Conditions: Treatment of Depression in Adults With Parkinson's Disease (PD)
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 47
Healthy volunteers: no

Brief summary:
The purpose of this study is to assess the efficacy of pimavanserin for the treatment of depression in adults with Parkinson's disease.

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: Pimavanserin
Intervention descriptions: intervention 1: Pimavanserin 34 mg total daily dose, tablets, once daily by mouth (provided as two 17 mg NUPLAZID® tablets)

Protocol document:
Prot_000.pdf: 
Official Title: An Open-label, 8-Week Study of Safety and Efficacy of Pimavanserin 
Treatment in Adults With Parkinson’s Disease and Depression  
NCT Number: NCT03482882 
Date of IRB Approval: 8 Jan 2019 


 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 1 of 68 
 
ACADIA Pharmaceuticals Inc. 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
An Open-label, 8-Week Study of Safety and Efficacy of Pimavanserin 
Treatment in Adults With Parkinson’s Disease and Depression 
 
Protocol Number: ACP-103-048 
Amendment 2 
 
Original Protocol Date: 08 September 2017 
Protocol Amendment 1 Date: 10 July 2018 
Protocol Amendment 2 Date: 08 January 2019 
 
 
Confidentiality Statement 
This protocol is the confidential information of ACADIA Pharmaceuticals Inc. and is 
intended solely for the guidance of the clinical investigation. This protocol may not be 
disclosed to parties not associated with the clinical investigation or used for any purpose 
without the prior written consent of ACADIA Pharmaceuticals Inc. 
ACADIK 
Pharmaceuticals 


Study: ACP-103-048 
Clinical Study Protocol Amendment 2 
SPONSOR SIGNATURE PAGE 
Final Version: 1.0 
Date: 8 January 2019 
Title: An Open-label, 8-Week Study of Safety and Efficacy of Pimavanserin Treatment in 
Adults With Parkinson's Disease and Depression 
ACADIA Chief Medical Officer: 
~~~~~~~~~~~~~~~~ 
Signature 
ACADIA Team Lead: 
Date 
 
} 15 Ja.yi 2o l 9 
Signature 
Date 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 2 of68 


Study: ACP-103-048 
Final Version: 1.0 
Clinical Study Protocol Amendment 2 
Date: 8 January 2019 
 
 
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Page 3 of 68 
DECLARATION OF INVESTIGATOR 
I confirm that I have read the above protocol. I understand it, and I will work according to the 
moral, ethical, and scientific principles governing clinical research as set out in the principles 
of Good Clinical Practice (GCP) (International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use [ICH] Guidelines E6 and E2a); as 
described in 21 CFR parts 50, 54, 56, 312, and 812; and according to applicable local 
requirements. 
Confidentiality Statement 
The confidential information in this document is provided to you as a Principal Investigator 
or Consultant for review by you, your staff, and the applicable Institutional Review 
Board/Ethics Committee. Your acceptance of this document constitutes agreement that you 
will not disclose the information contained herein to others without written authorization 
from the Sponsor. 
Principal Investigator 
 
Signature 
 
Date 
 
 
 
Name (printed) 
 
 


Study: ACP-103-048 
Final Version: 1.0 
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Date: 8 January 2019 
 
 
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PROTOCOL SYNOPSIS 
Protocol Number 
ACP-103-048 
Eudra CT Number Not applicable 
Protocol Title 
An Open-label, 8-Week Study of Safety and Efficacy of Pimavanserin 
Treatment in Adults With Parkinson’s Disease and Depression 
Name of 
Investigational 
Product 
Pimavanserin 
Indication  
Treatment of depression associated with Parkinson’s disease (PD) 
Phase of 
Development 
2 
Sponsor 
ACADIA Pharmaceuticals Inc. 
 
 
Primary Objective 
To assess the efficacy of pimavanserin for the treatment of depression 
in adults with Parkinson’s disease 
Primary Endpoint 
Change from Baseline to Week 8 in the Hamilton Depression Scale-17 
items (HAMD-17) total score 
Secondary 
Objectives 
To explore the efficacy of pimavanserin in the following domains: 
 Clinician’s global assessment of illness 
 Night time sleep and day time sleepiness 
 Quality of life (QoL) 
Secondary 
Endpoints 
 Clinical Global Impression-Improvement (CGI-I) 
 Change from Baseline in Clinical Global Impression-Severity 
(CGI-S) 
 Change from Baseline in Scale of Outcomes in PD-Sleep Scale 
(SCOPA) night time sleep score 
 Change from Baseline in SCOPA day time sleepiness score 
 Proportion of responders (defined as ≥50% reduction from 
Baseline in HAMD-17 total score) 
 Change from Baseline in EuroQol-5 dimensions-5 levels 
(EQ-5D-5L) 
Safety Objective 
To assess the safety of pimavanserin for the treatment of depression in 
adults with Parkinson’s disease 
Safety Endpoints 
 Adverse events (AEs) 
 Vital signs 
 12-lead electrocardiogram (ECG) 


Study: ACP-103-048 
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 Hematology, serum chemistry, urinalysis 
 Columbia Suicide Severity Rating Scale (C-SSRS) score 
 Mini-Mental State Examination (MMSE) 
 Unified Parkinson's Disease Rating Scale (UPDRS) Part III 
Number of Study 
Sites 
Approximately 20 sites will participate in this study. 
Number of Subjects 
Planned 
Approximately 40 subjects with PD and depression will be enrolled. 
Test Product, Dose, 
and Administration 
Pimavanserin 34 mg (provided as two 17 mg NUPLAZID® tablets) will 
be administered orally once daily (QD). 
Planned Duration 
of Treatment 
The duration of an individual subject’s participation in the study will 
be up to 13 weeks, consisting of a screening period of up to 3 weeks, 
followed by a treatment period of approximately 8 weeks, and a 
2-week safety follow-up. 
Study Design 
This will be a multi-center, open-label study to assess the efficacy and 
safety of treatment with 34 mg pimavanserin in subjects with PD and 
depression. Subjects can receive treatment as either a monotherapy or 
adjunctively if inadequately controlled with SSRIs/SNRIs 
monotherapy. Each subject will participate in a screening and treatment 
period with regularly scheduled assessments (see Figure S-1 and 
Table S–1). 
Screening Period 
Subjects will be assessed for eligibility and prohibited medications will 
be discontinued. Screening will be up to 3 weeks. 
Treatment Period 
After all screening assessments are completed, eligible subjects will 
return to the clinic for Baseline evaluation. After Baseline assessments 
are completed, subjects will be enrolled and receive the first dose of 
pimavanserin. Study medication will be provided to the subjects to take 
home with instructions to take the medication approximately the same 
time each day, and return all used containers and unused study drug as 
scheduled. 
At approximately 2, 4, and 6 weeks after start of dosing of study drug 
subjects will return to the clinic for assessments. Safety measures, 
HAMD-17, C- SSRS, CGI-S, and CGI-I will be evaluated at all visits. 
Subjects will complete the SCOPA, MMSE, EQ-5D-5L, and UPDRS 
Part III at Baseline and Week 4. 
At the end of the 8 weeks of study drug treatment, subjects will return 
to the clinic for their final clinical evaluation. All assessments will be 
completed and unused study drug and containers will be collected. 
Safety Follow-up Period  
Approximately 2 weeks after the last dose of study drug, subjects will 
have a safety follow-up telephone call. 


Study: ACP-103-048 
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Subjects who discontinue early or complete the study should return to 
standard of care. The Sponsor will provide investigative sites with 
3 months of after-study assistance to transition subjects to standard of 
care therapy after their participation in the study. 
Main Criteria for 
Inclusion and 
Exclusion 
Eligibility criteria 
Subjects must fulfill all of the inclusion criteria and none of the 
exclusion criteria at Screening (unless otherwise specified). 
Inclusion criteria: 
1. Is a male or female ≥50 years of age 
2. Can understand and provide signed informed consent, request 
for medical records and/or subject privacy form if applicable 
according to local regulations 
3. Is able to complete subject-reported outcome measures and can 
be reliably rated on assessment scales (in the opinion of the 
Investigator), and has a reliable study partner/caregiver (e.g., 
relative, housemate, close personal friend, or professional 
caregiver) who can report on the subject’s health-related quality 
of life 
4. Has a clinical diagnosis of idiopathic Parkinson’s disease with a 
minimum duration of 1 year, defined as the presence of at least 
three of the following cardinal features, in the absence of 
alternative explanations or atypical features: 
a. rest tremor 
b. rigidity 
c. bradykinesia and/or akinesia 
d. postural and gait abnormalities 
5. Meets clinical criteria for depression with Parkinson’s disease 
as listed in the NINDS/NIMH Guidelines (Marsh et al. 2006) 
6. Has a HAMD-17 total score ≥15 at Screening and Baseline 
7. If currently taking an antidepressant, is being treated with only 
one of the following SSRI or SNRI antidepressants at a dose 
within the United States Food and Drug Administration (US 
FDA)-approved dose range. Subjects who are currently taking a 
second antidepressant or antidepressant augmentation agent at a 
sub-therapeutic dose or for an inadequate duration at Screening, 
and can be discontinued from this agent before the Baseline 
visit (in the opinion of the Investigator), may be eligible for the 
study. 
a. Citalopram 
b. Escitalopram 
c. Paroxetine 


Study: ACP-103-048 
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d. Fluoxetine 
e. Sertraline 
f. Vortioxetine 
g. Duloxetine 
h. Venlafaxine 
i. Desvenlafaxine 
j. Venlafaxine XR 
k. Vilazodone 
l. Levomilnacipran 
Current or previous treatment with an antidepressant is not 
required. Investigators should not withdraw a subject’s 
medication unless clinically appropriate (e.g., symptoms are 
not well-controlled or the subject cannot tolerate the current 
medication). 
8. If the subject is currently taking an antidepressant and has an 
improvement in depression of less than 75% when working at 
its best, as confirmed by the Massachusetts General Hospital 
Antidepressant Treatment Questionnaire (MGH ATRQ) 
9. Has a Mini Mental State Exam (MMSE) score ≥21  
10. Is on a stable dose of anti-Parkinson’s medication for 1 month 
prior to Screening  
11. If the subject is female, she must be of non-childbearing 
potential (defined as either surgically sterilized [history of a 
bilateral oophorectomy, bilateral tubal ligation, or a partial or 
complete hysterectomy] or at least 1 year postmenopausal) OR 
must agree to use TWO clinically acceptable methods of 
contraception, if sexually active, throughout the study and for at 
least 1 month prior to the Baseline visit (Visit 2), and 41 days 
following completion of the study. 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. 
12. 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 
Exclusion criteria: 
1. 
Use of an antipsychotic within 3 weeks or 5 half-lives of 
Baseline (whichever is longer) 
2. 
Has greater than New York Heart Association (NYHA) Class 2 
congestive heart failure or Class 2 angina pectoris, sustained 


Study: ACP-103-048 
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Date: 8 January 2019 
 
 
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ventricular tachycardia, ventricular fibrillation, or torsade de 
pointes, or syncope due to an arrhythmia 
3. 
Had a myocardial infarction within the 6 months prior to 
Screening 
4. 
Has a known personal or family history or symptoms of long 
QT syndrome 
5. 
Has any of the following ECG results at Screening (the ECG 
may be repeated once at Screening in consultation with the 
Medical Monitor):  
a. If the subject is not on citalopram, escitalopram, or 
venlafaxine  
i. 
QTcF >450 ms, if QRS duration <120 ms  
ii. 
QTcF >470 ms, if QRS duration ≥120 ms  
b. If the subject is on citalopram, escitalopram, or 
venlafaxine  
i. QTcF >425 ms, if QRS duration <120 ms 
ii. QTcF >450 ms, if QRS duration ≥120 ms 
6. 
Has clinically significant laboratory abnormalities that, in the 
judgment of the Investigator or Medical Monitor, would 
jeopardize the safe participation of the subject in the study 
7. 
Evidence of severe or medically significant hepatic or renal 
impairment on laboratory tests as assessed by the Investigator 
or Medical Monitor  
8. 
Has uncontrolled diabetes or a glycosylated hemoglobin 
(HbA1c) >8% at Screening 
9. 
