Conditions: Adjunctive Treatment of Major Depressive Disorder
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 207
Healthy volunteers: no

Brief summary:
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

Detailed description:

Arms:
arm 1: Drug- pimavanserin, 34 mg, taken as two 17 mg tablets, once daily by mouth All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study. arm 2: Placebo, taken as two tablets, once daily by mouth All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.

Interventions: intervention 1: Pimavanserin intervention 2: Placebo
Intervention descriptions: intervention 1: Pimavanserin 34 mg, tablet, taken as two 17 mg tablets, once daily by mouth All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study. intervention 2: Placebo, taken as two tablets, once daily by mouth All patients continued to receive selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants at a stable dose for the duration of the study.

Protocol document:
Prot_000.pdf: 
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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ACADIA Pharmaceuticals Inc. 
Protocol Amendment 1 Date:  26 April 2017 
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UNMASKED VERSION 
 
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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Tohen M, Chengappa KNR, Suppes T, et al. Relapse prevention in bipolar I disorder: 18-
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Vanover KE. Pharmacological and behavioral profile of N-(4-Fluorophenylmethyl)-N-(1-
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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
Page 84 of 122
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc.


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. 
 
 
Page 85 of 122
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc.


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®) 
Page 86 of 122
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc.


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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Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc.

SAP_001.pdf: 
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 


 
STATISTICAL ANALYSIS PLAN 
Protocol No.: 
ACP-103-042 
Protocol Title: 
A Phase 2, Multicenter, Randomized, Double-blind, 
Placebo-controlled, Study to Evaluate the Efficacy and 
Safety of Adjunctive Pimavanserin in Major Depressive 
Disorder 
Drug: 
Pimavanserin 
Sponsor:  
ACADIA Pharmaceuticals Inc. 
Version No. and Date 
Version 1.0, 21 August 2018 
 
 
 
 
 
 
 




 
 
 
Protocol ACP-103-042  
 
Version 
1.0 
 
Statistical Analysis Plan 
 
 21 August 2018 
CONFIDENTIAL 
Page 2 of 64                               
 
TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................. 2 
LIST OF TABLES ............................................................................................................ 5 
ABBREVIATIONS .......................................................................................................... 6 
1. 
INTRODUCTION ................................................................................................ 8 
2. 
OBJECTIVES ...................................................................................................... 9 
2.1 
Primary Objective ................................................................................................. 9 
2.2 
Secondary Objectives ........................................................................................... 9 
2.3 
Other Secondary Objectives ................................................................................. 9 
3. 
STUDY DESIGN ............................................................................................... 10 
3.1 
General Study Design ......................................................................................... 10 
3.2 
Schedule of Assessments .................................................................................... 11 
3.3 
Randomization .................................................................................................... 16 
3.3.1 
Stage 1 Double-blind Treatment Period ...................................................... 16 
3.3.2 
Stage 2 Double-blind Treatment Period ...................................................... 16 
3.4 
Blinding .............................................................................................................. 16 
3.5 
Determination of Sample Size ............................................................................ 17 
4. 
ANALYSIS SETS .............................................................................................. 18 
5. 
DATA HANDLING CONVENTIONS ............................................................. 20 
5.1 
General Data Reporting Conventions ................................................................. 20 
5.2 
Derived Efficacy Variables ................................................................................ 20 
5.2.1 
Hamilton Rating Scale for Depression – 17 Items ...................................... 20 
5.2.2 
Sheehan Disability Scale (SDS) .................................................................. 21 
5.2.3 
Clinical Global Impressions – Severity (CGI-S) and Clinical Global 
Impressions – Improvement (CGI-I) Scales ................................................ 21 
5.2.4 
12-Item Short Form Health Survey (SF-12V2) ........................................... 22 


 
 
 
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5.2.5 
Drug Attitude Inventory (DAI-10) .............................................................. 24 
5.2.6 
Karolinska Sleepiness Scale (KSS) ............................................................. 24 
5.2.7 
Massachusetts General Hospital Sexual Functioning Index (MGH-SFI) .... 24 
5.2.8 
Barratt Impulsiveness Scale (BIS-11).......................................................... 25 
5.2.9 
Sheehan Irritability Scale (SIS) ................................................................... 25 
5.2.10 Montgomery Asberg Depression Rating Scale (MADRS) .......................... 25 
5.3 
Analysis Visit Windows ..................................................................................... 25 
5.3.1 
Unscheduled Assessments ........................................................................... 27 
5.3.2 
Multiple Measurements within Visit Windows ........................................... 27 
5.4 
Missing or Incomplete Date for Last Dose of Study Drug................................. 28 
5.5 
Missing or Incomplete Dates for Prior or Concomitant Medications ................ 28 
5.6 
Missing or incomplete Date for Adverse Events ................................................ 28 
5.7 
Missing Severity Assessment for Adverse Events ............................................. 28 
5.8 
Missing Relationship to Study Drug for Adverse Events .................................. 28 
5.9 
Character Values of Clinical Laboratory Variables ........................................... 29 
6. 
SUBJECT DISPOSITION ................................................................................. 30 
7. 
PROTOCOL DEVIATIONS .............................................................................. 31 
8. 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ........... 32 
9. 
MEDICAL HISTORY ....................................................................................... 33 
10. 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE ................... 34 
10.1 
Exposure to Study drug ...................................................................................... 34 
10.2 
Measurement of Treatment Compliance ............................................................ 34 
11. 
PRIOR AND CONCOMITANT MEDICATION .............................................. 35 
12. 
EFFICACY ANALYSES ................................................................................... 37 
12.1 
Efficacy Endpoints ............................................................................................. 37 
12.2 
Adjustment for Covariates .................................................................................. 38 
12.3 
Handling of Missing Data .................................................................................. 38 


 
 
 
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12.4 
Multiple Comparisons / Multiplicity .................................................................. 38 
12.5 
Examination of Subgroups ................................................................................. 39 
13. 
METHODS OF EFFICACY ANALYSES ........................................................ 40 
13.1 
Primary Efficacy Analysis .................................................................................. 40 
13.1.1 Primary Analysis.......................................................................................... 40 
13.1.2 Sensitivity Analyses ..................................................................................... 41 
13.2 
Key Secondary Efficacy Analysis ...................................................................... 43 
13.3 
Other Secondary Efficacy Analyses ................................................................... 43 
13.4 
Exploratory Efficacy Analyses ........................................................................... 46 
14. 
SAFETY ANALYSES ....................................................................................... 47 
14.1 
Adverse Events ................................................................................................... 47 
14.2 
Clinical Laboratory Variables ............................................................................ 48 
14.3 
Vital Signs .......................................................................................................... 51 
14.4 
Electrocardiogram (ECG) ................................................................................... 52 
14.5 
Physical Examination ......................................................................................... 53 
14.6 
Other Safety Endpoints ...................................................................................... 53 
15. 
CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC 
ANALYSES ....................................................................................................... 57 
16. 
INTERIM ANALYSIS ....................................................................................... 58 
17. 
DATA MONITORING/REVIEW COMMITTEE ............................................. 59 
18. 
COMPUTER METHODS .................................................................................. 60 
19. 
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL ............................. 61 
20. 
REFERENCES ................................................................................................... 62 
21. 
APPENDICES .................................................................................................... 63 
21.1 
Summary of Version Changes ............................................................................ 63 


 
 
 
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LIST OF TABLES 
Table 1 
Schedule of Assessments ............................................................................. 12 
Table 2 
Analysis Visit Windows .............................................................................. 26 
Table 3 
Analysis Visit for Side-by-side or Separate Presentation of Stages 1 and 2 
Data .............................................................................................................. 26 
Table 4 
Criteria for Potentially Clinically Important Laboratory Values – 
Hematology and Chemistry ......................................................................... 50 
Table 5  
Criteria for Potentially Clinically Important Laboratory Values - Urinalysis
 ..................................................................................................................... 51 
Table 6    Criteria for Potentially Clinically Important (PCI) Vital Signs ................... 52 
Table 7  
Criteria for Potentially Clinically Important ECG Values........................... 53 


 
 
 
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ABBREVIATIONS 
AE 
Adverse event 
AIMS 
Abnormal Involuntary Movement Scale 
ANCOVA 
analysis of covariance 
ATC 
Anatomical/Therapeutic/Chemical 
BARS 
Barnes Akathisia Rating Scale 
BIS-11 
Barratt Impulsiveness Scale 
BMI 
body mass index 
CI 
Confidence Interval 
CGI-I 
Clinical Global Impressions – Global Improvement 
CGI-S 
Clinical Global Impressions – Severity of Illness 
C-SSRS 
DMC 
Columbia Suicide Severity Rating Scale 
Data Monitoring Committee 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition  
eCRF 
electronic case report form 
ECG 
electrocardiogram 
FAS 
Full Analysis Set 
HAMD-17 
Hamilton Depression Scale (17 Items) 
IRT 
Interactive Response Technology 
KSS 
Karolinska Sleepiness Scale 
LOCF 
MADRS 
MDD 
MDE 
MedDRA 
MGH-ATRQ 
last observation carried forward 
Montgomery Asberg Depression Scale 
Major Depressive Disorder 
Major Depressive Episode 
Medical Dictionary for Regulatory Activities 
Massachusetts General Hospital Antidepressant Treatment Questionnaire 
MGH-SFI 
Massachusetts General Hospital Sexual Functioning Index 
MMRM 
mixed model for repeated measures 
OC 
observed cases 
PCI 
potentially clinically important 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
QTcB 
QT Interval Corrected for Heart Rate using Bazett’s Formula 
QTcF 
QT Interval Corrected for Heart Rate using Fridericia’s Formula 


 
 
 
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SAE 
serious adverse event 
SAP 
SCID-5-CT 
SD 
SDS 
SE 
SF-12 
statistical analysis plan 
Structured Clinical Interview for DSM-5, Clinical Trials Version 
Standard Deviation 
Sheehan Disability Scale 
Standard Error 
12-Item Short Form Health Survey 
SIS 
Sheehan Irritability Scale 
SNRI 
serotonin-norepinephrine reuptake inhibitors 
SOC 
SPCD 
SSRI 
system organ class 
Sequential Parallel Comparison Design 
selective serotonin reuptake inhibitors 
TEAE   
treatment-emergent adverse event 


 
 
 
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1. 
INTRODUCTION 
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the 
statistical analyses of efficacy and safety data as described in Protocol Amendment 1 dated 26 
April 2017. Specifications for tables, figures, and listings are contained in a separate 
document.   


