 
unless the discontinuation presents an unacceptable medical risk.  The justification to allow 
the subject to continue in the trial will be made by the Sponsor with medical input from the 
Investigator, and will be documented.  If allowed to remain in the trial, this will be reported 
as a major protocol deviation and not a waiver. 
Inhibitors of CYP3A4 are to be stopped at least 7 days or 5 half-lives prior to study drug 
administration, whichever is longer.  Inducers of CYP3A4 are to be stopped 30 days or 
5 half-lives prior to study drug administration, whichever is longer.  Moderate inhibitors and 
inducers of CYP3A4 may be allowed but should be used with caution.  The metabolism of 
pimavanserin is affected by strong CYP3A4 inhibitors, resulting in an increase in maximum 
plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of 
approximately 3-fold.   
STRONG 
INHIBITORS 
Boceprevir (Victrelis®) 
Clarithromycin (Biaxin®)  
Cobicistat (part of Stribild®) 
Conivaptan (Vaprisol®) 
Fluvoxamine (Luvox®) 
Grapefruit juicea  
Indinavir (Crixivan®)  
Itraconazole (Sporanox®)  
Ketoconazole (Nizoral®)  
Lopinavir and Ritonavir 
(Kaletra®) 
Mibefradil (Posicor®) 
Nefazodone (Serzone®)  
Nelfinavir (Viracept®)  
Posaconazole (Noxafil®) 
Quinupristin (Synercid®) 
Ritonavir (Norvir®, part of 
Viekira Pak™)  
Saquinavir (Invirase®)  
Telaprevir (Incivek®) 
Telithromycin (Ketek®)  
Voriconazole (Vfend®) 
MODERATE 
INHIBITORS 
Amprenavir (Agenerase®) 
Aprepitant (Emend®) 
Atazanavir (Reyataz®) 
Ciprofloxacin (Cipro®) 
Darunavir/ritonavir 
(Prezista®/Ritonavir) 
Diltiazem
Erythromycin (Erythrocin® 
Lactobionate) 
Fluconazole (Diflucan®) 
Fosamprenavir (Lexiva®) 
Grapefruit juicea 
Imatinib (Gleevec®) 
Verapamil (Calan®) 
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ACADIA Pharmaceuticals Inc. 
Protocol Amendment 1 Date:  26 April 2017  
Protocol ACP-103-042, Amendment 1 
UNMASKED VERSION 
 
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/DrugInteractionsLabeling/ucm093664. 
htm#classInhibit) 
 
 
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