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 
10. Has a body mass index (BMI) of <19 or >35 
11. Has a known history of a positive hepatitis B virus (HBV), 
hepatitis C virus (HCV), or human immunodeficiency virus 
(HIV) test 
12. Has a history of PD psychosis, 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.  


Study: ACP-103-048 
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13. Has a current diagnosis of delirium 
14. Has a current primary diagnosis of borderline, antisocial, 
paranoid, schizoid, schizotypal, or histrionic personality 
disorder, according to DSM-5 criteria 
15. 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 
16. Has a positive test for an illicit drug at Screening or Baseline. 
Subjects who test positive for a controlled substance and who 
have a valid prescription can be enrolled if the drug is not a 
prohibited medication  
17. Actively suicidal at Visit 1 (Screening) or Visit 2 (Baseline) 
(including an answer of “yes” to C-SSRS questions 4 or 5 
[current or over the last 6 months]) or has attempted suicide in 
the 2 years prior to Visit 1 (Screening) 
18. Is pregnant or breastfeeding. Female subjects of child-bearing 
potential must have a negative serum pregnancy test at 
Screening 
19. Has major surgery planned during the trial (including 
Screening and follow-up periods) 
20. Has participated in or is participating in a clinical trial of any 
investigational drug, device, or intervention, within 60 days (or 
five half-lives, whichever is longer) prior to Screening 
21. Has previously been treated with pimavanserin or is currently 
taking pimavanserin 
22. Has a sensitivity to pimavanserin or its excipients 
23. Is judged by the Investigator or the Medical Monitor to be 
inappropriate for the study 
Sample Size 
Calculations 
The initial sample size calculation was based on a standard deviation of 
8.0 and a dropout rate of 10%. An interim review of the statistical 
assumptions was conducted after 9 subjects completed the Week 8 
visit, and the sample size was recalculated. The standard deviation in 
HAMD-17 total score change from Baseline to Week 8 was observed to 
be lower, and the dropout rate higher, than the initial assumptions. 
Therefore, the sample size has been recalculated as follows. 
Assuming the standard deviation for the change in HAMD-17 total 
score from Baseline to Week 8 is 6.0 points, 34 evaluable subjects will 
provide 80% power to detect a minimum mean reduction of 3 points 
from Baseline to Week 8 at a significance level of 0.05 using a 2-sided 
paired t-test. 


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Adjusting for a potential non-evaluable rate of up to 15%, 
approximately 40 subjects will be enrolled. 
Statistical Methods The Safety Analysis Set includes all subjects who received at least one 
dose of pimavanserin. The Safety Analysis Set will be used for the 
analysis of all safety endpoints. 
The Full Analysis Set (FAS) includes all subjects who received at least 
one dose of pimavanserin and who have both a Baseline value and at 
least one post-Baseline value for the HAMD-17 total score. The FAS 
will be used for the analysis of all efficacy endpoints.  
Descriptive Statistics 
Continuous measurement results will be reported using the number of 
subjects with data values, mean, standard error of the mean, median, 
standard deviation, minimum, and maximum. For each categorical 
outcome, the number and percentage of subjects will be reported. 
Efficacy Analyses 
All efficacy endpoints will be summarized by time point using 
descriptive statistics. The primary efficacy endpoint is the change from 
Baseline to Week 8 in depression as measured by the HAMD-17 total 
score. 
The HAMD-17 total score will be analyzed using mixed model for 
repeated measures (MMRM). The model will include effects for visit, 
Baseline HAMD-17 total score, and the Baseline HAMD-17 total 
score-by-visit interaction. An unstructured covariance matrix will be 
used to model the within-subject errors and the Kenward-Roger 
approximation will be used to adjust the denominator degrees of 
freedom. The treatment effect for the primary endpoint will be 
estimated as the least-squares mean change from Baseline to Week 8, 
and will be tested at a significance level of 0.05. In addition, the 
treatment effect will also be estimated at each of the other time points 
(Weeks 2, 4, and 6) using the same MMRM model described above, 
and will be considered secondary analyses. 
Continuous secondary efficacy endpoints (CGI-I, CGI-S, SCOPA, and 
EQ-5D-5L) will be analyzed using similar MMRM models as for the 
primary efficacy endpoint, except that the Baseline value of the 
endpoint being analyzed will be included in the model as a covariate 
instead of the Baseline HAMD-17 total score. For CGI-I the response 
is the CGI-I score (as opposed to the change from Baseline), and the 
Baseline CGI-S score will be used as the covariate.  
For each of the continuous efficacy endpoints, in addition to MMRM, a 
paired t-test using a last observation carried forward imputation method 
will be performed at each visit. 
For the HAMD-17 responder endpoints (≥50% reduction from 


Study: ACP-103-048 
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Baseline in HAMD-17 total score), the proportion of responders will 
be summarized by visit, including 95% confidence intervals.  
Observed cases (subjects with missing values at a given visit are 
excluded) as well as missing values imputed as non-responders will 
be presented. 
Safety Analyses 
Safety endpoints will be summarized using descriptive statistics. 
UPDRS Part III and MMSE will be analyzed using similar MMRM 
models as for the primary efficacy endpoint, except that the Baseline 
value of the endpoint being analyzed (either UPDRS Part III or 
MMSE) will be included as a covariate, and in the Baseline score-by-
visit interaction term, instead of the HAMD-17 total score.  
Adverse events will be classified into standard terminology using the 
Medical Dictionary for Regulatory Activities (MedDRA). Treatment-
emergent adverse events (TEAEs), TEAEs leading to discontinuation, 
TEAEs related to study drug, TEAEs by maximum severity, serious 
adverse events (SAEs), and SAEs related to study drug will be 
summarized. 
Descriptive statistics for ECG, vital signs and weight, C-SSRS, 
MMSE, UPDRS Part III, and clinical laboratory parameters, including 
changes from Baseline, will be tabulated by time point. Additionally, 
categorical analyses will be conducted on the incidence of subjects 
with prolonged QTc intervals and changes in QTc intervals in 
accordance with International Council for Harmonisation (ICH) 
guidelines.  
Date 
8 January 2019 
 


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Figure S-1 
Schematic of Study Design for ACP-103-048 
 
 
 
 
 
 
 
 
 
 
Screening 3 weeks 
8 Weeks Open Label 
34 mg pimavanserin 
2 Week Safety 
Follow-up 
Screening 
Baseline 
Week 2 
Week 4 
Week 6 
Week 8 
End of Study 
Week 10 


Study: ACP-103-048 
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Table S–1 
Schedule of Assessments for ACP-103-048 
 
Screening 
Baseline 
Week 2 
Week 4 
Week 6 
EOT 
Week 8
g 
Safety 
Follow-up 
Week 10 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Study Day(s) 
-21 to -1 
1 
12 to 18 
26 to 32 
40 to 46 
54 to 60 
68 to 74 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/exclusion assessment 
X 
X 
 
 
 
 
 
MGH ATRQa 
X 
 
 
 
 
 
 
Medical history and demographics 
X 
 
 
 
 
 
 
Weight, height, BMI 
X 
Xf 
 
 
 
Xf 
 
Physical and neurological examination 
X 
 
 
 
 
X 
 
12-lead ECG
b 
X 
X 
X 
 
 
X 
 
Vital signsc 
X 
X 
X 
X 
X 
X 
 
Clinical laboratory testsd 
X 
X 
 
 
 
X 
 
Screen for drugs of abuse 
X 
X 
 
 
 
 
 
Pregnancy test
e 
X 
X 
 
 
 
X 
 
HAMD-17 
X 
X 
X 
X 
X 
X 
 
C-SSRS 
X 
X 
X 
X 
X 
X 
 
MMSE 
X 
X 
 
X 
 
X 
 
CGI-I 
 
 
X 
X 
X 
X 
 
CGI-S 
 
X 
X 
X 
X 
X 
 
SCOPA 
 
X 
 
X 
 
X 
 
EQ-5D-5L 
 
X 
 
X 
 
X 
 
UPDRS Part III 
 
X 
 
X 
 
X 
 
Dispense study drug 
 
X 
 
X 
 
 
 
Study drug accountability 
 
 
X 
X 
X 
X 
 
Phone Follow-Up 
 
 
 
 
 
 
X 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
AE assessment 
X 
X 
X 
X 
X 
X 
X 
Abbreviations and notes to this table are on the next page: 


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Abbreviations: AE=adverse event; BMI=body mass index; C-SSRS=Columbia-Suicide Severity Rating Scale; CGI-I=Clinical Global Impression–Improvement; 
CGI-S=Clinical Global Impression–Severity; ECG=electrocardiogram; EOT=end of treatment; EQ-5D-5L=EuroQol-5 dimensions-5 levels; 
HAMD-17=Hamilton Depression Scale–17 Item; MGH ATRQ=Massachusetts General Hospital Antidepressant Treatment Questionnaire; MMSE=Mini-
Mental State Exam; SCOPA-Sleep=Scales for Outcomes in Parkinson’s Disease-Sleep; UPDRS Part III=Unified Parkinson's Disease Rating Scale Part III. 
Notes: 
a 
Applicable only to subjects who are currently taking an antidepressant.  
b 
12-lead ECG at Screening is to be completed in triplicate within a 3 minute period. The ECG may be repeated once at Screening in consultation with the 
Medical Monitor. Single ECG recordings are to be collected at subsequent visits. ECGs can be performed any time before blood sampling or at least 
30 minutes after blood sampling during clinic visits  
c 
Vital signs (sitting or supine [at least 3 minutes] blood pressure, pulse rate, oral temperature, and respiratory rate) will be performed at Screening and each 
study visit. 
d 
Thyroid-stimulating hormone (TSH) will only be assessed at Screening. TSH will not be analyzed as part of the chemistry serum testing at other study visits. 
e 
Applicable only to women of childbearing potential. A serum pregnancy test is performed at Screening and a urine pregnancy test at Baseline and Week 8. 
f 
Only weight will be measured after Screening. 
g 
Subject terminating early should at a minimum complete assessments of safety (vital signs, ECG, AEs, clinical laboratories, C-SSRS) and, if possible, 
complete all Week 8 assessments. 