 
 
 
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2. 
OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is 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. 
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 
• quality of life 
• drug attitude 
• sleep 
• sexual functioning 
• impulsivity 
• irritability 
2.3 
Other Secondary Objectives 
• To assess the safety and tolerability of adjunctive pimavanserin compared to 
placebo 
• To characterize the PK of pimavanserin administered as adjunct to an SSRI/SNRI 
antidepressant in MDD patients 
• To assess the PK/PD using measures of safety, efficacy, and sleep parameters 


 
 
 
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3. 
STUDY DESIGN  
3.1 
General 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). 
The study drug will be pimavanserin 34 mg (provided as 2×17 mg tablets) and matching 
placebo (2×placebo tablets), administered orally as a single dose once daily (QD).  
The study duration is approximately 17 weeks 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. At the beginning of Stage 1 (Week 0), eligible 
subjects will be randomly assigned in a 1:3 ratio to pimavanserin or placebo, respectively.  At 
the end of Stage 1 (Study Week 5), subjects initially randomized to placebo and who meet the 
non-responder criteria (i.e., HAMD-17 total score at Week 5 >14 and percent-reduction from 
the Study Week 0 (Baseline) HAMD-17 total score of <50%) will be randomly assigned in a 
1:1 ratio to pimavanserin or placebo. Subjects who do not meet the criteria for re-
randomization will continue with the assigned treatment from Stage 1 until the end of Stage 2. 
Subjects initially randomized to pimavanserin in Stage 1 will continue to receive 
pimavanserin through the end of Stage 2. 
The study is 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. 
The study design is summarized in Figure 1. 
 
 
 
 
 
 


 
 
 
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Figure 1 
Schematic of Study Design 
 
 
 
 
 
 
 
 
3.2 
Schedule of Assessments  
 


 
 
 
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Table 1 
Schedule of Assessments 


 
 
 
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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 
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 
 
SDS 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


 
 
 
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21 August 2018 
 
CONFIDENTIAL 
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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 
 
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. 
dTo include hematology, serum chemistry, prolactin levels, and urinalysis; TSH and reflex free T4 will be done at Screening only. 


 
 
 
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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.  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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3.3 
Randomization 
This is a double-blind, placebo-controlled, 2-stage SPCD study.  At each stage, eligible 
subjects will be randomized to receive: 
• Pimavanserin (34 mg) + an SSRI/SNRI antidepressant or  
• Placebo + an SSRI/SNRI antidepressant 
The actual treatment given to an individual subject will be determined by randomization 
schedules. Randomization will be electronically performed using an Interactive Response 
Technology (IRT) based randomization system.   
3.3.1 
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 in a 
1:3 ratio to pimavanserin or placebo, respectively. 
3.3.2 
Stage 2 Double-blind Treatment Period 
At the end of Stage 1 (Study Week 5), subjects initially randomized to placebo and who meet 
the non-responder criteria will be randomly assigned in a 1:1 ratio to pimavanserin or placebo. 
Subjects initially randomized to pimavanserin in Stage 1 will continue to receive 
pimavanserin through the end of Stage 2. 
3.4 
Blinding  
This is a double-blind study. Blinding is achieved by means of identical appearance for 
pimavanserin and placebo. Neither the subjects nor the study personnel at the clinical sites 
will know which treatment is administered to each subject.  
All subjects and 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.   
Unplanned unblinding of treatment assignment during the study is discouraged. The 
investigator at a site may break the blind in the event of an immediate 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 must 


 
 
 
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first 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. 
For the final analysis, the treatment codes for all subjects will be released to ACADIA after all 
subjects have completed the study and the clinical database is locked. 
3.5 
Determination of Sample Size 
The primary efficacy endpoint is the change from Baseline to Week 5 in the Hamilton 
Depression Scale (17 Items) (HAMD-17) total score. For Stage 1, Baseline is Study Week 0 
and Week 5 is Study Week 5. For Stage 2, Baseline is Study Week 5 and Week 5 is Study 
Week 10.  
A total sample size of 168 evaluable subjects is estimated to provide at least 80% power at a 
two-sided significance level of 0.05 assuming a mean change in the HAMD-17 total score 
of -7.8 (SD=8) 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). 


 
 
 
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4. 
ANALYSIS SETS 
Randomized Analysis Sets 
Randomized Analysis Set for Stage 1 – The Randomized Analysis Set for Stage 1 (RAS1) 
will consist of all subjects who were randomized into Stage 1. 
Randomized Analysis Set for Stage 2 – The Randomized Analysis Set for Stage 2 (RAS2) 
will consist of all subjects who were placebo non-responders from Stage 1 and who were 
randomized into Stage 2. 
Subjects will be classified according to the randomized treatment assignment. 
Safety Analysis Sets 
Safety Analysis Set for Stage 1 – The Safety Analysis Set for Stage 1 (SAS1) will consist of 
all subjects who were randomized into Stage 1 and received at least one dose of study drug in 
Stage 1.  
Safety Analysis Set for Stage 2 – The Safety Analysis Set for Stage 2 (SAS2) will consist of 
all subjects who were placebo non-responders from Stage 1, were randomized into Stage 2, 
and received at least one dose of study drug in Stage 2. 
Subjects will be classified according to the actual treatment received. 
Full Analysis Sets 
Full Analysis Set for Stage 1 – The Full Analysis Set for Stage 1 (FAS1) will consist of all 
subjects who were randomized into Stage 1, received at least one dose of study drug in Stage 
1, and have both a Baseline (Study Week 0) value and at least one post-Baseline value for the 
HAMD-17 total score in Stage 1. 
Full Analysis Set for Stage 2 – The Full Analysis Set for Stage 2 (FAS2) will consist of all 
subjects who were placebo non-responders from Stage 1, were randomized into Stage 2, 
received at least one dose of study drug in Stage 2, and have both a Baseline (Study Week 5) 
value and at least one post-Baseline value for the HAMD-17 total score in Stage 2. 
Subjects will be classified according to the randomized treatment assignment. 
Per-protocol Analysis Sets 
Per-protocol Analysis Set for Stage 1 – The Per-protocol Analysis Set for Stage 1 (PAS1) 
will consist of a subset of subjects in FAS1 who do not have any protocol deviation which is 
considered to have substantial impact on the primary efficacy outcome. The precise reasons 


 
 
 
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for excluding subjects from PAS1 will be fully defined and documented a priori before the 
clinical database lock.  
Per-protocol Analysis Set for Stage 2 – The Per-protocol Analysis Set for Stage 2 (PAS2) 
will consist of a subset of subjects in FAS2 who do not have any protocol deviation which is 
considered to have substantial impact on the primary efficacy outcome. The precise reasons 
for excluding subjects from PAS2 will be fully defined and documented a priori before the 
clinical database lock.  
Subjects will be classified according to the randomized treatment assignment. 
Pharmacokinetics Analysis Set for Stage 1 – The Pharmacokinetics Analysis Set 1 will 
consist of subjects in SAS1 with at least one measurable pimavanserin plasma concentration. 
Pharmacokinetics Analysis Set for Stage 2 – The Pharmacokinetics Analysis Set 2 will 
consist of subjects in SAS2 with at least one measurable pimavanserin plasma concentration. 
Subjects will be classified according to the actual treatment received. 
 
 


 
 
 
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5. 
DATA HANDLING CONVENTIONS 
All data collected in the study will be listed. 
5.1 
General Data Reporting Conventions 
Continuous variables will be summarized using the following descriptive statistics:  number 
of subjects, mean, median, standard deviation, standard error, minimum, and maximum.  
Unless specified otherwise, means, medians, and confidence intervals will be presented to one 
more decimal place than the raw data, and the standard deviations and standard errors will be 
presented to two more decimal places than the raw data.  
Categorical and count variables will be summarized by the number of subjects and the percent 
of subjects in each category. Categories with zero counts will not have zero percentages 
displayed.  Percentages will be presented with one decimal place.  
Duration in months will be calculated as ([the number of days / 365.25] *12). 
Unless specified otherwise, all statistical tests will be 2-sided hypothesis tests performed at 
the significance level of 5% for main effects and all confidence intervals will be 2-sided 95% 
confidence intervals. P-values will generally be presented to 4 decimal places; values less 
than 0.0001 will be presented as <0.0001. 
5.2 
Derived Efficacy Variables  
In general, assessment total scores and subscores will be derived within the analysis datasets. 
In the event that total scores and/or subscores are also collected on the electronic case report 
from (eCRF), the derived values will be used for all analyses. Both the raw and derived scores 
will be presented in listings. 
5.2.1 
Hamilton Rating Scale for Depression – 17 Items  
The HAMD-17 includes a structured interview guide developed by Bech and colleagues and 
will be administered by the Investigator or designee based on an assessment of a subject’s 
symptoms.  This structured interview has been validated in the Danish University 
Antidepressant Group (DUAG) studies for use with time frames shorter than 1 week. The 
time frame for this scale is the past 7 days.  
The HAMD-17 consists of 8 items with a score on a 3 point scale and 9 items with a score on 
a 5 point scale. The total score ranging from 0 to 52 will be calculated as the sum of the scores 
for all 17 items. A higher total score indicates more severe depression. Missing item scores 
will be imputed and rounded to the nearest integer as follows: 


 
 
 
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• Missing scores for items with a score on a 3 point scale will be imputed using the 
arithmetic mean of the non-missing scores for items with a score on a 3 point scale 
• Missing scores for items with a score on a 5 point scale will be imputed using the 
arithmetic mean of the non-missing scores for items with a score on a 5 point scale 
The total score will be considered as missing if there are missing scores for 4 or more items.  
5.2.2 
Sheehan Disability Scale (SDS) 
The SDS is a 3-item subject-facing questionnaire used to evaluate impairments in the domains 
of work, social life/leisure, and family life/home responsibility. Subjects rate each item using 
an 11-point scale ranging from 0 (not at all) to 10 (extremely). The mean score ranging from 0 
to 10 will be calculated as the arithmetic mean of the scores for all 3 items and rounded to the 
nearest 2 decimal places. A higher mean score indicates greater disability. If a subject 
indicates that no work/school occurred,  the mean score will be calculated as the arithmetic 
mean of the other two item responses (Social Life and Family Life/Home Responsibilities) 
and rounded to the nearest 2 decimal places. If either of the other two item responses is 
missing, or if the work/school response is missing and the subject does not indicate that no 
work/school occurred, the mean score will be missing.  
The mean scores calculated based on only two item responses (Social Life and Family 
Life/Home Responsibilities) will be flagged in data listings. These results will be considered 
observed values for data summaries and analyses. 
5.2.3 
Clinical Global Impressions – Severity (CGI-S) and Clinical Global 
Impressions – Improvement (CGI-I) Scales  
The CGI-S and CGI-I are scales used by the Investigator or designee to rate the severity of the 
disorder and the global improvement since beginning of the study.  The CGI-S rates the 
severity of a subject’s depression over the past 7 days and the CGI-S score ranges from 1 to 7: 
 
1 = Normal, not at all ill  
 
5 = Markedly ill 
2 = Borderline mentally ill  
 
6 = Severely ill 
3 = Mildly ill   
 
 
7 = Among the most extremely ill patients 
4 = Moderately ill  
The CGI-I rates the change in a subject's depression over the past 7 days relative to the 
subject’s symptoms at Baseline and the CGI-I score ranges from 1 to 7: 
 
1 = Very much improved  
 
5 = Minimally worse 


 
 
 
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2 = Much improved   
 
6 = Much worse 
3 = Minimally improved  
 
7 = Very much worse 
4 = No change 
Higher CGI-S and CGI-I scores denote more severe depression and less improvement in 
depression respectively. Missing CGI-S and CGI-I scores will not be imputed. 
5.2.4 
12-Item Short Form Health Survey (SF-12V2) 
The SF-12V2 assesses overall health and well-being over the past 4 weeks using Likert scale 
items with 3 to 5 responses.   
Prior to calculating the scale scores, items #5, #6a, and #6b will be rescaled as 6 minus the 
original response.  This effectively rescales those responses so that a response of 1 is recoded 
to 5 and a response of 5 is recoded to 1, etc.  In addition, item #1 will be rescaled as follows: 
1 recoded to 5.0, 2 recoded to 4.4, 3 recoded to 3.4, 4 recoded to 2.0, and 5 recoded to 1.0. 
After the necessary rescaling, the following raw scale scores are calculated as follows: 
• Physical Functioning: sum of responses to items #2a and #2b 
• Role Physical: sum of responses to items #3a and #3b 
• Bodily Pain: response to item #5 
• General Health: response to item #1 
• Vitality: response to item #6b 
• Social Functioning: response to item #7 
• Role Emotional: sum of responses to items #4a and #4b 
• Mental Health: sum of responses to items #6a and #6c 
Each raw scale is then transformed to a 0-100 scale (transformed raw score) by applying 
100*(raw scale score – lowest possible raw score)/(possible raw score range). 
Scale  
 
Lowest Possible Raw Score Possible Raw Score Range 
Physical Functioning  
2 
 
 
 
4 
Role Physical  
 
2 
 
 
 
8 
Bodily Pain 
 
 
1 
 
 
 
4 


 
 
 
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General Health 
 
1 
 
 
 
4 
Vitality 
 
 
1 
 
 
 
4 
Social Functioning 
 
1 
 
 
 
4 
Role Emotional 
 
2 
 
 
 
8 
Mental Health  
 
2 
 
 
 
8 
 
 
The transformed raw scores are then converted to standardized scale scores (Z-scores) using 
the following equations, based on the 1998 general U. S. population. 
Z-score 
 
 
 
Equation 
 
 
 
 
 
Physical Functioning  
(Transformed Raw Score – 81.18122)/29.10588 
Role Physical  
 
(Transformed Raw Score – 80.52856)/27.13526 
Bodily Pain 
 
 
(Transformed Raw Score – 81.74015)/24.53019 
General Health 
 
(Transformed Raw Score – 72.19795)/23.19041 
Vitality 
 
 
(Transformed Raw Score – 55.59090)/24.84380 
Social Functioning 
 
(Transformed Raw Score – 83.73973)/24.75775 
Role Emotional 
 
(Transformed Raw Score – 86.41051)/22.35543 
Mental Health  
 
(Transformed Raw Score – 70.18217)/20.50597 
 
The aggregate physical and mental summary scores are then calculated using the standardized 
scale scores and coefficients from the 1990 general U. S. population. 
Aggregate Physical Score: = (Physical Functioning * 0.42402) + (Role Physical * 0.35119) + 
(Bodily Pain * 0.31754) + (General Health * 0.24954) + (Vitality * 0.02877) + (Social 
Functioning * -0.00753) + (Role Emotional * -0.19206) + (Mental Health * -0.22069). 
Aggregate Mental Score: = (Physical Functioning * -0.22999) + (Role Physical * -0.12329) + 
(Bodily Pain * -0.09731) + (General Health * -0.01571) + (Vitality * 0.23534) + (Social 
Functioning * 0.26876) + (Role Emotional * 0.43407) + (Mental Health * 0.48581). 
Each aggregate score and standardized scale score is then transformed into a norm-based 
score (T-score) by multiplying the aggregate or standardized score by 10 and adding the 
resulting product to 50.  The norm-based scores are distributed with a mean of 50 and a 
standard deviation of 10. A higher score is indicative of a better health state. Note: The T-
score for Aggregate Physical Score and Aggregate Mental Score is called Physical 
Component Summary (PCS) score and Mental Component Summary (MCS) score 
respectively.  
QualityMetric Health Outcomes™ Scoring Software 5.0 will be used to verify the norm-based 
T-scores calculated using the above formula. 


 
 
 
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5.2.5 
Drug Attitude Inventory (DAI-10) 
The DAI-10 contains 6 items (1, 3, 4, 7, 9, and 10) that a subject who is fully adherent to the 
prescribed medication would answer as "True", and 4 items (2, 5, 6, and 8) that a subject who 
is fully adherent to the prescribed medication would rate as "False." A correct answer is 
scored +1 and an incorrect answer is scored -1. The total score ranging from -10 to 10 
(increment by 2) is the sum of pluses and minuses. A positive total score indicates a positive 
subjective response (adherent) and a negative total score indicates a negative subjective 
response (non-adherent). Higher scores denote better adherence. The total score will be 
considered as missing if at least one item score is missing. 
5.2.6 
Karolinska Sleepiness Scale (KSS) 
The KSS is a scale that measures the subject's drowsiness and is frequently used in studies 
measuring subjective sleepiness. Scoring is based on a 9-point verbally anchored scale going 
from "1 = extremely alert" to "9 = very sleepy, great effort to keep awake, fighting sleep". 
Higher scores denote more drowsiness. Missing scores will not be imputed. 
5.2.7 
Massachusetts General Hospital Sexual Functioning Index (MGH-SFI) 
Sexual functioning will be assessed using the MGH-SFI at Baseline (Study Week 0) and the 
MGH-SFI (follow-up version) at Study Weeks 5 and 10.  MGH-SFI is a 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”).  Subjects rate each item using a 6-point scale ranging from 1 (greater than 
normal) to 6 (totally absent). MGH-SFI (follow-up version) asks one more question (in 
addition to the 5 functional domains in MGH-SFI) on “overall improvement since your last 
medication change”. Subjects rate this item using a 6-point scale ranging from 1 (very much 
improved) to 6 (much worse). Higher scores denote worse sexual dysfunction. 
The MGH-SFI score to be analyzed will be calculated as the arithmetic mean of the item 
scores for the 5 domains and rounded to the nearest 2 decimal places. For MGH-SFI at 
Baseline (Study Week 0), the arithmetic mean will be calculated over all 5 domains for males 
and the 4 domains for females. For MGH-SFI (follow-up version) at Study Weeks 5 and 10, 
the arithmetic mean will be calculated in the same way as MGH-SFI at Baseline excluding the 
item score for the additional domain of “overall improvement since your last medication 
change”. The MGH-SFI arithmetic mean score will be considered as missing if at least one 
item score is missing. 


 
 
 
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5.2.8 
Barratt Impulsiveness Scale (BIS-11) 
The BIS-11 is a questionnaire designed to assess the personality/behavioral construct of 
impulsiveness.  It is composed of 30 items describing common impulsive or non-impulsive 
(reverse scored items: 1, 7, 8, 9, 10, 12, 13, 15, 20, 29, and 30) behaviors and preferences.  
Items are scored on the following 4-point scale:  Rarely/Never = 1; Occasionally = 2; Often = 
3; Almost Always/Always = 4. For reverse scored items, a response of 1 is recoded to 4; 2 is 
recoded to 3; 3 is recoded to 2; and 4 is recoded to 1. The BIS-11 score ranging from 30 to 
120 will be calculated as the sum of the scores for all 30 items. Higher scores denote more 
impulsiveness. Missing item scores will be imputed with the arithmetic mean of the non-
missing item scores and rounded to the nearest integer. The BIS-11 score will be considered 
as missing if there are missing scores for 7 or more items. 
5.2.9 
Sheehan Irritability Scale (SIS) 
The SIS is a 7-item subject-reported outcome measure that was developed to measure the 
frequency, severity, and impairment associated with irritability in psychiatric subjects.  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). The total score ranging from 0 to 70 will be calculated as the sum of the 
scores for all 7 items. Missing item scores will be imputed with the arithmetic mean of the 
non-missing item scores and rounded to the nearest integer. The total score will be considered 
as missing if there are missing scores for 2 or more items. 
5.2.10 
Montgomery Asberg Depression Rating Scale (MADRS) 
The MADRS is a 10-item, clinician-rated instrument measuring depression severity. It is 
scored on a fixed scale of 7 points (0-6) following a structured clinician interview. The total 
score ranging from 0 to 60 will be calculated as the sum of the scores for all 10 items. Higher 
scores reflect more severe symptomatology. The total score will be considered missing if 
there are at least one missing item scores.  
5.3 
Analysis Visit Windows  
Baseline for Stage 1 of the study is defined as the last non-missing result, including results 
from repeated and unscheduled measurements, before first dosing in Stage 1. Baseline for 
subjects randomized into Stage 2 is defined as the results at Study Week 5.     