 


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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ............................................................................................... 2 
DECLARATION OF INVESTIGATOR ................................................................................... 3 
PROTOCOL SYNOPSIS ........................................................................................................... 4 
TABLE OF CONTENTS ......................................................................................................... 15 
LIST OF TABLES ................................................................................................................... 19 
LIST OF FIGURES ................................................................................................................. 19 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................. 20 
1 
INTRODUCTION ...................................................................................................... 22 
1.1 
Background Information ............................................................................................ 22 
1.2 
Investigational Product ............................................................................................... 23 
1.3 
Previous Clinical Experience ..................................................................................... 23 
1.3.1 
Parkinson’s Disease Psychosis Program .................................................................... 24 
1.3.2 
Alzheimer’s Disease Psychosis .................................................................................. 25 
1.4 
Study Rationale .......................................................................................................... 27 
2 
STUDY OBJECTIVES AND ENDPOINTS .............................................................. 28 
2.1 
Primary Objective....................................................................................................... 28 
2.1.1 
Primary Endpoint ....................................................................................................... 28 
2.2 
Secondary Objectives ................................................................................................. 28 
2.2.1 
Secondary Endpoints .................................................................................................. 28 
2.3 
Safety Objective ......................................................................................................... 28 
2.3.1 
Safety Endpoints......................................................................................................... 28 
3 
STUDY DESCRIPTION ............................................................................................ 29 
3.1 
Overview of Study Design ......................................................................................... 29 
3.2 
Screening Period (1-21 Days) .................................................................................... 29 
3.3 
Treatment Period (8 Weeks) ....................................................................................... 29 
3.4 
Safety Follow-up Period (Approximately 2 Weeks) .................................................. 30 
4 
SUBJECT ELIGIBILTY AND WITHDRAWAL CRITERIA.................................... 30 
4.1 
Subject Selection and Withdrawal .............................................................................. 30 
4.2 
Inclusion Criteria ........................................................................................................ 30 
4.3 
Exclusion Criteria ....................................................................................................... 32 
4.4 
Subject Withdrawal or Termination ............................................................................ 34 


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4.5 
Prior and Concomitant Therapy ................................................................................. 35 
4.5.1 
Permitted, Restricted, and Prohibited Medications .................................................... 35 
5 
INVESTIGATIONAL PRODUCT ............................................................................. 36 
5.1 
Investigational Product Description ........................................................................... 36 
5.1.1 
Formulation, Appearance, Packaging, and Labeling .................................................. 36 
5.1.2 
Product Storage and Stability ..................................................................................... 36 
5.1.3 
Dosing and Administration ......................................................................................... 37 
5.1.4 
Blinding ...................................................................................................................... 37 
5.1.5 
Study Drug Compliance ............................................................................................. 37 
5.1.6 
Overdose ..................................................................................................................... 37 
5.2 
Investigational Product Accountability Procedures ................................................... 37 
6 
STUDY PROCEDURES ............................................................................................ 37 
6.1 
Screening Assessments ............................................................................................... 38 
6.1.1 
Mini-Mental State Examination ................................................................................. 38 
6.1.2 
Medical History and Demographics ........................................................................... 38 
6.1.3 
Massachusetts General Hospital Antidepressant Treatment Response 
Questionnaire.............................................................................................................. 38 
6.2 
Efficacy Assessments ................................................................................................. 38 
6.2.1 
Hamilton Depression Scale–17 item .......................................................................... 38 
6.2.2 
Clinical Global Impression–Severity and Improvement Scales ................................. 39 
6.2.3 
Scale of Outcomes in Parkinson’s Disease - Sleep Scale .......................................... 39 
6.2.4 
EQ-5D-5L ................................................................................................................... 39 
6.3 
Safety Assessments..................................................................................................... 39 
6.3.1 
Physical Examinations ............................................................................................... 39 
6.3.2 
Neurological Examination .......................................................................................... 40 
6.3.3 
Vital Signs .................................................................................................................. 40 
6.3.4 
Height, Weight, and Body Mass Index ....................................................................... 40 
6.3.5 
Electrocardiograms ..................................................................................................... 40 
6.3.6 
Columbia-Suicide Severity Rating Scale ................................................................... 40 
6.3.7 
Unified Parkinson’s Disease Rating Scale ................................................................. 41 
6.3.8 
Laboratory Evaluations .............................................................................................. 41 
6.3.9 
Safety Follow-up ........................................................................................................ 43 
6.4 
Unscheduled Visits ..................................................................................................... 43 
7 
ADVERSE EVENTS ................................................................................................. 43 
7.1 
Specification of Safety Parameters............................................................................. 43 
7.1.1 
Definition of Adverse Event ....................................................................................... 43 


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7.1.2 
Definition of Serious Adverse Event .......................................................................... 44 
7.2 
Classification of an Adverse Event ............................................................................ 46 
7.2.1 
Severity of Event ........................................................................................................ 46 
7.2.2 
Relationship to Study Drug ........................................................................................ 46 
7.2.2.1 Duration ...................................................................................................................... 46 
7.2.2.2 Frequency ................................................................................................................... 46 
7.2.2.3 Action Taken with Study Drug ................................................................................... 47 
7.2.2.4 Therapy ....................................................................................................................... 47 
7.2.2.5 Outcome ..................................................................................................................... 47 
7.2.2.6 Seriousness ................................................................................................................. 47 
7.2.3 
Definition of Unexpectedness .................................................................................... 47 
7.3 
Time Period and Frequency for Event Assessment and Follow-up ........................... 47 
7.4 
Reporting Procedures ................................................................................................. 47 
7.4.1 
Adverse Event Reporting ........................................................................................... 47 
7.4.2 
Serious Adverse Event Reporting............................................................................... 48 
7.4.3 
Reporting of Pregnancy .............................................................................................. 49 
7.4.4 
Reporting of Overdose ............................................................................................... 49 
8 
CLINICAL MONITORING ....................................................................................... 49 
9 
STATISTICAL METHODS AND DATA ANALYSIS .............................................. 50 
9.1 
Statistical and Analytical Plans .................................................................................. 50 
9.2 
Description of Statistical Methods ............................................................................. 50 
9.3 
Handling of Dropouts and Missing Data .................................................................... 50 
9.4 
Sample Size Determination ........................................................................................ 50 
9.5 
Unblinding .................................................................................................................. 51 
9.6 
Additional Subgroup Analyses ................................................................................... 51 
9.7 
Study Subjects ............................................................................................................ 51 
9.7.1 
Analysis Sets .............................................................................................................. 51 
9.7.2 
Subject Accountability and Subject Disposition ........................................................ 51 
9.7.3 
Demographics and Baseline Characteristics .............................................................. 51 
9.8 
Efficacy Analyses ....................................................................................................... 51 
9.8.1 
Primary Efficacy Analyses ......................................................................................... 52 
9.8.2 
Secondary Efficacy Analyses ..................................................................................... 52 
9.9 
Safety Analyses .......................................................................................................... 53 
9.9.1 
Adverse Events ........................................................................................................... 53 
9.9.2 
Concomitant Medications........................................................................................... 53 


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9.9.3 
Clinical Laboratory Values ......................................................................................... 54 
9.9.4 
Vital Signs and Body Weight ..................................................................................... 54 
9.9.5 
Electrocardiogram ...................................................................................................... 54 
9.9.6 
Physical Examination ................................................................................................. 54 
9.9.7 
Suicidal Ideation and Behavior .................................................................................. 54 
9.9.8 
Mini Mental State Examination ................................................................................. 54 
9.9.9 
UPDRS Part III ........................................................................................................... 55 
10 
STUDY MANAGEMENT AND DATA COLLECTION .......................................... 55 
10.1 
Data Collection and Management Responsibilities.................................................... 55 
10.2 
Source Documents ...................................................................................................... 55 
10.3 
Case Report Forms ..................................................................................................... 55 
10.4 
Confidentiality ............................................................................................................ 55 
10.5 
Study Records Retention ............................................................................................ 56 
10.6 
Protocol Exceptions and Deviations........................................................................... 56 
10.7 
Protocol Amendments ................................................................................................ 56 
11 
STUDY MONITORING, AUDITING, AND INSPECTING .................................... 57 
11.1 
Quality Control and Quality Assurance...................................................................... 57 
12 
ETHICAL CONSIDERATIONS ................................................................................ 57 
12.1 
Ethical Standard ......................................................................................................... 57 
12.2 
Institutional Review Board/Ethics Committee ........................................................... 58 
12.3 
Informed Consent Process .......................................................................................... 58 
12.3.1 Consent and Other Informational Documents Provided to Subjects .......................... 58 
12.3.2 Consent Procedures and Documentation .................................................................... 58 
13 
PUBLICATION PLAN .............................................................................................. 59 
14 
CONFLICT OF INTEREST POLICY ....................................................................... 59 
14.1 
Finance, Insurance, and Indemnity............................................................................. 59 
15 
LITERATURE REFERENCES .................................................................................. 60 
16 
APPENDICES ............................................................................................................ 63 
Appendix A  Prohibited and Restricted Medications ............................................................ 63 
Appendix B Prohibited and Restricted Concomitant Medications: Inhibitors and 
Inducers of Cytochrome P450 Enzyme 3A4 .............................................................. 67 
 


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LIST OF TABLES 
Table S–1 
Schedule of Assessments for ACP-103-048 .................................................... 13 
Table 1-1 
NPI-NH Psychosis Score Percent Responder Analysis – Full Analysis Set 
– Week 6 (Day 43) ........................................................................................... 26 
Table 1-2 
Receptor Profiles of Pimavanserin and Compounds With Antidepressant 
Activity ............................................................................................................ 27 
Table 6-1 
Safety Laboratory Evaluations......................................................................... 43 
 
LIST OF FIGURES 
Figure S-1 
Schematic of Study Design for ACP-103-048 ................................................. 12 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Term 
Definition 
AD 
Alzheimer’s disease 
ADHD 
attention deficit hyperactivity disorder 
ADP 
Alzheimer’s disease psychosis 
AE(s) 
adverse event(s) 
BMI 
Body mass index 
CGI-I 
Clinical Global Impression-Improvement 
CGI-S 
Clinical Global Impression-Severity 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DPD 
depression in Parkinson’s disease 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition  
EC 
ethics committee 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EOT 
end-of-treatment 
EQ-5D-5L 
EuroQol-5 dimensions-5 levels 
FAS 
Full Analysis Set 
FDA 
United States Food and Drug Administration 
GCP 
Good Clinical Practice 
HbA1c 
glycosylated hemoglobin 
HAMD-17 
Hamilton Depression Scale–17 items 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonisation  
IRB 
institutional review board 
IUD 
intrauterine device 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGH ATRQ 
Massachusetts General Hospital Antidepressant Treatment 
Questionnaire 
MMRM 
mixed model repeated measures 
MMSE 
Mini-Mental State Examination 
NIMH 
National Institute of Mental Health 
NINDS 
National Institute of Neurological Disorders and Stroke 
NPI-NH 
Neuropsychiatric Inventory-Nursing Home Version 
NYHA 
New York Heart Association 
PD 
Parkinson’s disease 
PDP 
Parkinson’s disease psychosis 


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Term 
Definition 
QoL 
Quality of Life 
SAE(s) 
serious adverse event(s) 
SAP 
Statistical Analysis Plan 
SCOPA 
Scale of Outcomes in PD-Sleep Scale 
SSRI/SNRI 
selective serotonin reuptake inhibitor/selective norepinephrine 
reuptake inhibitor 
T4 
reflex free thyroxine 
TEAE(s) 
treatment emergent adverse event(s) 
TSH 
thyroid-stimulating hormone 
UPDRS 
Unified Parkinson's Disease Rating Scale 
US 
United States 
WHO 
World Health Organization 


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1 INTRODUCTION 
This document is a research protocol and the described study will be conducted in 
compliance with the protocol and the International Council for Harmonisation (ICH) Good 
Clinical Practice Guideline (GCP). All key personnel (all individuals responsible for the 
design and conduct of this study) have completed or will complete human subjects protection 
training. 
1.1 
Background Information 
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized primarily 
by motor deficits; however, there are also associated behavioral symptoms that are frequent, 
severe, and disabling. Mood disorders and, in particular, depression occur in approximately 
50% of patients with PD, can occur at any stage, and increase in duration and severity as the 
disease progresses (Marsh 2013). Symptoms of depression in Parkinson’s disease (DPD) are 
associated with increased morbidity and diminished quality of life. Conversely, improved 
depression is associated with reduced physical disability and improved quality of life 
(Menza et al. 2009). The pathophysiology and underlying mechanisms of DPD are unknown. 
Psychological factors related to the progressive disability in this incurable disease are likely 
to contribute significantly. In addition, involvement of widespread neurodegeneration and 
dysregulation, particularly in the mesolimbic system, can also contribute to depression. 
Regardless of the cause, the presence of DPD is a significant concern that requires treatment 
to improve the patient’s quality of life. 
It is important to note that, in the diagnosis of depression, consideration should be given to 
motor deficits associated with PD, particularly decreased activity, cognitive dysfunction, and 
somatic complaints, which can complicate the diagnosis using standard Diagnostic and 
Statistical Manual of Mental Disorders-Fifth Edition (DSM-5) criteria (Goodarzi et al. 2016). 
To address the unique challenges in the diagnosis of DPD, a National Institute of 
Neurological Disorders and Stroke/ National Institute of Mental Health (NINDS/NIMH) Task 
Force has developed recommendations for the diagnosis of DPD (Marsh et al. 2006). 
Recommendations for an appropriate diagnosis of DPD, which will be applied in this study, 
include: (1) an inclusive approach to symptom assessment to enhance reliability of ratings in 
PD and avoid the need to attribute symptoms to a particular cause; (2) the inclusion of 
subsyndromal depression in clinical research studies of depression of PD; (3) the 
specification of timing of assessments for PD patients with motor fluctuations; and (4) the 
use of informants for cognitively impaired patients (Marsh et al. 2006).  