 
 
 
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Efficacy, safety, and PK assessments will be summarized by analysis visit as presented in 
Table 2 below. For the Week 5 visit window only, the assessments collected on the date of 
randomization for the subjects who are randomized into Stage 2 will be selected for the 
analysis even if the Stage 2 randomization date is outside of the Study Day Interval, 33 - 39. 
Table 2 
Analysis Visit Windows 
Analysis Visit  
Study Visit 
Target Study 
Day @ 
Study Day Interval 
Baseline (Day 1 for Stage 1) 
2 (Week 0) 
1 
< 1 
Week 1 
3 (Week 1) 
8 
2 – 11 
Week 2 
4 (Week 2) 
15 
12 – 18 
Week 3 
5 (Week 3) 
22 
19 – 25 
Week 4 
6 (Week 4) 
29 
26 – 32 
Week 5  
7 (Week 5) 
36 
33 – 39 
Week 6 
8 (Week 6) 
43 
40 – 46 
Week 7 
9 (Week 7) 
50 
47 – 53 
Week 8 
10 (Week 8) 
57 
54 – 60 
Week 9 
11 (Week 9) 
64 
61 – 67 
Week 10 
12 (Week 10) 
71 
68 – 78 
Follow-up 
~30-Day Follow-
Up 
101 
>79 
@ Derivation of study day: study day = assessment date - first dose date + 1 if the assessment date ≥ first dose 
date, otherwise study day = assessment date – first dose date. Study day 1 is the day of first administration of 
study drug (pimavanserin or placebo). 
Efficacy and safety assessments for Stages 1 and 2, when presented side by side or separately, 
will be summarized by analysis visit as presented in Table 3. 
Table 3 
Analysis Visit for Side-by-side or Separate Presentation of Stages 1 and 2 


 
 
 
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Data 
Analysis Visit  
Study Visit in Stage 1 
Study Visit in Stage 2 
Baseline (Day 1) 
2 (Week 0) 
7 (Week 5) 
Week 1 
3 (Week 1) 
8 (Week 6) 
Week 2 
4 (Week 2) 
9 (Week 7) 
Week 3 
5 (Week 3) 
10 (Week 8) 
Week 4 
6 (Week 4) 
11 (Week 9) 
Week 5 
7 (Week 5) 
12 (Week 10) 
 
5.3.1 
Unscheduled Assessments 
Both Scheduled and Unscheduled assessments, including the assessments at early termination 
visits, will be used for planned timepoint analyses. All assessments will be presented in data 
listings. 
5.3.2 
Multiple Measurements within Visit Windows 
In the event that more than one assessment falls within a given window the assessment closest 
to the target study day will be selected for the by-visit analysis. If two assessments are 
equidistant from the target study day then the chronologically last assessment will be used. 
Exceptions may be made for incomplete assessments, in which case, more complete 
assessments may be given priority.  Details are provided in a separate programming 
conventions document. 
For safety analyses where the extreme values should be selected (e.g. overall post-Baseline 
minimum, overall post-Baseline maximum, and overall post-Baseline potentially clinically 
important values), all non-missing post-Baseline values should be considered, regardless of 
whether the value is selected for the by-visit summaries. All assessments will be presented in 
data listings. 
 


 
 
 
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5.4 
Missing or Incomplete Date for Last Dose of Study Drug  
In the Safety Analysis Set, if the last dose date of study drug is missing for a subject who 
completed or early terminated from the study, then the date of the end-of-study/early 
termination visit will be used in the calculation of treatment duration. For the incomplete last 
dose date of study drug, the imputation algorithms will be detailed in the analysis dataset 
specification document. The missing or incomplete dates will be displayed in the data listings 
as reported on the eCRF rather than the imputed dates. 
5.5 
Missing or Incomplete Dates for Prior or Concomitant Medications  
Missing or incomplete medication start or stop dates will be imputed for the purpose of 
determining whether the medication is taken concomitantly or not (see Section 11 for 
definition). When the chronological order of medication use relative to the study drug 
treatment period is unclear due to missing or incomplete date(s), the medication will be 
considered as concomitant. The imputation algorithms will be detailed in the analysis dataset 
specification document. The missing or incomplete dates as captured on the eCRF will be 
displayed in the data listings.    
5.6 
Missing or incomplete Date for Adverse Events  
Missing or incomplete adverse event (AE) start dates will be imputed for the purpose of 
determining whether the AEs are treatment-emergent or not (see Section 14.1 for definition). 
When the chronological order of an AE onset relative to the study drug treatment period is 
unclear due to missing or incomplete date(s), the AE will be considered as treatment-
emergent. The imputation algorithms will be detailed in the analysis dataset specification 
document. The missing or incomplete dates captured on the eCRF will be displayed in the 
data listings.    
5.7 
Missing Severity Assessment for Adverse Events 
If the severity is missing for an AE starting on or after the date of the first dose of study drug, 
then a severity of “Severe” will be assigned.  The imputed values for severity assessment will 
be used for incidence summaries, while the actual values will be used in data listings. 
5.8 
Missing Relationship to Study Drug for Adverse Events 
If the relationship to study drug is missing for an AE starting on or after the date of the first 
dose of study drug, a causality of “Related” will be assigned.  The imputed values for 


 
 
 
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relationship to study drug will be used for incidence summaries, while the actual values will 
be presented in data listings.  
5.9 
Character Values of Clinical Laboratory Variables  
If the reported value of a clinical laboratory variable cannot be used in a statistical analysis 
due to, for example, a character string reported for a numeric variable, an appropriately 
determined coded value may be used in the statistical analysis. The coding algorithms will be 
detailed in the analysis dataset specification document. The actual values as reported in the 
database will be presented in data listings. 


 
 
 
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6. 
SUBJECT DISPOSITION 
For subjects who participate in the screening phase but are not randomized (screen failures), 
their demographics information (including age, sex, and primary race), screen failure reasons 
(the specific inclusion/exclusion criterion (or criteria) not met or other reason) and protocol 
version will be listed. If a subject is re-screened, then the re-screening subject ID and the final 
enrollment status (whether eventually enrolled) will also be displayed in this listing. In 
addition, the frequency that the screen failure reasons are reported will also be summarized. 
Note that one subject may be deemed ineligible for multiple inclusion/exclusion criteria and 
may be allowed to rescreen with the permission of the Medical Monitor, provided the screen 
failure was due to a temporary condition that subsequently resolved. 
Subject disposition will be summarized to show the number of subjects screened, randomized by 
treatment group and stage, received study drug by treatment group and stage, discontinued by 
reason and treatment group and stage, and completed study by treatment group and stage. 
Reasons for discontinuation will be summarized by treatment arm and overall for RAS1 and 
RAS2; SAS1 and SAS2; and FAS1 and FAS2. A listing will be provided displaying all 
subjects excluded from the Safety, Full or Per-protocol analysis sets, and will include 
reason(s) for exclusion. 
The number of subjects screened, the number of unique subjects screened, the number of 
subjects randomized into Stage 1, and the number of subjects randomized into Stage 2 will be 
summarized overall and by site. The number of subjects enrolled at each site will also be 
tabulated by treatment arm and overall for RAS1 and RAS2; SAS1 and SAS2; FAS1 and 
FAS2; and PAS1 and PAS2.  
 
 
 


 
 
 
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7. 
PROTOCOL DEVIATIONS 
Protocol deviations will be reviewed periodically over the course of the study. The review 
process, definition of the deviation categories, and the classification of a deviation as major or 
minor are detailed in the Protocol Deviation Management Plan. 
Major protocol deviations will be assigned to 2 stages for the summary of major protocol 
deviations by stage. If a major protocol deviation happens or is identified on or after the Stage 
2 randomization date or the Study Week 5 visit date for those who were not randomized into 
Stage 2, the major protocol deviation will be assigned to Stage 2; else it will be assigned to 
Stage 1. 
A summary of the number and percentage of subjects with major protocol deviations by 
deviation category and treatment group will be provided for RAS1 (up to Study Week 5/Early 
termination) and RAS2 (from Study Week 5 to Study Week 10/Early termination). A listing 
of protocol deviations by site and subject will also be provided. 


 
 
 
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8. 
DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS 
Demographics and baseline characteristics will be summarized by treatment group and overall 
for RAS1, RAS2, SAS1, SAS2, FAS1, FAS2, PAS1, and PAS2 using descriptive statistics. 
Variables include age, age group (18-40 years and > 40 years), sex, race, ethnicity, height, 
weight, BMI, current smoker, highest education level, marital status, employment status, 
Montgomery Asberg Depression Rating Scale (MADRS) total score, Baseline HAMD-17 
total score, Baseline HAMD-17 total score < 24 and ≥ 24, Baseline SDS mean score, and 
Baseline Clinical Global Impressions-Severity Illness (CGI-S).  
Race will also be categorized by White vs. Non-White. The reported age reflects a subject’s 
age at the informed consent date. Baseline CGI-S will be summarized as both a continuous 
variable and a categorical variable. 
Depression history will be summarized by treatment group for RAS1, RAS2, SAS1, SAS2, 
FAS1, FAS2, PAS1, and PAS2 using descriptive statistics. Variables include:  
• Age at first onset of depression symptoms 
• Age at MDD diagnosis 
• Duration of the current MDE (months relative to the informed consent date) 
• Number of depression episodes during the subject's lifetime 
• Number of hospitalizations for depression during the subject's lifetime  
Depression history as described above, date of last hospitalization (if number of 
hospitalizations is greater than 0), and onset date for the current episode of depression will 
also be presented in a data listing. 
Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH 
ATRQ) examines a patient’s antidepressant treatment history and determines the adequacy of 
treatment response. MGH ATRQ is collected at Screening visit. Drug type, generic name, 
took during this current episode of depression (Yes/No), dose, and took at least this dose for 
at least 8 weeks (Yes/No), and the amount of improvement in percentage will be listed. 


 
 
 
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9. 
MEDICAL HISTORY 
Medical history reported terms will be coded with Medical Dictionary for Regulatory 
Activities (MedDRA), version 19.0 or newer. The subject incidence will be summarized for 
each system organ class (SOC) and preferred term by treatment group and overall for FAS1, 
FAS2, SAS1, and SAS2. A subject will be counted only once per SOC or per preferred term 
for the summary. 
A listing of the SOC, preferred term, body system, verbatim for the medical history 
condition/event, start and stop dates (when available), and an indicator for whether or not the 
condition is ongoing will be provided. 
 


 
 
 
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10. 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE 
Extent of exposure and treatment compliance will be summarized as continuous variables by 
treatment group for SAS1 in Stage 1 (5 weeks), SAS2 in Stage 2 (5 weeks), and the subjects 
in SAS1 who were not randomized to the pimavanserin group in Stage 2 (10 weeks).  
10.1 
Exposure to Study drug  
Duration of exposure to study drug will be calculated for each subject as (last dose date – first 
dose date + 1).  
For SAS1 and SAS2, the number and percentage of subjects within each of the following 
exposure levels (a maximum of 5 weeks [approximately 35 days]) in terms of duration (days) 
of exposure will also be tabulated: <10, 11-<20, 21-<30, and >30. For the PIM subjects vs. 
the placebo subjects in SAS1 who were not randomized to the pimavanserin group in Stage 2, 
the exposure levels will be: <20, 21-<40, 41-<60, and >60. Kaplan-Meier curves of duration 
on study drug will also be presented for each treatment group. 
10.2 
Measurement of Treatment Compliance 
Study drug dosing compliance for a specified period is defined as the total number of tablets 
actually taken by a subject during that period divided by the number of tablets expected to be 
taken during the same period multiplied by 100. The total number of tablets actually taken is 
calculated by the total number of tablets dispensed minus the number of tablets returned.  The 
number of tablets expected to be taken for a specified period is calculated as (last dose date – 
first dose date + 1) x 2 (the planned number of tablets taken per day).  
Treatment compliance will be summarized as both a continuous variable and a categorical 
variable. For the categorical presentation, the number and percentage of subjects within each 
of the following compliance levels will be tabulated: <40%, 40 - <60%, 60 - <80%, 80 - 
≤120%, and >120%.  
 


 
 
 
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11. 
PRIOR AND CONCOMITANT MEDICATION  
Prior medication is defined as any medication with the start and stop dates prior to the date of 
the first dose of study drug. Concomitant medication is defined as any medication with a start 
date prior to the date of the first dose of study drug and continuing past the first dose of study 
drug or with a start date between the dates of the first and last doses of study drug, inclusive.  
Any medication with a start date after the date of the last dose of study drug will be 
considered as post-treatment medication. Medications will be coded using WHO Drug 
Dictionary March 2016 or newer version.   
Concomitant medication will be assigned to 2 stages for the summary of concomitant 
medication by stage. A concomitant medication may be assigned to both Stage 1 and Stage 2. 
The concomitant medication will be assigned to Stage 1 if the start date of any concomitant 
medication is prior to or on the Stage 2 randomization date (or the Study Week 5 visit date for 
those who were not randomized into Stage 2). 
The concomitant medication will be assigned to Stage 2 if the stop date of any concomitant 
medication is on or after the Stage 2 randomization date (or the Study Week 5 visit date for 
those who were not randomized into Stage 2).  
Please refer to Section 5.5 for the imputation of missing or incomplete medication start or 
stop dates. In general, if missing or incomplete dates make the determination impossible, the 
medication will be considered as concomitant and the concomitant medication will be 
assigned to both Stage 1 and Stage 2. 
Psychiatric Medication History 
The number and percentage of subjects taking psychiatric medications collected on the 
Psychiatric Medication History CRF pages will be tabulated by 
Anatomical/Therapeutic/Chemical (ATC) Level 3, preferred term, treatment group, and 
overall for SAS1 and SAS2 separately. Multiple medication usage by a subject in the same 
category will be counted only once. Listing of all psychiatric medications will be provided. 
Prior and Concomitant Medications 
Prior and concomitant medications will be summarized separately. The number and 
percentage of subjects will be tabulated by ATC Level 3, preferred term, treatment group, and 
overall for SAS1 (up to Study Week 5 for concomitant medications) and SAS2 (from Study 
Week 5 to Study Week 10 for concomitant medications) separately. Multiple medication 
usage by a subject in the same category will be counted only once. Listing of all prior and 
concomitant medications will be provided. 


 
 
 
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Concomitant medications and the incidences will also be summarized for SAS1 over 10 
weeks of the study by ATC Level 3, preferred term, and treatment group. The concomitant 
medication incidence is determined with the number of subjects exposed to a treatment 
(placebo vs. pimavanserin) who took a concomitant medication while on that treatment 
divided by the total number of subjects exposed to that treatment. 
Post-Treatment Medications 
Post-treatment medications will be summarized for SAS1 by ATC Level 3, preferred term, 
and the study drug (placebo vs. pimavanserin) of which subjects received their last doses. 


 
 
 
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12. 
EFFICACY ANALYSES 
All efficacy analyses will be performed using the planned treatment assignments for FAS1 
and FAS2. Sensitivity analyses of the primary and key secondary efficacy endpoints will be 
performed using the planned treatment assignments for PAS1 and PAS2. 
For Stage 1, Baseline is Study Week 0 and Week 5 is Study Week 5. For Stage 2, Baseline is 
Study Week 5 and Week 5 is Study Week 10.   
Summary statistics for all the efficacy endpoints will be provided by visit and treatment group 
for FAS1 in Stage 1 (5 weeks), FAS2 in Stage 2 (5 weeks), and the subjects in FAS1 who 
were not randomized to the pimavanserin group in Stage 2 (10 weeks). Summary statistics for 
all the efficacy endpoints will also be provided by treatment group in Stage 2 for FAS2 from 
Baseline (Study Week 0) to Study Week 5.  
12.1 
Efficacy Endpoints 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from Baseline to Week 5 in the HAMD-17 total 
score.   
Key Secondary Efficacy Endpoint 
The key secondary efficacy endpoint is the change from Baseline to Week 5 in the SDS mean 
score.  
Other Secondary Efficacy Endpoints 
Other secondary efficacy endpoints are the following: 
• Treatment response and remission rates at the end of 5-week treatment period 
• Change from Baseline to Week 5 in CGI-S score 
• CGI-I score at Week 5 
• Change from Baseline to Week 5 in SF-12 score 
• Change from Baseline to Week 5 in DAI-10 score 
• Change from Baseline to Week 5 in KSS score 


 
 
 
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• Change from Baseline to Week 5 in MGH-SFI score 
• Change from Baseline to Week 5 in BIS-11 score 
• Change from Baseline to Week 5 in 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. 
12.2 
Adjustment for Covariates 
The corresponding baseline value will be included as a covariate for the analysis of HAMD-
17 and SDS mean scores using the mixed model for repeated measures (MMRM) as described 
in Sections 13.1 and 13.2.  
12.3 
Handling of Missing Data 
The primary analyses of the primary and key secondary efficacy endpoints will be performed 
in 2 steps and the missing data issue is only involved in Step 1: 
1. Data from Stages 1 and 2 will be analyzed separately assuming missing at random 
(MAR) using the stage-specific, direct likelihood-based MMRMs and scores that are 
missing, after any imputation of individual missing items as described in Sections 
5.2.1 and 5.2.2, will not be imputed. The MMRM method is unbiased under the MAR 
assumption and can be thought of as aiming to estimate the treatment effect that would 
have been observed if all subjects had continued on treatment for the full study 
duration (EMA, 2009). 
2. Weighted combination of statistics from the stage-specific MMRMs will be used to 
perform the hypothesis testing.  
12.4 
Multiple Comparisons / Multiplicity 
The hypothesis testing for the primary and key secondary efficacy endpoints will be 
performed in a sequential order. That is, if there is no evidence to show the superiority of the 
pimavanserin treatment to the placebo with respect to the primary efficacy endpoint at the 
two-sided significance level of 0.05, no further testing for the key secondary efficacy endpoint 
will be performed. Thus, there is no need to adjust the alpha for the two comparisons between 
the 2 treatment groups and the family-wise Type I error rate is controlled strongly for the 
hypothesis testing for the primary and key secondary efficacy endpoints. Unadjusted p-values 
will be reported and the testing sequence will be used to determine statistical significance. 


 
 
 
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12.5 
Examination of Subgroups 
Treatment effect will be examined with respect to the primary and key secondary efficacy 
endpoints within the subgroups of sex (male and female), race (white and non-white), age 
(18-40 years and > 40 years), and the severity of depression at Baseline (Baseline HAMD-17 
total score < 24 and ≥ 24). 


 
 
 
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13. 
METHODS OF EFFICACY ANALYSES 
13.1 
Primary Efficacy Analysis  
13.1.1 
Primary Analysis 
The primary efficacy endpoint is the change from Baseline to Week 5 in the Hamilton 
Depression Scale (17 Items) (HAMD-17) total score.  
Let Δ1 and Δ2 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 and Stage 2 respectively. 
Let w be the weight for Stage 1 and 1-w the weight for Stage 2. 
The null hypothesis is: 
𝑤𝑤∆1 + (1 −𝑤𝑤)∆2= 0. 
The alternative hypothesis is:  
𝑤𝑤∆1 + (1 −𝑤𝑤)∆2≠0. 
The hypothesis testing will be performed using the weighted combination of statistics from 
the stage-specific MMRM. The MMRMs 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 degrees of freedom. 
 
 
        
 
        
 
        
 
        
 
In the event that the model fails to converge using the unstructured covariance matrix, the 
following covariance structures will be modeled in the order given (i.e. from least 
parsimonious to most parsimonious): heterogeneous Toeplitz, heterogeneous compound 
symmetry, heterogeneous autoregressive(1), Toeplitz, compound symmetry, 
autoregressive(1), variance components. The first covariance structure that allows for 
convergence will be selected for the final model. 


 
 
 
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The overall treatment effect will be assessed as the weighted differences between the 
pimavanserin and placebo groups in least-squares mean change from Baseline to Week 5. The 
prespecified weight w, is 0.5/0.5 for Stage 1/Stage 2. 
Inference will be conducted using the following weighted linear combination of stage-wise 
treatment effects (Chen et al., 2011 and Fava et al., 2003): 
𝑍𝑍=
𝑤𝑤∆෠1+(1−𝑤𝑤)∆෠2
ට𝑤𝑤2𝑉𝑉𝑉𝑉𝑉𝑉൫∆෠1൯+(1−𝑤𝑤)2𝑉𝑉𝑉𝑉𝑉𝑉൫∆෠2൯
 ~ 𝑁𝑁(0, 1)   
 
                                 (1) 
 
 
In the above formula, w = 0.5 and ∆෠1 and ∆෠2 are the differences in least squares (LS) means 
between pimavanserin and placebo at Week 5, for Stages 1 and 2, respectively. 
Summary statistics for the HAMD-17 total score (observed and change from Baseline), LS 
means, the between-group difference in LS mean with the corresponding 95% confidence 
interval,  p-value, and the effect size (Cohen’s d) will be presented at each post-Baseline visit 
for FAS1 and FAS2.  
The treatment effect size (Cohen’s d) is calculated using the following formula: 
Effect Size = LS mean difference / SD 
 
 
 
 
                     (2) 
SD is the model-based estimate, i.e., the estimated standard deviation from the unstructured 
covariance matrix. The sign (+ or -) of the effect size will be chosen so that a positive value 
favors pimavanserin.  
LS mean ± SE from the MMRM models over time for the change from Baseline values by 
treatment group will be displayed in line plots for FAS1 in Stage 1 and FAS2 in Stage 2.   
The weighted treatment differences in LS means between pimavanserin and placebo, the 
corresponding 95% CI, and the p-value will be presented at Week 5. 
13.1.2 
Sensitivity Analyses 
The following 2 sensitivity analyses of HAMD-17 total score are planned. 
1. Per-protocol Analysis 
A sensitivity analysis similar to the primary analysis will be performed for PAS1 and PAS2.  
2. Pattern-Mixture Models Assuming Missing Not At Random (MNAR) 


 
 
 
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The sensitivity analysis is implemented using multiple imputations that are based on the 
distribution of placebo group responses over time. The underlying assumption is that subjects 
with missing data follow the distribution of the placebo responses. The following 3 steps are 
involved for both FAS1 and FAS2 separately: 
• The posterior mean and covariance estimates from the SAS MI procedure using the 
available non-missing placebo data and random number seeds of 1030421 for Stage 1 
and 103042 for Stage 2 will be utilized to impute missing data in the HAMD-17 total 
score. The imputed values will be constrained to be within the range of 0 to 52. 
 