After a diagnosis of DPD has been made, treatment options are to be considered. Behavioral 
interventions appear to have some benefit; however, behavioral therapies typically have at 


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best modest benefit with a large degree of variability (Xie et al. 2015). In general, traditional 
antidepressants have been found to be safe and well tolerated and have efficacy in DPD, 
although the time course and magnitude of response can differ (Liu et al. 2013; 
Moonen et al. 2014; Rocha et al. 2013). As in the general population, despite the availability 
of numerous pharmacological and psychological treatment options, residual depressive 
symptoms are often evident despite a significant response to an antidepressant medication or 
other intervention (Marsh 2013; Rush et al. 2006). Patients with PD may benefit less from 
antidepressant treatment, particularly selective serotonin reuptake inhibitors, than do elderly 
patients without PD (Weintraub et al. 2005). 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.  
1.2 
Investigational Product 
Pimavanserin is an atypical antipsychotic that is present in the investigational product as 
pimavanserin tartrate salt with the chemical name, urea, N-[(4-fluorophenyl)methyl]-N-(1-
methyl-4-piperidinyl)-N’-[[4-(2-methylpropoxy)phenyl]methyl]-,(2R,3R)-2,3-
dihydroxybutanedioate (2:1). In April 2016, pimavanserin was approved in the United States 
(US) for the treatment of hallucinations and delusions associated with Parkinson’s disease 
psychosis (PDP). 
Pimavanserin is a novel small molecule designed to specifically block serotoninergic 
neurotransmission mediated by the 5-hydroxytryptamine (5-HT [serotonin]) 2A (5-HT2A) 
receptor. At higher doses, pimavanserin may block 5HT2C receptors (Vanover et al. 2006). 
Pimavanserin shows no appreciable activity at dopaminergic, adrenergic, histaminergic, or 
muscarinic receptors. Activity at these receptors has been implicated in a range of 
dose-limiting side effects associated with existing antipsychotic drugs including cognitive 
dulling (Saeedi et al. 2006; Mehta et al. 2004; Peretti et al. 1997) and an increased risk of 
mortality in elderly patients with dementia (Wang et al. 2005). On the basis of its novel 
receptor binding profile, pimavanserin may be effective in treating behavioral problems and 
mood disorders, and have added benefits with regard to overall tolerability relative to other 
antipsychotic agents. 
In this study, subjects will be asked to take pimavanserin tablets once daily as an oral 
formulation. 
1.3 
Previous Clinical Experience 
Pimavanserin is an atypical antipsychotic that is approved for the treatment of hallucinations 
and delusions associated with PDP. Studies have also been conducted in Alzheimer’s disease 


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psychosis (ADP) and schizophrenia and studies are ongoing in schizophrenia, Alzheimer’s 
disease agitation and aggression, and major depressive disorder. The clinical program for 
PDP and the Phase 2 ADP study are reviewed below as the study population (elderly 
subjects) is most closely aligned with the intended study population of this protocol. A more 
complete discussion of these studies, as well as other completed and ongoing pimavanserin 
clinical studies, is available in the pimavanserin Investigator’s Brochure (IB).
1.3.1 
Parkinson’s Disease Psychosis Program
The scope of the development program for pimavanserin is the largest ever conducted in 
PDP. At the time of approval, 616 mostly older, late-stage PDP subjects had been evaluated in 
16 countries over a span of >10 years. Clinically meaningful efficacy was established in 
Study ACP-103-020, a 6-week, placebo-controlled Phase 3 study. This efficacy was 
supported by data from additional short-term Phase 2b/3 studies. In ACP-103-020, 
pimavanserin 34 mg consistently demonstrated statistically significant efficacy across 
multiple and independent endpoints, subject subgroups, and sensitivity analyses. 
Improvements in sleep and daytime wakefulness were also observed. These clinical benefits 
were achieved without worsening of PD motor symptoms and without a number of other 
safety concerns associated with atypical antipsychotics.
Pimavanserin is considered to be generally safe and well tolerated. Across all clinical studies 
of pimavanserin, the most frequently reported treatment-emergent adverse events (TEAEs) 
were in the central nervous system (CNS), gastrointestinal, and psychiatric systems. Most 
events were mild to moderate in intensity. The most common CNS TEAEs included dizziness 
(including postural), headache, and somnolence (drowsiness). Common gastrointestinal 
disturbances included dyspepsia, nausea, constipation, and vomiting. Severe nausea and 
vomiting were dose limiting in a few cases. Reported psychiatric conditions included 
agitation, insomnia, and confusional state. Refer to the current IB for the most up-to-date 
Reference Safety Information for pimavanserin.
Clinical and nonclinical safety pharmacology studies of pimavanserin suggest a potential risk 
for QT prolongation. The magnitude of effect in humans has been assessed in a thorough QT 
study with doses of pimavanserin ranging from 17 to 68 mg. In the Phase 3 PDP program, an 
average prolongation of approximately 5 to 8 ms was observed with pimavanserin 34 mg.
The US package insert for pimavanserin has a boxed warning that elderly patients with 
dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. 
Pimavanserin is not approved in the treatment of patients with dementia-related psychosis 
unrelated to the hallucinations and delusions associated with PDP.


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Additional information is provided in the pimavanserin IB and in the NUPLAZID® 
(pimavanserin) US package insert. 
1.3.2 
Alzheimer’s Disease Psychosis 
Evidence from the recently completed Phase 2 study (ACP-103-019) suggests that 
pimavanserin is effective in reducing hallucinations and delusions in subjects with ADP. 
Study ACP-103-019 was a Phase 2, 12-week randomized, double-blind, placebo-controlled, 
single-center study to assess the safety and efficacy of pimavanserin 34 mg once daily in 
nursing home subjects with ADP. Eligible subjects were required to have a score of 4 or 
greater on either the hallucinations or delusions scale of the Neuropsychiatric Inventory-
Nursing Home Version (NPI-NH) or a combined hallucinations and delusions score of 6 or 
greater. The primary efficacy endpoint was change from Baseline to Day 43 in the NPI-NH 
psychosis score (delusions+hallucinations domains). 
A total of 181 subjects were randomized (n=90 pimavanserin 34 mg and n=91 placebo) with 
178 subjects included in the Full Analysis Set (FAS) (n=87 pimavanserin and n=91 placebo). 
The mean (standard error [SE]) age of subjects was 85.9 (0.48) years. The mean (SE) 
Baseline NPI-NH psychosis score for all FAS subjects was 9.8 (0.39) with comparable mean 
scores in the pimavanserin (9.5) and placebo (10.0) groups. The mean (SE) Mini-mental State 
Examination (MMSE) score for all FAS subjects was 10.1 (0.40). 
Efficacy results for the primary endpoint (NPI-NH psychosis score after 6 weeks of treatment 
[Day 43] demonstrated a significant (p=0.0451; effect size [Cohen’s d]= -0.320) treatment 
effect for pimavanserin compared with placebo. Prespecified subgroup analyses supported a 
clinically relevant treatment effect in the pimavanserin group, as a larger effect size was 
generally observed in subjects with more severe psychosis. Similarly, the proportion of 
responders (subjects with 30% and 50% reductions from Baseline) was statistically 
significantly greater in the pimavanserin group compared to placebo (Table 1-1). On the 
endpoint of mean change in NPI-NH psychosis score at Week 12, pimavanserin achieved 
improvement to Week 12 but the difference from placebo was not maintained due to an 
observed improvement in the mean score in the placebo group between Weeks 6 and 12. 
 


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Table 1-1 
NPI-NH Psychosis Score Percent Responder Analysis – Full 
Analysis Set – Week 6 (Day 43) 
 
Percent Improvement from Baseline 
Treatment Group 
(% Responder) 
≥20% 
≥30% 
≥50% 
≥75% 
100% 
 
Pimavanserin 34 mg 
58.6% 
55.2% 
50.6% 
27.6% 
12.6% 
 
Placebo 
46.2% 
37.4% 
34.1% 
16.5% 
9.9% 
p-value for test of group difference 
0.0937 
0.0159 
0.0240 
0.0656 
0.5514 
Source: ACP-103-019 Clinical Study Report 
Note: Missing values were imputed as nonresponders. 
 
With respect to safety, pimavanserin appeared to be well-tolerated with no new safety 
observations in this elderly and frail patient population compared to the pimavanserin PDP 
safety database. An equal number of post-randomization deaths were reported: 4 deaths in the 
pimavanserin group and 4 in the placebo group. 
There were more serious adverse events (SAEs) reported in pimavanserin group (16.7%) than 
in the placebo group (11.0%). A review of the reported SAEs, both in the placebo and 
pimavanserin groups, did not reveal the presence of any common, underlying 
pathophysiologic mechanism or cause.  However, there were fewer discontinuations due to 
treatment emergent adverse events (TEAEs) in the pimavanserin group (8.9%) compared 
with the placebo group (12.1%). 
The most common TEAEs in the pimavanserin group were fall (23.3%), urinary tract 
infection (22.2%), and agitation (21.1%), which have been described as associated with this 
elderly frail patient population. Of these, agitation was reported more often in the 
pimavanserin group than in the placebo group. 
The mean change from Baseline in the QTc interval in subjects treated with pimavanserin 
was 9.4 ms at 12 weeks (Day 85) with no significant outliers reported at Day 85 (>500 ms or 
delta ≥60 ms). One subject in the pimavanserin group and one subject in the placebo group 
had a delta ≥60 ms at Day 15. Each subject continued in the study. 
Weight data were available for about half of the study participants at Day 85. Mean body 
weight and body mass index (BMI) remained relatively unchanged from Baseline to Day 85 
in both treatment groups. Overall, 1 (1.8%) subject in the placebo group and 7 (14.6%) 
subjects in the pimavanserin group experienced weight decrease of ≥7% and 5 (8.8%) 
subjects in the placebo group and 4 (8.3%) subjects in the pimavanserin group experienced 
weight increase of ≥7%. 
Changes from Baseline in MMSE were similar in placebo and pimavanserin group indicating 
that pimavanserin did not affect cognitive function in these patients. Similarly, treatment with 


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pimavanserin had no negative effect on motor function as measured by the Unified 
Parkinson's Disease Rating Scale (UPDRS) Part III scores. 
1.4 
Study Rationale 
The rationale for the use of pimavanserin as monotherapy or adjunctive treatment for DPD 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 
serotonin, norepinephrine, and dopamine transporters, either alone or when co-administered 
with selective serotonin reuptake inhibitors (SSRIs; see Table 1-2). These compounds include 
volinanserin, pruvanserin, ketanserin, ritanserin, mirtazapine, mianserin, and trazodone (see 
Table 1-2). Pimavanserin, with its potent activity as a 5-HT2A antagonist/inverse agonist and 
lesser activity as a 5-HT2C antagonist/inverse agonist, has a similar receptor profile to many 
compounds with antidepressant activity. Therefore, although there are no preclinical data on 
pimavanserin in animal models of depression, it would also be expected to have 
antidepressant activity. 
Table 1-2 
Receptor Profiles of Pimavanserin and Compounds With 
Antidepressant Activity 
Target 
PIM 
RIT 
VOL 
PRUV 
PIP 
KET 
MIRT 
MIAN 
TRAZ 
SERT 
NET 
DAT 
Low 
Low 
Low 
Low 
Low 
Low 
Low 
Low 
Low 
na 
na 
na 
Low 
Low 
Low 
Low 
Low 
Low 
Low 
70 
Low 
350 
Low 
Low 
5-HT2A 
5-HT2C 
0.1 
3 
0.2 
125 
0.7 
Low 
5 
120 
2 
125 
70 
40 
3 
3 
35 
200 
Other 
noteworthy
targets 
None 
None 
None 
D4 (5) 
 
α2 (35) 
α1 (15-20) α2 (15-20) 
 
H1 (1) 
α2 (4-20) 
 
H1 (1) 
5-HT1A 
(100) 
Source: Data on file except for: pipamperone (Schotte et al. 1996); trazodone and mianserin (PDSP Ki database, 
see Roth et al. 2000); mirtazepine (Brayfield 2014); and (Wikström et al. 2002). 
Abbreviations: α1=alpha1 adrenergic receptor; α2=alpha2 adrenergic receptor; DAT=dopamine transporter; 
H1=histamine 1 receptor; KET=ketanserin; MIAN=mianserin; MIRT=mirtazepine; NET=norepinephrine 
transporter; PIM=pimavanserin; PIP=pipamperone; PRUV=pruvanserin; RIT=ritanserin; SERT=serotonin 
transporter; TRAZ=trazodone; VOL=volinanserin.  