  
 
        
                        
 
        
  
        
 
 
 
        
 
        
 
        
 
             
                                   
 
             
 
       
 
 
       
        
 
        
                       
 
  
• The change from Baseline to Week 5 in the HAMD-17 total score will then be 
calculated and analyzed for each of the 100 fully imputed datasets using an ANCOVA 
model with treatment group as a factor and the Baseline value as a covariate.  
• The treatment LSMEAN differences will be averaged and the associated standard 
errors will be summarized based on within-imputation and between-imputation 
variance using the SAS MIANALYZE procedure, to yield a combined estimate for 
treatment effect with its associated 95% CI and p-value. 
Inference will be made using the weighted linear combination of stage-wise, combined 
estimates for treatment effect using Equation (1). 


 
 
 
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13.2 
Key Secondary Efficacy Analysis  
The key secondary efficacy endpoint is the change from Baseline to Week 5 in the SDS mean 
score. The hypotheses, the primary analysis method, and the line plots for the key secondary 
efficacy endpoint are the same as the hypotheses, the primary analysis method, and line plots 
for the primary efficacy endpoint described in Section 13.1.1 but with SDS replacing HAMD-
17. A per-protocol analysis similar to the primary analysis will be performed for PAS1 and 
PAS2.  
13.3 
Other Secondary Efficacy Analyses 
ANCOVA analyses for the secondary efficacy endpoints in this section will be performed 
using (1) the observed values (i.e., missing data will not be imputed) and (2) the last 
observation carried forward (LOCF) method for missing data (Note: for subjects without post-
Baseline values, the Baseline values will be carried forward). 
 
Remission rate at the end of the two 5-week treatment periods 
Remission is defined as a HAMD-17 total score less than or equal to 7. Missing HAMD-17 
total scores will be considered as non-remissions and the subjects with missing HAMD-17 
total scores will be included in the denominator of the remission rate. 
The remission rate will be compared between the pimavanserin and placebo groups within 
each stage using Pearson’s chi-square test.  
Let n be the total number of subjects in FAS1, n1q be the number of placebo subjects in FAS1, 
n1p be the number of pimavanserin subjects in FAS1, n2q be the number of placebo subjects in 
FAS2 (i.e., placebo non-responders in Stage 1, were randomized to the placebo group in Stage 
2, received at least one dose of study drug in Stage 2, and have both a Baseline [Study Week 
5] value and at least one post-Baseline value for the HAMD-17 total score in Stage 2), and n2p 
be the number of pimavanserin subjects in FAS2 (i.e., placebo non-responders in Stage 1, 
were randomized to the pimavanserin group in Stage 2, received at least one dose of study 
drug in Stage 2, and have both a Baseline [Study Week 5] value and at least one post-Baseline 
value for the HAMD-17 total score in Stage 2).    
Let r1q be the number of placebo remission subjects in FAS1 in Stage 1, r1p be the number of 
pimavanserin remission subjects in FAS1 in Stage 1, r2q be the number of placebo remission 
subjects in FAS2 in Stage 2, and r2p be the number of pimavanserin remission subjects in 
FAS2 in Stage 2. 
Let q1 = r1q / n1q and p1 = r1p / n1p be placebo and pimavanserin remission rate in Stage 1.  Let 
q2 = r2q / n2q and p2 = r2p / n2p be placebo and pimavanserin remission rate in Stage 2, among 


 
 
 
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placebo non-responders in Stage 1. Let w be the weight for Stage 1 and 1-w be the weight for 
Stage 2 (Note: w is 0.5 for this study).  
The null hypothesis is:  
w (P1 ˗ Q1) + (1 ˗ w) (P2 ˗ Q2) = 0. 
The alternative hypothesis is:  
w (P1 ˗ Q1) + (1 ˗ w) (P2 ˗ Q2) ≠ 0. 
Inference will be made using the following weighted linear combination of stage-wise 
treatment effects:  
𝑍𝑍=
𝑤𝑤(𝑝𝑝1 −𝑞𝑞1) + (1 −𝑤𝑤)(𝑝𝑝2 −𝑞𝑞2)
ඥ𝑤𝑤2𝑉𝑉𝑉𝑉𝑉𝑉(𝑝𝑝1 −𝑞𝑞1) + (1 −𝑤𝑤)2𝑉𝑉𝑉𝑉𝑉𝑉(𝑝𝑝2 −𝑞𝑞2)
 ~ 𝑁𝑁(0, 1),  
where,  𝑉𝑉𝑉𝑉𝑉𝑉(𝑝𝑝𝑖𝑖−𝑞𝑞𝑖𝑖) =
𝑝𝑝𝑖𝑖(1−𝑝𝑝𝑖𝑖)
𝑛𝑛𝑖𝑖𝑖𝑖
+
𝑞𝑞𝑖𝑖(1−𝑞𝑞𝑖𝑖)
𝑛𝑛𝑖𝑖𝑖𝑖
, 𝑖𝑖= 1, 2.                                                                   (3)      
 
Treatment response rate at the end of the two 5-week treatment periods 
Treatment response is defined as a reduction from Baseline in HAMD-17 total score of 50% 
or more. The hypotheses and the analysis method for treatment response rate are the same as 
the hypotheses and the analysis method for the remission rate but with treatment response 
replacing remission.  
Change from Baseline to Week 5 in CGI-S score 
The change from Baseline to Week 5 in CGI-S score will be analyzed in a similar way as the 
primary analysis of the primary efficacy endpoint using the weighted linear combination test 
with the Baseline HAMD-17 total score replaced by the Baseline CGI-S score.  
CGI-I score at Week 5 
The CGI-I score will be analyzed in a similar way as the primary analysis of the primary 
efficacy endpoint using the weighted linear combination test. The differences are (1) the 
response is CGI-I score (as opposed to the change from Baseline in CGI-I score) and (2) the 
Baseline CGI-S score will be used as the covariate in the MMRM models. 
The CGI-I data will also be dichotomized by combining “very much improved” and “much 
improved” into 1 category (“Improved”), and the remaining items into the other (“Not 
Improved”). For analysis purposes, missing CGI-I scores and CGI-I scores of 0 (“not 
assessed”) will be treated as “Not Improved”.  


 
 
 
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The observed score and dichotomized data will be descriptively summarized by treatment 
group and visit. Treatment comparisons with respect to the dichotomized data within each 
stage for FAS1 and FAS2 will be performed using Pearson’s chi-square test. No overall 
treatment comparisons combining Stages 1 and 2 will be made with respect to the 
dichotomized data. 
Change from Baseline to Week 5 in SF-12 scores 
The change from Baseline to Week 5 in the norm-based Aggregate Physical Score and the 
norm-based Aggregate Mental Score will be summarized by treatment group and analyzed 
within each stage for FAS1 and FAS2 using the analysis of covariance (ANCOVA) model 
with treatment group as a factor and the corresponding Baseline value as a covariate. The 
overall treatment effect combining the 2 stages will be tested in a similar way as the primary 
efficacy endpoint using the weighted linear combination test in Equation (1). 
Change from Baseline to Week 5 in DAI-10 score 
The change from Baseline to Week 5 in DAI-10 score will be analyzed in a similar way as the 
SF-12 scores are analyzed. 
Change from Baseline to Week 5 in KSS score 
The change from Baseline to Week 5 in the 9-point KSS scale score will be analyzed in a 
similar way as the primary analysis of the primary efficacy endpoint using the weighted linear 
combination test with the Baseline HAMD-17 total score replaced by the Baseline KSS score. 
Change from Baseline to Week 5 in MGH-SFI score 
The change from Baseline to Week 5 in MGH-SFI score will be analyzed in a similar way as 
the SF-12 scores are analyzed.  
Change from Baseline to Week 5 in BIS-11 score 
The change from Baseline to Week 5 in BIS-11 score will be analyzed in a similar way as the 
primary analysis of the primary efficacy endpoint using the weighted linear combination test 
with the Baseline HAMD-17 total score replaced by the Baseline BIS-11 score. 
Change from Baseline to Week 5 in SIS score 
The change from Baseline to Week 5 in SIS score will be analyzed in a similar way as the 
primary analysis of the primary efficacy endpoint using the weighted linear combination test 
with the Baseline HAMD-17 total score replaced by the Baseline SIS score. 


 
 
 
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13.4 
Exploratory Efficacy Analyses  
No planned exploratory efficacy analyses are defined. 


 
 
 
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14. 
SAFETY ANALYSES 
All safety analyses including the analysis of plasma concentration data will be performed 
using the actual treatment for SAS1 in Stage 1 (5 weeks) and SAS2 in Stage 2 (5 weeks). To 
evaluate treatment differences in 10-week safety data, unless otherwise specified, safety data 
from Baseline (Study Week 0) to Study Week 10 will also be summarized by treatment group 
for subjects in SAS1 who were not randomized to the pimavanserin group in Stage 2.  
For Stage 1, Baseline is Study Week 0 and Week 5 is Study Week 5. For Stage 2, Baseline is 
Study Week 5 and Week 5 is Study Week 10.   
14.1 
Adverse Events  
Adverse events will be coded using MedDRA dictionary, Version 19.0 or newer. 
An AE (classified by preferred term) will be considered a treatment-emergent AE (TEAE) if 
started after first study dose administration and no later than last study dose date + 30. AEs 
reported on Day 1 based on Baseline (pre-dose) findings (e.g. clinically significantly 
abnormal vital signs, laboratory test results, or electrocardiogram parameters) will not be 
considered as TEAEs. 
TEAEs will be classified into 2 stages for the summary of TEAEs by stage. If the onset date 
of a TEAE is on or after the Stage 2 randomization date or the Study Week 5 visit date for 
those who were not randomized into Stage 2, the TEAE will be assigned to Stage 2; else it 
will be assigned to Stage 1.  
The number and percentage of subjects reporting TEAEs in each treatment group will be 
tabulated by system organ class (SOC) and preferred term; by SOC, preferred term, and 
maximum severity. The number and percentage of subjects reporting related TEAEs in each 
treatment group will also be tabulated by SOC and preferred term. If more than 1 AE occurs 
with the same preferred term for the same subject, then the subject will be counted only once 
for that preferred term using the most severe and most related occurrence for the 
summarization by severity and by relationship to study drug. 
TEAEs will also be tabulated by treatment group and without displaying the SOC terms; this 
table will be sorted in descending order of frequency of preferred term within the 
pimavanserin group. 
The incidence of most frequently reported (preferred terms reported by ≥ 5% of subjects in 
any treatment group) TEAEs for Stages 1 and 2 only, treatment emergent SAEs, and TEAEs 
leading to discontinuation of study drug will be summarized by SOC, preferred term, and 
treatment group. The tables will be sorted alphabetically by SOC and then by descending 