Values represent the affinity (Ki) in nM of the indicated ligands and transporters/receptors. For “Other 
Noteworthy Targets”, Ki values are provided in parentheses. "na" denotes not available. Low denotes Ki 
>1000 nM. 
 


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2 STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objective 
To assess the efficacy of pimavanserin for the treatment of depression in adults with 
Parkinson’s disease 
2.1.1 
Primary Endpoint 
Change from Baseline to Week 8 in the Hamilton Depression Scale–17 items (HAMD-17) 
total score 
2.2 
Secondary Objectives 
To explore the efficacy of pimavanserin in the following domains: 
 Clinician’s global assessment of treatment benefits 
 Night time sleep and day time sleepiness 
 Quality of life 
2.2.1 
Secondary Endpoints 
 Clinical Global Impression-Improvement (CGI-I) 
 Change from Baseline in CGI-Severity (CGI-S) 
 Change from Baseline in Scale of Outcomes in PD-Sleep Scale (SCOPA) night time 
sleep score 
 Change from Baseline in SCOPA day time sleepiness score 
 Proportion of responders (defined as ≥50% reduction from Baseline in HAMD-17 total 
score)  
 Change from Baseline in EuroQol-5 dimensions-5 levels (EQ-5D-5L) 
2.3 
Safety Objective 
To assess the safety of pimavanserin for the treatment of depression in adults with 
Parkinson’s disease 
2.3.1 
Safety Endpoints 
The safety endpoints for this study are as follows: 
 Adverse events 
 Vital signs 
 12-lead electrocardiogram (ECG) 


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 Hematology, serum chemistry, urinalysis 
 Columbia Suicide Severity Rating Scale (C-SSRS) 
 Mini-Mental State Examination (MMSE) 
 Unified Parkinson's Disease Rating Scale (UPDRS) Part III 
3 STUDY DESCRIPTION 
3.1 
Overview of Study Design 
This will be a multi-center, open-label study to assess the efficacy and safety of treatment 
with 34 mg pimavanserin in subjects with PD and depression. Approximately 20 sites will 
participate in this study. Each subject will participate in a screening and treatment period with 
regularly scheduled assessments (see Figure S-1 and Table S–1). 
3.2 
Screening Period (1-21 Days) 
Subjects will be assessed for eligibility and prohibited medications will be discontinued. 
Screening will be up to 3 weeks. 
Investigators should not discontinue a subject’s prohibited medication for the purpose of 
enrolling them into the study. Medications should be discontinued only if it is deemed 
clinically appropriate to do so. Subjects who are currently taking an SSRI/SNRI and a second 
antidepressant or antidepressant augmentation agent at a sub-therapeutic dose or for an 
inadequate duration at Screening can discontinue the second antidepressant or antidepressant 
augmentation agent before the Baseline visit if, in the opinion of the Investigator, the current 
treatment has been inadequate. Current or previous treatment with an antidepressant is not 
required. The Medical Monitor may also be consulted.   
3.3 
Treatment Period (8 Weeks) 
After all screening assessments are completed, eligible subjects will return to the clinic for 
the Baseline evaluation. After Baseline assessments are completed, subjects will be enrolled 
and will begin receiving pimavanserin 34 mg once daily (QD). Study medication will be 
provided to the subjects to take home with instructions to take the medication approximately 
the same time each day. Drug should be dispensed at Baseline and Week 4, with returned 
used container(s) at Week 4 and all containers and unused drugs returned at Week 8.  
At approximately 2, 4, and 6 weeks after start of dosing of study drug, subjects will return to 
the clinic for assessments. Safety measures, HAMD-17, C-SSRS, CGI-S, and CGI-I will be 
evaluated at all visits. Subjects will complete the SCOPA, EQ-5D-5L, MMSE, and UPDRS 
Part III at Baseline and Week 4.  


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At the end of the 8 weeks of study drug treatment, subjects will return to the clinic for their 
final clinical evaluation. All assessments will be completed and unused study drug and 
containers will be collected. 
3.4 
Safety Follow-up Period (Approximately 2 Weeks) 
Approximately 2 weeks after the last dose of study drug, subjects will have a safety follow up 
telephone call visit. 
4 SUBJECT ELIGIBILTY AND WITHDRAWAL CRITERIA 
4.1 
Subject Selection and Withdrawal 
To be eligible for this study, subjects must meet all of the inclusion criteria and none of the 
exclusion criteria. 
Protocol waivers for eligibility will not be granted by the Sponsor under any circumstances. 
If, during the course of 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 
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. 
Subjects who screen fail will be allowed to re-screen with the permission of the Medical 
Monitor, provided the screen failure was due to a temporary condition that subsequently 
resolved. 
4.2 
Inclusion Criteria 
1. Is a male or female ≥50 years of age 
2. Can understand and provide signed informed consent, request for medical records 
and/or subject privacy form if applicable according to local regulations 
3. Is able to complete subject-reported outcome measures and can be reliably rated on 
assessment scales (in the opinion of the Investigator), and has a reliable study 
partner/caregiver (e.g., relative, housemate, close personal friend, or professional 
caregiver) who can report on the subject’s health-related quality of life 
4. Has a clinical diagnosis of idiopathic Parkinson’s disease with a minimum duration of 
1 year, defined as the presence of at least three of the following cardinal features, in 
the absence of alternative explanations or atypical features:  
a. rest tremor 
b. rigidity 
c. bradykinesia and/or akinesia 


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d. postural and gait abnormalities  
5. Meets clinical criteria for depression with Parkinson’s disease as listed in the 
NINDS/NIMH Guidelines (Marsh et al. 2006) 
6. Has a Hamilton Depression Scale–17 item (HAMD-17) total score ≥15 at Screening 
and Baseline  
7. If currently taking an antidepressant, is being treated with only one of the following 
SSRI or SNRI antidepressants at a dose within the United States Food and Drug 
Administration (US FDA)-approved dose range. Subjects who are currently taking a 
second antidepressant or antidepressant augmentation agent at a sub-therapeutic dose 
or for an inadequate duration at Screening, and can be discontinued from this agent 
before the Baseline visit (in the opinion of the Investigator), may be eligible for the 
study.  
a. Citalopram 
b. Escitalopram 
c. Paroxetine 
d. Fluoxetine 
e. Sertraline 
f. Vortioxetine 
g. Duloxetine 
h. Venlafaxine 
i. Desvenlafaxine 
j. Venlafaxine XR 
k. Vilazodone 
l. Levomilnacipran 
Current or previous treatment with an antidepressant is not required. Investigators 
should not withdraw a subject’s medication unless clinically appropriate (e.g., 
symptoms are not well controlled or the subject cannot tolerate the current 
medication). 
8. If the subject is currently taking an antidepressant and has an improvement in 
depression of  less than 75% when working at its best, as confirmed by the 
Massachusetts General Hospital Antidepressant Treatment Questionnaire 
(MGH ATRQ)  
9. Has a Mini Mental State Exam (MMSE) score ≥21  
10. Is on a stable dose of anti-Parkinson’s medication for at least 1 month prior to 
Screening  


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11. If the subject is female, she must be of non-childbearing potential (defined as either 
surgically sterilized [history of a bilateral oophorectomy, bilateral tubal ligation, or a 
partial or complete hysterectomy] or at least 1 year postmenopausal) OR must agree 
to use TWO clinically acceptable methods of contraception, if sexually active, 
throughout the study and for at least 1 month prior to the Baseline visit (Visit 2) and 
41 days following completion of the study. 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. 
12. 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  
4.3 
Exclusion Criteria 
1. Use of an antipsychotic within 3 weeks or 5 half-lives of Baseline (whichever is 
longer)  
2. Has greater than New York Heart Association (NYHA) Class 2 congestive heart 
failure or Class 2 angina pectoris, sustained ventricular tachycardia, ventricular 
fibrillation, or torsade de pointes, or syncope due to an arrhythmia 
3. Had a myocardial infarction within the 6 months prior to Screening  
4. Has a known personal or family history or symptoms of long QT syndrome  
5. Has any of the following ECG results at Screening (the ECG may be repeated once at 
Screening in consultation with the Medical Monitor):  
a. If the subject is not on citalopram, escitalopram, or venlafaxine 
i. 
QTcF >450 ms, if QRS duration <120 ms  
ii. 
QTcF >470 ms, if QRS duration ≥120 ms  
b. If the subject is on citalopram, escitalopram, or venlafaxine 
i. 
QTcF >425 ms, if QRS duration <120 ms 
ii. 
QTcF >450 ms, if QRS duration ≥120 ms 
6. Has clinically significant laboratory abnormalities that, in the judgment of the 
Investigator or Medical Monitor, would jeopardize the safe participation of the subject 
in the study  
7. Evidence of severe or medically significant hepatic or renal impairment on laboratory 
tests as assessed by the Investigator or Medical Monitor 
8. Has uncontrolled diabetes or a glycosylated hemoglobin (HbA1c) >8% at Screening  


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9. 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 
10. Has a body mass index (BMI) of <19 or >35 
11. Has a known history of a positive hepatitis B virus (HBV), hepatitis C virus (HCV), 
or human immunodeficiency virus (HIV) test 
12. Has a history of PD psychosis, 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. 
13. Has a current diagnosis of delirium 
14. Has a current primary diagnosis of borderline, antisocial, paranoid, schizoid, 
schizotypal, or histrionic personality disorder, according to DSM-5 criteria 
15. 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 
16. Has a positive test for an illicit drug at Screening or Baseline. Subjects who test 
positive for a controlled substance and who have a valid prescription can be enrolled 
if the drug is not a prohibited medication 
17. Actively suicidal at Visit 1 (Screening) or Visit 2 (Baseline) (including an answer of 
“yes” to Columbia Suicide Severity Rating Scale [C-SSRS] question 4 or 5 [current 
or over the last 6 months]) or has attempted suicide in the 2 years prior to Visit 1 
(Screening) 
18. Is pregnant or breastfeeding. Female subjects of child-bearing potential must have a 
negative serum pregnancy test at Screening 
19. Has major surgery planned during the trial (including Screening and follow-up 
periods)  
20. Has participated in or is participating in a clinical trial of any investigational drug, 
device, or intervention, within 60 days (or five half-lives, whichever is longer) prior 
to Screening 
21. Has previously been treated with pimavanserin or is currently taking pimavanserin 
22. Has a sensitivity to pimavanserin or its excipients 
23. Is judged by the Investigator or the Medical Monitor to be inappropriate for the study 


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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: 
 Lack of efficacy 
 Adverse event 
 Death 
 Lost to follow-up 
 Non-compliance with study drug 
 Use of prohibited medications 
 Physician decision 
 Pregnancy 
 Protocol deviation 
 Study terminated by Sponsor 
 Subject withdraws consent 
 Lack of a reliable caregiver/informant 
 Other 
If at any time the C-SSRS results for a given subject reveal potential suicidality, then the 
Investigator should assess the clinical significance of such results. If a clinically significant 
risk of suicidality is identified for a subject, then the Investigator should discontinue the 
subject and implement appropriate treatment (Section 6.3.6). 
Every reasonable effort should be made to complete the Visit 6 /end of treatment (EOT) and 
the safety follow-up period if a subject discontinues from the study for any reason. 
If a subject is lost to follow-up, every reasonable effort should be made to phone the subject 
approximately 2 weeks after last known contact with the subject in order to assess the 
subject’s current status. All phone or other contact with the subject should be documented. 
For subjects who continue to be followed for safety, SAEs should continue to be reported as 
described in Section 7.4.2. 


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If a subject is discontinued from the study because of an AE, every reasonable attempt should 
be made to follow the subject until the AE resolves or until the Investigator deems the AE to 
be chronic or stable. 
All SAEs will continue to be followed until such events have resolved or the Investigator 
deems them to be chronic or stable. 
Should a subject request or decide to withdraw, every reasonable effort will be made to 
complete and report observations as thoroughly as possible up to the date of withdrawal, 
including the evaluations specified at the EOT visit outlined in Table S–1. Unless the subject 
has withdrawn consent to be contacted for this study, every reasonable effort will be made to 
complete the 2-week safety follow-up telephone call for all subjects who withdraw 
prematurely. All information will be reported on the applicable pages of the electronic case 
report form (eCRF). 