 
 
 
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order of subjects frequency within the pimavanserin group. In addition, the incidence of fatal 
treatment-emergent AEs (i.e., events that cause death) will be summarized separately by 
preferred term and treatment group.   
An AE listing by subject will display all events, including those which occur during 
screening, and will include the verbatim term in addition to the MedDRA SOC and preferred 
term. This listing will also include all relevant eCRF data associated with the event: date of 
onset, date resolved, date of last dose, severity, frequency, outcome, relationship to study 
drug, and action taken with study drug. Separate listings will be presented for subjects with 
treatment-emergent SAEs, subjects with TEAEs leading to discontinuation and subject who 
died (if any). 
14.2 
Clinical Laboratory Variables 
Clinical laboratory assessments are performed at Screening Visit 1, Baseline (Study Week 0), 
Study Week 5, and Study Week 10/Early termination.  
• Clinical chemistry serum tests include the following: 
o Sodium (Na), potassium (K), chloride (Cl), phosphorus (P), calcium (Ca), 
carbon dioxide (CO2), blood urea nitrogen (BUN), creatinine (CR), uric acid 
o Alanine aminotransferase (ALT/SGPT), aspartate aminotransferase 
(AST/SGOT), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase 
(ALP), total bilirubin (TBIL), lactate dehydrogenase (LDH) 
o HbA1c (Screening only) 
o Glucose 
o Albumin (ALB), total protein 
o Prolactin 
o Creatine kinase (CK)/creatine phosphokinase (CPK) 
o Lipid panel 
- Total cholesterol, HDL-cholesterol, triglycerides, LDL-cholesterol, 
Cholesterol/HDL ratio, Non-HDL cholesterol 
• Hematology tests include the following: 


 
 
 
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o Complete blood count (CBC) including: 
- White blood cell (WBC) count 
- Complete differential (relative and absolute) 
- Hematocrit (Hct), hemoglobin, red blood cells (RBC), platelets 
- Reticulocyte count 
• Urinalysis tests include the following: 
o Blood, RBCs, WBCs, protein, glucose, ketones, specific gravity, pH 
Clinical laboratory values (in Système International [SI] units) and the change from Baseline 
values will be summarized by treatment group at each post-Baseline visit using descriptive 
statistics. The overall minimum and maximum post-Baseline observed and change from 
Baseline values will also be summarized. For hemoglobin, hematocrit and uric acid, the above 
summaries will be presented for each gender as well as for both genders combined. For 
urinalysis with categorical results, the number and percentage of subjects will be tabulated by 
category at Baseline, Study Week 5 and Study Week 10, and the denominator is the number 
of subjects with non-missing values for the given parameter, visit and treatment group.  
Laboratory values will also be summarized in shift tables by treatment group, to determine the 
number and percentage of subjects with values classified as below, within, and above normal 
ranges at each post-Baseline visit relative to the same classification at the Baseline visit. For 
the by-visit shit summary, the denominator is the number of subjects with non-missing values 
at Baseline and the given visit for the given parameter and treatment group. For the shift to 
the overall post-Baseline minimum or maximum, all post-Baseline values will be considered, 
including unscheduled and out of window values and the denominator is the number of 
subjects with non-missing Baseline value and at least 1 post-Baseline value for the given 
parameter and treatment group. For hemoglobin, hematocrit and uric acid, the shift summaries 
will be presented for each gender as well as for both genders combined. 
Clinical laboratory values are potentially clinically important (PCI) if they meet either the low 
or high PCI criteria listed in Tables 4 and 5. The number and percentage of subjects with post-
Baseline PCI values for each of the categories in Table 4 and 5 will be summarized by 
treatment group for selected parameters. For the overall post-Baseline summaries of PCI 
values, all post-Baseline values will be considered, including unscheduled and out of window 
values. Subjects with multiple PCI values for a given parameter will be counted only once for 
that parameter. For the overall post-Baseline summary, the numerator of the percentage is the 
number of subjects with at least 1 post-Baseline PCI laboratory value for the given parameter 
and treatment group, and the denominator is the number of subjects with at least 1 post-


 
 
 
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Baseline laboratory value for the given parameter and treatment group. For hemoglobin, 
hematocrit and uric acid, the count and percentage of subjects with PCI values will be 
presented for each gender as well as for both genders combined. Subjects with PCI values will 
be presented in an additional listing.  
 
Table 4 
Criteria for Potentially Clinically Important Laboratory Values – 
Hematology and Chemistry 
 
Analyte 
Conventional 
Unit 
Low PCI 
Criteria 
High PCI 
Criteria 
 
SI Unit 
Low PCI 
Criteria 
High PCI 
Criteria 
Hematology (whole 
blood) 
 
 
 
 
 
 
Hemoglobin (male) 
g/dL 
<11 
>18 
g/L 
<110 
>180 
Hemoglobin (female) 
g/dL 
<10 
>17 
g/L 
<100 
>170 
Hematocrit (male) 
% 
<30 
>55  
L/L 
<0.3 
>0.55  
Hematocrit (female) 
% 
<30 
>50  
L/L 
<0.3 
>0.5  
Leukocyte (White 
Blood Cell Count) 
x 103/uL 
≤2.8 
≥15 
x 109/L 
≤2.8 
≥15 
Neutrophils 
x 103/uL 
≤1.5 
No upper 
limit 
x 109/L 
≤1.5 
No upper 
limit 
Platelet Count 
x 103/uL 
≤75 
≥700 
109/L 
≤75 
≥700 
Chemistry (serum 
or plasma) 
 
 
 
 
 
 
ALT (SGPT) 
U/L 
No lower 
limit  
≥3 X ULN 
U/L 
No lower 
limit  
≥3 X ULN 
AST (SGOT) 
U/L 
No lower 
limit  
≥3 X ULN 
U/L 
No lower 
limit  
≥3 X ULN 
Total Bilirubin 
mg/dL 
No lower 
limit 
≥1.5 ULN 
umol/L 
No lower 
limit 
≥1.5 ULN 
BUN 
mg/dL 
No lower 
limit 
≥30.0 
mmol/L 
No lower 
limit 
≥10.71 
Creatine Kinase (CK) 
U/L 
No lower 
limit 
≥3 ULN 
U/L 
No lower 
limit 
≥3 ULN 
Sodium 
mEq/L 
≤125 
≥155 
mmol/L 
≤125 
≥155 
Potassium 
mEq/L 
≤3.0 
≥5.5 
mmol/L 
≤3.0 
≥5.5 
Calcium, total 
mg/dL 
<8.0 
>11.0 
mmol/L 
<2.0 
>2.75 
Lactate 
Dehydrogenase 
(LDH) 
U/L 
No lower 
limit 
≥3 X ULN 
U/L 
No lower 
limit 
≥3 X ULN 
Alkaline Phosphatase 
U/L 
No lower 
limit 
≥3 X ULN 
U/L 
No lower 
limit 
≥3 X ULN 
Uric acid (male) 
mg/dL 
No lower 
limit 
≥10.5 
umol/L 
No lower 
limit 
≥624.75 
Uric acid (female) 
mg/dL 
No lower 
limit 
≥8.5 
umol/L 
No lower 
limit 
≥505.75 
Albumin 
g/dL 
≤2.6 
≥6.0 
g/L 
≤26 
≥60 


 
 
 
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Analyte 
Conventional 
Unit 
Low PCI 
Criteria 
High PCI 
Criteria 
 
SI Unit 
Low PCI 
Criteria 
High PCI 
Criteria 
Total Protein 
g/dL 
≤5.0 
≥10.0 
g/L 
≤50 
≥100 
Chloride 
mEq/L 
≤85 
≥120 
mmol/L 
≤85 
≥120 
Glucose (random) 
mg/dL 
≤45.1 
≥200.0 
mmol/L 
≤2.48 
≥11 
Serum Creatinine 
mg/dL 
Not 
Applicable 
>1.5 ULN 
umol/L 
Not 
Applicable 
>1.5 ULN 
Triglycerides 
mg/dL 
Not 
Applicable 
>300 
mmol/L 
Not 
Applicable 
>3.39 
Gamma-Glutamyl 
Transferase (GGT) 
U/L 
Not 
Applicable 
≥3 ULN 
U/L 
Not 
Applicable 
≥3 ULN 
 
Table 5  
Criteria for Potentially Clinically Important Laboratory Values - Urinalysis 
Urinalysis (qualitative dipstick) 
Low PCI Criteria 
High PCI Criteria 
Blood (Occult Blood) 
Not Applicable 
≥+2 
Protein 
Not Applicable 
≥+2 
Glucose 
Not Applicable 
≥+2 
 
Clinical laboratory data will be displayed in data listings with date and study day of 
collection.  All units will be displayed according to SI conventions for units.  Out of range 
values will be flagged in the data listings (i.e., ‘L’ or ‘H’).  A separate listing will be provided 
for a subset of the chemistry, hematology, and urinalysis analytes with values classified as 
PCI.  
The pregnancy results (positive or negative) for female subjects will be presented in a listing.  
14.3 
Vital Signs 
Vital signs including weight and the derived BMI will be collected throughout the study at 
every visit. Observed vital signs and the changes from Baseline at each post-Baseline visit 
will be summarized by treatment group using descriptive statistics. 
Vital sign values will be considered PCI if they meet the criteria listed in Table 6. The number 
and percentage of subjects with post-Baseline vital signs that are PCI will be summarized by 
treatment group at each post-Baseline visit and for overall post-Baseline.  For the overall post-
Baseline summaries, all post-Baseline values will be considered, including unscheduled and 
out of window values. Subjects with multiple PCI values for a given parameter will be 
counted only once for that parameter. For the by-visit summary, the numerator for the 
percentage is the number of subjects with a post-Baseline PCI vital sign for the given 
parameter, visit and treatment group, and the denominator is the number of subjects with non-
missing values for the given parameter, visit and treatment group. For the overall post-


 
 
 
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Baseline summary, the numerator for the percentage is the number of subjects with at least 1 
post-Baseline PCI vital sign for the given parameter and treatment group, and the 
denominator is the number of subjects with at least 1 post-Baseline vital sign for the given 
parameter and treatment group.   A listing of subjects with any PCI value will be provided.   
Table 6    Criteria for Potentially Clinically Important (PCI) Vital Signs 
 
Vital Sign 
Parameter 
 
Unit 
Criteria 
Observed Value 
And/Or 
Change Relative 
to Baseline 
Change from Supine 
to Standing 
Systolic blood 
pressure 
(supine or sitting) 
mmHg 
≥180 
And 
Increase of ≥20 
- 
≤90 
And 
Decrease of ≥20 
- 
Diastolic blood 
pressure (supine or 
sitting) 
mmHg 
≥105 
And 
Increase of ≥15 
- 
≤50 
And 
Decrease of ≥15 
- 
Pulse (supine or 
sitting) 
bpm 
≥120 
And 
Increase of ≥15 
- 
≤50 
And 
Decrease of ≥15 
- 
Weight  
kg 
Not Applicable 
Increase of ≥7% 
- 
Decrease of ≥7% 
- 
 
14.4 
Electrocardiogram (ECG) 
12-lead ECGs are collected at Screening Visit 1, Baseline (Study Week 0), Study Week 1, 
Study Week 5, Study Week 6, and Study Week 10/Early termination. Observed values of 
ECG variables (e.g., heart rate, PR interval, QRS interval, QT interval, and QTc interval) and 
the changes from Baseline at each assessment time point will be summarized by treatment 
group.  
QTcF will also be categorized into the following categories (msec) and the number and 
percentage of subjects in each category will be summarized by treatment group at each visit 
and for the overall post-Baseline maximum: 
• Observed: ≤450, 451 - ≤480, 481 - ≤500, and >500; >450; >480. 
• Change from Baseline: ≤10, 11 – 30, 31 – 60, and >60; >30. 
 