The Sponsor reserves the right to discontinue the study at any time for any reason. Such 
reasons may include, but not be 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 
Regulatory Authorities also have the right to terminate the conduct of the study in their 
region for any reason. 
4.5 
Prior and Concomitant Therapy 
Lifetime antidepressant use and response is to be recorded. All other medications used within 
24 weeks prior to Visit 2 through Visit 7 (telephone visit) or EOT are to 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). 
4.5.1 
Permitted, Restricted, and Prohibited Medications 
Prohibitions and restrictions for concomitant medications, as specified in Appendix A and 
Appendix B, should be followed between Visit 1 (Screening) and Visit 6/EOT. Medications 
that can prolong QT interval are prohibited (or restricted if approved by the Medical Monitor 
or appropriate designee) as specified in Appendix A. These appendices do not constitute an 
exhaustive list and any questions regarding prohibited and restricted medications or the use 
of medications that could interfere with study conduct should be discussed with the Medical 
Monitor or appropriate designee. 


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If a subject is on a restricted or prohibited medication at Screening, the medication should be 
adjusted or discontinued only if it is determined by the Investigator to be clinically 
appropriate (e.g., if the subject's symptoms are not well-controlled or if the subject cannot 
tolerate the current medication). 
The Investigator may prescribe, adjust, or discontinue appropriate medication to treat or 
manage AEs. If a prohibited medication is prescribed to treat an AE, the subject may remain 
in the study if the Sponsor and Investigator (or designee) determines that it is appropriate for 
the subject to remain in the study. 
All other subjects who take a prohibited medication during the study will be discontinued, 
unless the discontinuation presents an unacceptable medical risk. The justification to allow a 
subject to continue in the study will be made by the Sponsor, with medical input from the 
Investigator, and will be documented. If a subject is allowed to remain in the study on 
prohibited medication that is not prescribed to treat an AE, this will be reported as a major 
protocol deviation and not a waiver. 
5 INVESTIGATIONAL PRODUCT 
5.1 
Investigational Product Description 
The investigational product will be pimavanserin 34 mg (provided as two 17 mg NUPLAZID 
tablets). Tablets will be administered orally as a single dose once daily (QD). 
5.1.1 
Formulation, Appearance, Packaging, and Labeling 
The Sponsor will supply pimavanserin (NUPLAZID) 17 mg tablets. 
NUPLAZID tablets are intended for oral administration only. Each round, white to off-white, 
immediate-release, film-coated tablet is debossed with “P” on one side and “17” on the 
reverse. Each 17 mg NUPLAZID tablet contains 20 mg of pimavanserin tartrate, which is 
equivalent to 17 mg of pimavanserin free base. Inactive ingredients include
 
 Additionally, the 
following inactive ingredients are present as components of the film coat:
 
 
During the treatment period, study drug will be supplied in 60 count bottle(s) 
(NDC 63090-170-60). Bottle(s) will be distributed in a quantity sufficient to ensure the 
subject has an adequate supply of study drug between study visits. 
5.1.2 
Product Storage and Stability 
Study drug Investigational product must be stored at 20°C to 25°C (68°F to 77°F); excursions 
permitted between 15°C and 30°C (59°F and 86°F) (see US Pharmacopeia [USP] Controlled 


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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; study drug will then be 
dispensed to the subject to take home. Each daily dose consists of 2 individual tablets that 
should be taken together. Subjects should be instructed to take 2 whole tablets, orally, once 
each day. Subjects should be instructed to not crush the tablets. The tablets may be taken with 
or without food. 
5.1.4 
Blinding 
This is an unblinded, open-label study. Subjects, site staff, and the sponsor will be aware that 
the subject is on a 34 mg dose of pimavanserin. 
5.1.5 
Study Drug Compliance 
If a subject misses 1 dose of study drug, he or she should not take an extra dose the next day. 
5.1.6 
Overdose 
An overdose is a deliberate or inadvertent administration of a treatment at a dose higher than 
the maximum recommended dose per protocol. It must be reported, irrespective of outcome, 
even if toxic effects were not observed (Section 7.4.4). All events of overdose are to be 
captured as protocol deviations. 
5.2 
Investigational Product Accountability Procedures 
The 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 the Sponsor 
that the study drug is being handled appropriately. Subjects should be instructed to return all 
NUPLAZID bottles and unused tablets to the Investigator at regularly scheduled clinic visits 
and at the Week-8 (EOT) visit.  
At the conclusion of the study, final study drug reconciliation will be conducted at the site. 
Final study drug accountability documentation will be maintained at both the site and at the 
Sponsor. Any remaining unused study drug and all used and unused packaging will be 
destroyed at the study site or returned to the Sponsor or its designee as per the applicable 
regulations. Documentation of study drug destruction will be recorded and maintained by 
both the Sponsor and the Sponsor’s designee. 
6 STUDY PROCEDURES 
Study-specific procedures are detailed below. All assessments will be completed according to 
the schedule described in Table S–1. Every reasonable effort should be made to complete the 
required procedures and evaluations at the designated visits and times. 


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6.1 
Screening Assessments 
6.1.1 
Mini-Mental State Examination 
The MMSE is a brief 30-point questionnaire that is used to quantitatively assess cognition 
(Folstein et al. 1975). The MMSE includes simple questions and problems in a number of 
areas: the time and place of testing, repeating lists of words, arithmetic, language use and 
comprehension, and copying a drawing. The MMSE is being used in this study to screen for 
cognitive impairment and it will also be used for safety assessment at other time points. 
6.1.2 
Medical History and Demographics 
A complete medical history will be obtained from each potential subject, including details of 
the subject’s PD and DPD diagnoses and treatments (including approximate dates of onset). 
Subjects may be asked to provide pharmacy or medical records to substantiate the medication 
history (Section 4.5). 
Demographic information, including date of birth, sex, race, and ethnicity will be recorded as 
well. Any new medical condition reported after the ICF has been signed will be captured as 
an AE. 
6.1.3 
Massachusetts General Hospital Antidepressant Treatment Response 
Questionnaire 
The MGH ATRQ (Fava and Davidson 1996; Fava 2003) is a clinician-assisted questionnaire 
that is to be completed only for subjects who are currently taking an antidepressant at 
Screening. The MGH ATRQ 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 Chandler et al. 2010). If taking an approved SSRI/SNRI, subjects 
should be exposed to an antidepressant for at least 4 weeks at a dose appropriate for this 
population.  
6.2 
Efficacy Assessments 
6.2.1 
Hamilton Depression Scale–17 item 
The Hamilton Depression Scale–17 items (HAMD-17), is a multiple item questionnaire used 
to provide an indication of depression, and as a guide to evaluate recovery (Hamilton 1960). 
The questionnaire is designed for adults to rate the severity of depression by probing mood, 
feelings of guilt, suicide ideation, insomnia, agitation or retardation, anxiety, weight loss, and 
somatic symptoms. Each item on the questionnaire is scored on a 3 or 5 point scale, 
depending on the item, and the total score is compared to the corresponding descriptor. A 


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score of 0-7 is considered to be normal. Scores of 14 or higher indicate moderate, severe, or 
very severe depression. Assessment time is estimated at 20 minutes. 
6.2.2 
Clinical Global Impression–Severity and Improvement Scales 
The CGI-S scale is a clinician-rated, 7-point scale that is designed to rate the severity of the 
subject’s depression at the time of assessment using the Investigator’s judgment and past 
experience with subjects who have the same disorder (i.e., depression in Parkinson’s disease) 
(Guy 1976). 
The CGI-I is a clinician-rated, 7-point scale that is designed to rate the improvement in the 
subject’s depression at the time of assessment, relative to the symptoms at Baseline.  
6.2.3 
Scale of Outcomes in Parkinson’s Disease - Sleep Scale 
The SCOPA Sleep Scale was developed for research in Parkinson disease to evaluate 
nighttime sleep and daytime sleepiness (Marinus et al. 2003). This scale has high internal 
consistency for the nighttime sleep and daytime sleepiness scales (0.88 and 0.91, 
respectively), and test-retest reliabilities (0.94 and 0.89, respectively). Scores on the SCOPA 
Sleep Scale show high correlations between the nighttime sleep scale and the Pittsburgh 
Sleep Quality Index (0.83), and between the daytime sleepiness scale and the Epworth 
Sleepiness Scale (0.81). The coefficient of variation of both the nighttime sleep and the 
daytime sleepiness scale is higher than that of the Pittsburgh Sleep Quality Index and the 
Epworth Sleepiness Scale, indicating a better ability to detect differences between 
individuals. 
6.2.4 
EQ-5D-5L 
The EQ-5D-5L is a standardized instrument used as a measure of health outcome 
(Kind 1996). It measures 5 dimensions (mobility, self-care, usual activities, pain/discomfort, 
anxiety/depression), each of which has 5 potential responses. The responses record 5 levels of 
severity (no problems/slight problems/moderate problems/severe problems/extreme 
problems) within a particular EQ-5D dimension. The EQ-5D-5L Proxy Version 1 will be 
used. For this version, a study partner/caregiver (the proxy) is asked to rate subject's 
health-related quality of life in their (the proxy’s) opinion. 
6.3 
Safety Assessments 
6.3.1 
Physical Examinations 
A general physical examination will be conducted. The physical exam procedures will 
include the following organ systems: 
 Head, ears, eyes, nose, and throat 
 Skin 


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 Cardiovascular 
 Respiratory 
 Abdomen 
 Genitourinary (optional) 
 Musculoskeletal 
 Lymph nodes 
6.3.2 
Neurological Examination 
A neurological examination (cranial nerves, motor, sensory, reflexes, gait, and coordination) 
will be conducted. 
6.3.3 
Vital Signs 
Vital signs will include resting respiration rate, sitting systolic and diastolic blood pressure, 
temperature, and pulse rate. The resting blood pressure should be measured after the subject 
has been sitting or supine for ≥3 minutes. 
6.3.4 
Height, Weight, and Body Mass Index 
Height will be measured in centimeters. 
Weight will be measured in kilograms. 
Body mass index (BMI) will be calculated using the following formula: 
Weight (kg) / [height (m)]2 
6.3.5 
Electrocardiograms 
All 12-lead ECGs will be complete, standardized recordings. 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, QRS, QT, QTcF, and QTcB intervals) will be included and summarized in the subject's 
study records. The ECG will be completed in triplicate at Visit 1 (Screening) within 
3 minutes, and as a single tracing at all other visits. 
6.3.6 
Columbia-Suicide Severity Rating Scale 
The C-SSRS monitors changes in suicidal thinking and behavior over time, in order to 
determine risk (Posner et al. 2011). The following 4 constructs are measured: the severity of 
ideation, the intensity of ideation, behavior, and lethality. 
The C-SSRS will be used to assess suicidal ideations and behaviors. The Baseline/Screening 
version will be administered at Visit 1 (Screening), and the Since Last Visit version will be 


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administered at subsequent visits. The C-SSRS results for each subject should be reviewed by 
the Investigator at each visit. If at any time the C-SSRS results for a given subject reveal 
potential suicidality, then the Investigator should assess the clinical significance of such 
results. If a clinically significant risk of suicidality is identified for a subject, then the 
Investigator should discontinue the subject and implement appropriate treatment 
(Section 4.4). 
6.3.7 
Unified Parkinson’s Disease Rating Scale 
The UPDRS is a comprehensive battery of motor and behavioral indices derived from the 
Columbia Scale (Goetz et al. 2007), providing explicit rating criteria that have undergone 
testing for reliability. Only Part III (motor examination) will be administered. 
The UPDRS assessments should be conducted in the “on” state. This will ensure that noise 
associated with a subject’s “on/off” status does not confound interpretation of the motor 
function data. 