 
 
 
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Electrocardiogram variable values will be considered PCI if they meet the criteria listed in 
Table 7. The number and percentage of subjects with post-baseline PCI values will be 
summarized by treatment group at each post-Baseline visit and for overall post-Baseline. For 
the by-visit summary, the numerator for the percentage is the number of subjects with a post-
Baseline PCI ECG for the given parameter, visit and treatment group, and the denominator is 
the number of subjects with non-missing values for the given parameter, visit and treatment 
group. For the overall post-Baseline summary, the numerator for the percentage is the number 
of subjects with at least 1 post-Baseline PCI ECG for the given parameter and treatment 
group, and the denominator is the number of subjects with at least 1 post-Baseline ECG value 
for the given parameter and treatment group. A listing of all subjects with any PCI value will 
be provided.  
Table 7  
Criteria for Potentially Clinically Important ECG Values 
ECG Parameter 
Unit 
High PCI Criteria 
QRS Interval 
msec 
≥120 
PR Interval 
msec 
≥220 
QTcB or QTcF 
msec 
>500 
QTcB or QTcF: change from baseline  
>60 msec  
 
14.5 
Physical Examination 
Physical examinations are performed at Screening Visit 1, Baseline (Study Week 0), Study 
Week 5, and Study Week 10. Physical examination results (normal, abnormal, and not done) 
will be summarized in a frequency table by treatment group, body system and visit.   
14.6 
Other Safety Endpoints 
Unless otherwise specified, scores derived based on sub-scores for the safety endpoints in this 
section will be considered missing if any corresponding sub-scores are missing. No 
imputations will be performed. Summary statistics for all safety questionnaire data discussed 
in this section will also be provided by treatment group in Stage 2 for SAS2 from Baseline 
(Study Week 0) to Study Week 5. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS Baseline/Screening version will be completed at the Screening visit and the 
version assessing information since the last visit will be completed at all following visits 
(including the Baseline visit).   


 
 
 
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There are 5 questions about suicidal ideation, representing 5 types of suicidal ideation: wish 
to be dead; non-specific active suicidal thoughts; active suicidal ideation with any methods 
(not plan) without intent to act; active suicidal ideation with some intent to act, without 
specific plan; active suicidal ideation with specific plan and intent.  If a subject answers “yes” 
to any of these 5 questions at any post-Baseline visit including unscheduled and out of 
window visits, this subject will be counted as having suicidal ideation in this study. 
There are 5 questions about suicidal behavior, representing 5 types of suicidal behavior: 
actual attempt; interrupted attempt; aborted attempt; preparatory acts or behavior; suicide.  If 
a subject answers “yes” to any of these 5 questions at any post-Baseline visit including 
unscheduled and out of window visits, this subject will be counted as having suicidal behavior 
in this study. 
Suicidality is defined as a subject who reported at least 1 occurrence of suicidal ideation or at 
least 1 occurrence of suicidal behavior at any post-Baseline visit including unscheduled and 
out of window visits.   
All data will be listed. The event counts and the number and percentage of subjects reporting 
any post-Baseline suicidal ideation, suicidal behavior, or suicidality will be summarized by 
treatment group for SAS1 over Stage 1 (5 weeks), SAS2 over Stage 2 (5 weeks), and the 
subjects in SAS1 who were not randomized to the pimavanserin group in Stage 2 over the 
whole study (10 weeks). 
Abnormal Involuntary Movement Scale (AIMS) 
The AIMS 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. 
Total AIMS scores range from 0 to 42.  
Observed total AIMS score and the changes from Baseline at each post-Baseline visit will be 
summarized by treatment group using descriptive statistics.  
The number and percentage of subjects with dyskinesia will be summarized by treatment 
group at each visit and for overall post-Baseline for SAS1 over Stage 1 (5 weeks), SAS2 over 
Stage 2 (5 weeks), the subjects in SAS1 who were not randomized to the pimavanserin group 
in Stage 2 over the whole study (10 weeks), and SAS2 over Stage 1 (5 weeks). Dyskinesia is 
defined as having a score of 3 or more on any of the first 7 AIMS items or a score of 2 or 
more on any two of the first 7 AIMS items. The tabulations will be presented for subjects who 
have at least 1 AIMS assessment as well as for a subset of these subjects who do not have 
dyskinesia at Baseline. 


 
 
 
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The individual item scores will be listed but not summarized. 
Barnes Akathisia Scale (BARS)  
The BARS is a clinician-rated scale to assess drug-induced akathisia and classify it as absent, 
mild, moderate, or severe. The BARS consists of items that assess the objective presence and 
frequency of akathisia, the level of an individual’s subjective awareness and distress, and 
global severity. Objective Akathisia, Subjective Awareness of Restlessness, and Subjective 
Distress Related to Restlessness are rated on a 4-point scale from 0 – 3 and are summed 
yielding a total score ranging from 0 to 9. The Global Clinical Assessment of Akathisia uses a 
6-point scale ranging from 0 – 5.  
Observed total score, the score of Global Clinical Assessment of Akathisia, and the 
corresponding changes from Baseline at each post-Baseline visit will be summarized by 
treatment group using descriptive statistics.  
The number and percentage of subjects with akathisia will be summarized by treatment group 
at each visit and for overall post-Baseline for SAS1 over Stage 1 (5 weeks), SAS2 over Stage 
2 (5 weeks), the subjects in SAS1 who were not randomized to the pimavanserin group in 
Stage 2 over the whole study (10 weeks), and SAS2 over Stage 1 (5 weeks). Akathisia is 
defined as having a Global Clinical Assessment of Akathisia score ≥2. The tabulations will be 
presented for subjects who have at least 1 BARS assessment as well as for a subset of these 
subjects who do not have akathisia at Baseline. 
The individual item scores will be listed but not summarized. . 
Simpson Angus Scale (SAS) 
The SAS 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. . 
Observed total SAS score and the changes from Baseline at each post-Baseline visit will be 
summarized by treatment group using descriptive statistics.  
The number and percentage of subjects with Parkinsonism will be summarized by treatment 
group at each visit and for overall post-Baseline for SAS1 over Stage 1 (5 weeks), SAS2 over 
Stage 2 (5 weeks), the subjects in SAS1 who were not randomized to the pimavanserin group 
in Stage 2 over the whole study (10 weeks), and SAS2 over Stage 1 (5 weeks). Parkinsonism 
is defined as having a SAS total score >3. The tabulations will be presented for subjects who 
have at least 1 SAS assessment as well as for a subset of these subjects who do not have 
Parkinsonism at Baseline. 


 
 
 
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The individual item scores will be listed but not summarized. 
 
For the overall post-Baseline summaries, all post-Baseline values will be considered, 
including unscheduled and out of window values. 
 


 
 
 
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15. 
CLINICAL PHARMACOKINETIC AND 
PHARMACODYNAMIC ANALYSES 
For pimavanserin-treated subjects, plasma concentration for pimavanserin and AC-279 will be 
listed. Plasma concentration data for pimavanserin and AC-279 will be summarized at each 
visit using descriptive statistics. Concentrations that are below the limit of quantification 
(BLQ) will be displayed as “BLQ” in the data listings and imputed as 0 for computing 
summary statistics. 
Plasma concentration data for the concomitant SSRIs/SNRIs will be listed. 
If data allow, population PK and PK/PD analyses will be performed to further characterize the 
PK profile and exposure response relationship of pimavanserin and its metabolite using 
measures of safety, and efficacy parameters.  The results of population PK and PK/PD 
modeling will be presented in a separate report.  Pimavanserin plasma concentration data will 
remain blinded until the unblinding of the clinical database at the end of the study.  


 
 
 
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16. 
INTERIM ANALYSIS 
No interim analysis is planned in this study. 


 
 
 
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17. 
DATA MONITORING/REVIEW COMMITTEE 
There is no Data Monitoring Committee in this study. 


 
 
 
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18. 
COMPUTER METHODS  
Statistical analyses will be performed using Version 9.4 (or newer) of SAS (SAS® Institute, 
Inc., Cary, North Carolina) on a suitably qualified and validated environment. 
Validation and quality control of the tables, listings and figures containing the results of the 
statistical analyses will follow appropriate standard operating procedures. 
 


 
 
 
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19. 
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL 
No changes are made to the analyses specified in the protocol.   
 
  


 
 
 
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20. 
REFERENCES 
Chen Y.F., Yang Y., Hung H., Wang S. (2011). Evaluation of performance of some 
enrichment designs dealing with high placebo response in psychiatric clinical trials. 
Contemporary Clinical Trials, 32, 592-604. 
EMA (2009). Guideline on Missing Data in Confirmatory Clinical Trials, European 
Medicines Agency, London, UK. 
Fava M., Evins A.E., Dorer D.J., Schoenfeld D.A. (2003). The problem of the placebo 
response in clinical trials for psychiatric disorders: culprits, possible remedies, and a novel 
study design approach. Psychotherapy and Psychosomatics, 72, 115–127. 


 
 
 
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21. 
APPENDICES 
21.1 
Summary of Version Changes  
Version No: 
Document History 
Description of Update 
Author(s) 
Version Date 
Final 
Original version 
 
21AUGUST2018