6.3.8 
Laboratory Evaluations 
The laboratory evaluations will include, but are not be limited to, the following: 
Clinical chemistry tests 
o Sodium (Na), potassium (K), chloride (Cl), phosphorus (P), calcium (Ca), carbon 
dioxide (CO2), blood urea nitrogen (BUN), creatinine (CR), uric acid 
o Alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-
glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), total bilirubin 
(TBIL), lactate dehydrogenase (LDH) 
o HbA1c 
 HbA1c test should only be performed at Visit 1 (Screening), and 
Visit 6/EOT 
o Glucose 
o Albumin (ALB), total protein 
o Prolactin 
o Thyroid stimulating hormone (TSH) and free T4 
 TSH and free T4 reflex will only be performed at Visit 1 (Screening). A 
free T4 reflex will only be done if the TSH is outside of the reference lab 
normal range. 
o Lipid Panel 


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Pregnancy test 
o A serum pregnancy test should only be performed at Visit 1(Table 6-1) for women 
of child-bearing potential 
o A urine pregnancy test should be performed at all designated visits after Visit 1 
(Table 6-1) for women of child-bearing potential 
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 Color, clarity, blood, RBCs, WBCs, protein, glucose, ketones, specific gravity, 
pH, leukocyte esterase, nitrite, microscopic analysis 
Note: A urinalysis is not applicable for those subjects who are unable to provide a urine 
sample (e.g., incontinent subjects). The reason for not completing the urine sample will be 
documented. 
Urine toxicity screen 
o Subjects who test positive for amphetamines may be retested if they agree to 
abstain from the medication for the length of their participation in the study and if 
abstinence from medication usage is achieved at least 7 days prior to Visit 2 
(Baseline). The repeat test, and any other tests, must be negative for them to 
participate in the study. 
o Subjects who test positive for benzodiazepines, THC, or opiates may continue in 
the study and last usage should be noted at visit. In addition, restrictions listed in 
Appendix A should be followed. 
Laboratory evaluations will be completed according to the schedule presented in Table 6-1 
and procedures detailed in the study Laboratory Manual. Additional safety testing may be 
performed at the discretion of the Investigator or designee. 


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Table 6-1 
Safety Laboratory Evaluations 
Visit 
Testsa,b,c 
Visit 1 (Screening) 
CHEM (including HbA1c, TSH, free T4 reflex), CBC, UA, urine 
toxicity screen, serum pregnancy test 
Visit 2 (Baseline) 
CHEM, CBC, UA, urine toxicity screen, urine pregnancy test 
Visit 6 (Week 8) 
CHEM (including HbA1c), CBC, UA, urine pregnancy test 
Abbreviations: CBC=complete blood count; CHEM=clinical chemistry serum tests; UA=urinalysis 
a 
A pregnancy test is only required for women of child-bearing potential.  
b 
An HbA1c test is only required at Visit 1 (Screening) and Visit 6/EOT. 
c 
TSH and free T4 reflex are only required at Visit 1 (Screening). 
6.3.9 
Safety Follow-up 
A 2-week safety follow-up telephone contact is to be completed for all subjects. Subjects will 
have the following completed via telephone approximately 2 weeks after the last dose of 
study drug: 
 Assessment of concomitant medications/treatments 
 Assessment of AEs 
Subjects who discontinue early or complete the study should return to standard of care. The 
Sponsor will provide investigative sites with 3 months of after-study assistance to transition 
subjects to standard of care therapy after their participation in the study. 
6.4 
Unscheduled Visits 
Unscheduled visits may occur as determined by the Investigator. The following safety 
assessments generally should be recorded at each unscheduled visit: assessment of AEs, 
assessment of concomitant medications/treatments, and measurement of vital signs. The 
Investigator may perform any additional safety evaluations deemed by the Investigator to be 
clinically indicated. 
7 ADVERSE EVENTS 
7.1 
Specification of Safety Parameters 
7.1.1 
Definition of Adverse Event 
An AE is defined as “any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related” (US FDA 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-


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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 
 Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, 
transfusion). The condition that leads to the procedure is an AE if not present at 
Baseline 
 Overdose of concomitant medication without any signs or symptoms unless the subject 
is hospitalized for observation 
 Hospitalization for elective surgery planned prior to study (situation where an 
untoward medical occurrence has not occurred) 
 Pregnancy will not be considered an AE, but if it occurs, it will be reported on a 
pregnancy form 
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 


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Definition of Life Threatening 
A life threatening event places the subject at immediate risk of death from the event as it 
occurred. This does not include an AE, which, had it occurred in a more severe form, might 
have caused death. 
Definition of Hospitalization 
Hospitalization is defined by the Sponsor as a full admission to the hospital for diagnosis and 
treatment. This includes prolongation of an existing inpatient hospitalization.  
Examples of visits to a hospital facility that do not meet the serious criteria for hospitalization 
include: 
 Emergency room visits (that do not result in a full hospital admission) 
 Outpatient surgery 
 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. 


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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 study drug under investigation (i.e., there are facts, evidence, or 
arguments to suggest possible causation). 
Consider the following when assessing causality: 
 Temporal associations between the agent and the event 
 Response to 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 


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 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 
 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 IB. 
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 


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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 will be coded by Data Management using MedDRA. 
All AEs, serious and not serious, will be recorded on the AE eCRF page using appropriate 
medical terminology. Severity and relationship to study drug will be assessed by the 
Investigator. 
When possible, clinical AEs should be described by diagnosis and not by symptoms 
(e.g., “cold” or “seasonal allergies” instead of “runny nose”). 
All AEs, whether or not related to the study drug, must be fully and completely documented 
on the AE eCRF and in the subject’s notes. 
7.4.2 
Serious Adverse Event Reporting 
The reporting of SAEs by the Sponsor to the Regulatory Authorities is a regulatory 
requirement. Each Regulatory Authority has established a timetable for reporting SAEs based 
upon established criteria. 
Serious AEs must be reported within 24 hours of discovery to the Sponsor or its designee; use 
the appropriate form for initial and/or follow-up reporting. 
At a minimum, events identified by the Sponsor to require expedited reporting as serious, 
unexpected, and related to study drug must be brought to the attention of the responsible 
Institutional Review Board/Ethics Committee (IRB/EC). These will be provided by the 
Sponsor after their assessment. For European Union member states, the Sponsor or its 
designee will provide reports of suspected unexpected serious adverse reactions 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 (Section 7.4.3) and/or Overdose 
(Section 7.4.4) 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 
contact information provided on the SAE, Pregnancy, and Overdose forms. 


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Subjects will be followed until Visit 6/Safety Follow-up for any SAEs and/or other reportable 
information or until such events have resolved or the Investigator, in conjunction with the 
Sponsor, deems them to be chronic or stable. 
In the event of any SAE (other than death), the study subject will be instructed to contact the 
Investigator (or designee) using the telephone number provided in the ICF. All subjects 
experiencing an SAE will be seen by the Investigator or designee as soon as is feasible 
following the report of the SAE. 
Serious AEs occurring after the study Follow-up Period should be reported if in the judgment 
of the Investigator there is “a reasonable possibility” that the event may have been caused by 
the product. 
SAEs should also be reported to the IRB/EC according to local regulations. 
7.4.3 
Reporting of Pregnancy 
Any female subject who becomes pregnant during the study (with or without AEs) must be 
withdrawn from the study and the pregnancy must be reported on the pregnancy form within 
24 hours of discovery to the Sponsor or its designee. Any female subject who becomes 
pregnant during the study will be followed through the 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 form. 
7.4.4 
Reporting of Overdose 
An overdose is a deliberate or inadvertent administration of a treatment at a dose higher than 
the maximum recommended dose per protocol. It must be reported to the Sponsor or 
designee on the Overdose Form within 24 hours of discovery. 
8 CLINICAL MONITORING  
Routine monitoring of study sites is described in Section 11. 
Clinical site monitoring is conducted to ensure that the rights and well-being of human 
subjects are protected, that the reported study data are accurate, complete, and verifiable, and 
that the conduct of the study is in compliance with the currently approved protocol and 
amendment(s) as applicable, with GCP, and with applicable regulatory requirements. Details 
of the study site monitoring process are described in a separate clinical monitoring plan 
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9  STATISTICAL METHODS AND DATA ANALYSIS 
9.1 
Statistical and Analytical Plans 
Statistical methods will be documented in detail in a statistical analysis plan (SAP) to be 
approved by the Sponsor prior to database lock. 
9.2 
Description of Statistical Methods 
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). 
 Unless otherwise specified, all reported p-values will be 2-sided hypothesis tests 
performed at the significance level of 5%, and all confidence intervals (CIs) will be 
2-sided 95% CIs. All analyses will be performed using SAS® software, Version 9.4 
(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. 
9.3 
Handling of Dropouts and Missing Data 
Handling of missing values will be described in detail in the SAP. 
9.4 
Sample Size Determination 
The initial sample size calculation was based on a standard deviation of 8.0 and a dropout 
rate of 10%. An interim review of the statistical assumptions was conducted after 9 subjects 
completed the Week 8 visit, and the sample size was recalculated. The standard deviation in 
HAMD-17 total score change from Baseline to Week 8 was observed to be lower, and the 
dropout rate higher, than the initial assumptions. Therefore, the sample size has been 
recalculated as follows. 
Assuming the standard deviation for the change in HAMD-17 total score from Baseline to 
Week 8 is 6.0 points, 34 evaluable subjects will provide 80% power to detect a minimum 
mean reduction of 3 points from Baseline to Week 8 at a significance level of 0.05 using a 
2-sided paired t-test. 
Adjusting for a potential non-evaluable rate of up to 15%, approximately 40 subjects will be 
enrolled. 


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9.5 
Unblinding 
This is an open-label, single arm study; therefore, subjects, site staff, and the Sponsor will be 
unblinded to the treatment administered. 
9.6 
Additional Subgroup Analyses 
Selected analyses will be performed in subgroups defined by treatment regimen: 
 pimavanserin monotherapy 
 pimavanserin adjunctive therapy 
Additional subgroup analyses may be specified in the statistical analysis plan. 
9.7 
Study Subjects 
9.7.1 
Analysis Sets 
The Safety Analysis Set includes all subjects who received at least one dose of pimavanserin. 
The Safety Analysis Set will be used for analyses of all safety endpoints. 
The FAS includes all subjects who received at least one dose of pimavanserin and who have 
both a Baseline value and at least one post-Baseline value for the HAMD-17 total score. The 
FAS will be used for the analysis of all efficacy endpoints. 
9.7.2 
Subject Accountability and Subject Disposition  
Study enrollment will be summarized. The number and percentage of subjects enrolled and 
treated in the study will be presented together with the number and percentage in each 
analysis set, and the number and percentage of subjects who completed the study and those 
who withdrew early. A summary of reasons for early withdrawal from the study will be 
provided. 
A listing of the reasons for exclusions from the analysis sets will be provided. 
9.7.3 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized using descriptive statistics 
and the corresponding listings will be provided. 
9.8 
Efficacy Analyses 
All efficacy endpoints will be summarized by time point using descriptive statistics. Details 
regarding the scoring for each instrument will be provided in the SAP. 
Continuous measurement results will be reported using the number of subjects with data 
values, mean, standard error of the mean, median, standard deviation, minimum, and 
maximum. For each categorical outcome, the number and percentage of subjects will be 
reported. 


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9.8.1 
Primary Efficacy Analyses 
The primary efficacy endpoint is the change from Baseline to Week 8 in the HAMD-17 total 
score. The primary analysis will be based on the FAS. 
The null and alternative hypotheses for the primary endpoint are as follows: 
 The null hypothesis is that the mean change from Baseline to Week 8 in HAMD-17 
total score is equal to 0.  
 The alternative hypothesis is that the mean change from Baseline to Week 8 in 
HAMD-17 total score is not equal to 0.  
The HAMD-17 total score will be analyzed using the mixed model repeated measures 
(MMRM). The dependent variable will be the change from Baseline in the HAMD-17 total 
score, and the independent variables will include the following: Baseline HAMD-17 total 
score, visit (Weeks 2, 4, 6, and 8), and Baseline HAMD-17 total score-by-visit interaction. 
An unstructured covariance matrix will be used to model the within-subject errors, and the 
Kenward-Roger approximation will be used to adjust the denominator degrees of freedom. 
The treatment effect for the primary endpoint will be estimated as the least-squares mean 
change from Baseline to Week 8, and will be tested at a significance level of 0.05. In 
addition, the treatment effect will also be estimated at each of the other time points (Weeks 2, 
4, and 6) using the same MMRM, and will be considered secondary endpoints. 
In addition, a paired t-test using a last observation carried forward (LOCF) imputation 
method will be performed at each post-baseline visit. 
9.8.2 
Secondary Efficacy Analyses 
Secondary efficacy endpoints will include the following: 
 CGI-Improvement (CGI-I) 
 Change from Baseline in CGI-Severity (CGI-S) 
 Change from Baseline in Scale of Outcomes in PD-Sleep Scale (SCOPA) night time 
sleep score 
 Change from Baseline in SCOPA day time sleepiness score 
 Proportion of responders (defined as ≥50% reduction from Baseline in HAMD-17 total 
score) 
 Change from Baseline in EuroQOL-5 dimensions-5 levels (EQ-5D-5L) 
All continuous secondary efficacy endpoints (CGI-I, CGI-S, SCOPA, and EQ-5D-5L) will be 
summarized by time point using descriptive statistics. Continuous secondary efficacy 


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endpoints will be analyzed using similar MMRM models as for the primary efficacy 
endpoint, except that the Baseline value of the endpoint being analyzed will be included as a 
covariate, and in the Baseline score-by-visit interaction term, instead of the HAMD-17 total 
score.  
In the case of CGI-I, it will be analyzed using an MMRM model with CGI-I score (rather 
than the change from Baseline) as the dependent variable, and with independent variables of 
Baseline CGI-S score, visit, and Baseline CGI-S score-by-visit interaction. 
For the HAMD-17 responder endpoint (≥50% reduction from Baseline in HAMD-17 total 
score), the proportion of responders will be summarized by visit, including 95% confidence 
intervals. Observed cases (subjects with missing values at a given visit are excluded) as well 
as missing values imputed as non-responders will be presented. 
For the EQ-5D-5L endpoint, the dependent variable will be the score from the EQ visual 
analogue scale. Additionally, for each EQ-5D dimension, the number and percentage of 
patients reporting no, slight, moderate, severe, or extreme problems will be summarized at 
each timepoint. 
In addition, for each of the continuous secondary efficacy endpoints, a paired t-test using a 
last observation carried forward (LOCF) imputation method will be performed at each post-
baseline visit. 
9.9 
Safety Analyses 
All safety endpoints will be summarized using descriptive statistics. UPDRS Part III and 
MMSE will be analyzed using similar MMRM models as for the primary efficacy endpoint, 
except that the Baseline value of the endpoint being analyzed (either UPDRS Part III or 
MMSE) will be included as a covariate, and in the Baseline score-by-visit interaction term, 
instead of the HAMD-17 total score.  
9.9.1 
Adverse Events 
Adverse events will be classified into standard terminology using MedDRA. Treatment-
emergent adverse events, TEAEs leading to discontinuation, TEAEs related to study drug, 
TEAEs by maximum severity, SAEs, and SAEs related to study drug will be summarized. 
Other TEAEs of special interest may also be summarized. 
9.9.2 
Concomitant Medications 
Prior, concomitant, and post-treatment medications will be summarized separately. 
Medications will be coded using the World Health Organization (WHO) Drug Dictionary 
(2016 March or newer version). The number and percentage of subjects taking each drug 


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class (Anatomical Therapeutic Chemical [ATC] Level 3) and medication preferred term will 
be tabulated. 
9.9.3 
Clinical Laboratory Values 
Serum clinical chemistry, hematology, and urinalysis results at Baseline and Week 8 will be 
summarized, including change from Baseline. 
The number and percentage of subjects with potentially important post-baseline laboratory 
values will be summarized. The potentially clinically important criteria will be specified in 
the SAP. 
9.9.4 
Vital Signs and Body Weight 
Vital signs and body weight (including BMI) will be summarized at Baseline and each post-
Baseline visit (weight and BMI are only collected at Screening, Baseline, and Week 8/EOT; 
height is collected only at Baseline). Change from Baseline will also be summarized. The 
number and percentage of subjects with change from Baseline in body weight of 7% or more 
(both increases and decreases) will be presented. 
9.9.5 
Electrocardiogram 
ECG parameters at Baseline and at Weeks 2 and 8 will be summarized by time point; change 
from Baseline will also be summarized. Additionally, categorical analyses will be conducted 
on the incidence of subjects with prolonged QTc intervals and changes in QTc intervals in 
accordance with International Council for Harmonisation (ICH) guidelines and based on the 
FDA E14 Guidance Document. Details will be provided in the SAP. 
9.9.6 
Physical Examination 
The results of the physical examinations at each visit (Screening and Week 8/EOT) will be 
tabulated. 
9.9.7 
Suicidal Ideation and Behavior 
The number and percentage of subjects for C-SSRS will be tabulated by visit. The number 
and percentage of subjects who are actively suicidal post-Baseline, including answer of “yes” 
to C-SSRS questions 4 or 5, will be tabulated. 
9.9.8 
Mini Mental State Examination 
The MMSE total score will be summarized by time point (Baseline, Weeks 4, and 8) using 
descriptive statistics and will be analyzed using similar MMRM models as for the primary 
efficacy endpoint, except that the Baseline value will be included as a covariate, and in the 
Baseline score-by-visit interaction term, instead of the HAMD-17 total score. 


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9.9.9 
UPDRS Part III 
The UPDRS Part III total score will be summarized by time point (Baseline, Weeks 4, and 8) 
using descriptive statistics and will be analyzed using similar MMRM models as for the 
primary efficacy endpoint, except that the Baseline value will be included as a covariate, and 
in the Baseline score-by-visit interaction term, instead of the HAMD-17 total score. 
10 STUDY MANAGEMENT AND DATA COLLECTION 
10.1 Data Collection and Management Responsibilities 
All documents required for the conduct of the study as specified in the ICH GCP guidelines 
will be maintained by the Investigator in an orderly manner and made available for 
monitoring and/or auditing by the Sponsor and regulatory agencies. 
The Investigator and institution must permit authorized representatives of the Sponsor or 
designees (including monitors and auditors), Regulatory Agencies (including inspectors), and 
the IRB/EC direct access to source documents (such as original medical records). Direct 
access includes permission to examine, analyze, verify, and reproduce any records and 
reports that are needed for the evaluation of the study. The Investigator must ensure the 
reliability and availability of source documents from which the information on the eCRF was 
derived. 
10.2 Source Documents 
All study specific information obtained at each study visit must be recorded in the subject’s 
record (source documentation), and then entered into a validated electronic data capture 
(EDC) database by trained site personnel. The source documentation may consist of source 
notes captured by site personnel as well as laboratory reports, ECG reports, and electronic 
source data. 
10.3 Case Report Forms 
Subject data required by this protocol are to be recorded in an EDC system on eCRFs. The 
Investigator and his or her site personnel will be responsible for completing the eCRFs. The 
Investigator is responsible for the accuracy and reliability of all the information recorded on 
the eCRFs. All information requested on the eCRFs needs to be supplied, including subject 
identification data, visit date(s), assessment values, etc., and any omission or discrepancy will 
require explanation. All information on eCRFs must be traceable to source documentation at 
the site. 
10.4 Confidentiality 
The Investigator must ensure that each subject’s anonymity is maintained. On the eCRFs or 
other documents submitted to the Sponsor or designees, subjects must be identified by a 


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Subject Identification Number only. Documents that are not for submission to the Sponsor or 
designees (e.g., signed ICFs) should be kept in strict confidence by the Investigator in 
compliance with Federal regulations or other applicable laws or ICH Guidance on GCP. 
10.5 Study Records Retention 
Investigators are required to maintain all essential study documentation as per ICH GCP 
guidelines. This includes, but is not limited to, copies of signed, dated and completed eCRFs, 
documentation of eCRF corrections, signed ICFs, audio recordings, subject-related source 
documentation, and adequate records for the receipt and disposition of all study drug. 
Investigators should maintain all essential study documentation, for a period of at least 
2 years following the last approval of marketing application in an ICH region (US, Europe, 
and Japan), or until at least 2 years after the drug investigational program is discontinued, 
unless a longer period is required by applicable law or regulation. Only the Sponsor can 
notify an Investigator or vendor when any records may be discarded. Investigators should 
contact the Sponsor before destroying any files. 
10.6 Protocol Exceptions and Deviations 
No prospective entry criteria protocol deviations are allowed; all subjects must meet all 
eligibility criteria in order to participate in the study. 
Protocol waivers for eligibility and use of prohibited medication during the study 
(Section 4.5.1) will not be granted by the Sponsor under any circumstances. If, during the 
course of a subject’s participation in the trial it is discovered that the subject did not meet all 
eligibility criteria, he or she 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. All follow-up safety assessments must be completed and documented as outlined in 
the protocol (Section 6.3.9). The Investigator must report any protocol deviation to the 
Sponsor and, if required, to the IRB/EC in accordance with local regulations, within 
reasonable time. 
10.7 Protocol Amendments 
Changes to the protocol may be made only by the Sponsor (with or without consultation with 
the Investigator). All protocol modifications must be submitted to the site IRB/EC in 
accordance with local requirements and, if required, to Regulatory Agencies, as either an 
amendment or a notification. Approval for amendments must be awaited before any changes 
can be implemented, except for changes necessary to eliminate an immediate hazard to trial 


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subjects, or when the changes involve only logistical or administrative aspects of the trial. No 
approval is required for notifications. 
11 STUDY MONITORING, AUDITING, AND INSPECTING 
11.1 Quality Control and Quality Assurance 
The Sponsor or designee and Regulatory Agency inspectors are responsible for contacting 
and visiting the Investigator for the purpose of inspecting the facilities and, upon request, 
inspecting the various records of the trial (e.g., eCRFs and other pertinent data) provided that 
subject confidentiality is respected. 
The Sponsor’s or designee’s monitor is responsible for inspecting the eCRFs at regular 
intervals throughout the study to verify adherence to the protocol; completeness, accuracy, 
and consistency of the data; and adherence to local regulations on the conduct of clinical 
research. The monitor should have access to subject medical records and other study-related 
records needed to verify the entries on the eCRFs. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in 
the course of these monitoring visits are resolved. 
In accordance with ICH Guidance on GCP and the Sponsor’s audit plans, a certain 
percentage of sites participating in this study will be audited. These audits may include a 
review of site facilities (e.g., pharmacy, drug storage areas, and laboratories) and review of 
study-related records may occur in order to evaluate the trial conduct and compliance with 
the protocol, ICH Guidance on GCP, and applicable regulatory requirements. 
The Sponsor’s or designee’s representatives, Regulatory Agency inspectors, and IRB/EC 
representatives who obtain direct access to source documents should also respect subject 
confidentiality, taking all reasonable precautions in accordance with applicable regulatory 
requirements to maintain the confidentiality of subjects’ identities. 
12 ETHICAL CONSIDERATIONS 
12.1 Ethical Standard 
The study will be conducted in compliance with the protocol, the Declaration of Helsinki, 
ICH GCP, and other applicable regulatory requirements. 
The study will be performed in accordance with Health Insurance Portability and 
Accountability Act (HIPAA) regulations, US FDA GCP Regulations (US CFR 21 parts 50, 
54, 56, and 312), and ICH Guidance on GCP (E6) and clinical safety data management 
(E2A). 


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In accordance with Directive 75/318/EEC, as amended by Directive 91/507/EEC, the final 
clinical study report will be signed by an Investigator and/or Coordinating Investigator who 
will be designated prior to the writing of the clinical study report. 
12.2 Institutional Review Board/Ethics Committee 
The Investigator or designee will provide the IRB/EC with all requisite material, including a 
copy of the protocol, informed consent, and any subject information or advertising materials. 
The study will not be initiated until the IRB/EC provides written approval of the protocol and 
the informed consent and until approved documents have been obtained by the Investigator 
and copies received by the Sponsor. All amendments will be sent to the IRB/EC for 
information (minor amendment) or for submission (major amendment) before 
implementation. The Investigator will supply the IRB/EC and the Sponsor with appropriate 
reports on the progress of this study, including any necessary safety updates, in accordance 
with the applicable government regulations and in agreement with policy established by the 
Sponsor. 
12.3 Informed Consent Process 
Properly executed, written informed consent must be obtained from each subject prior to any 
screening procedures. 
The informed consent must, at a minimum, include the elements of consent described in the 
ICH Guidance on GCP and the US CFR 21 part 50.25. A copy of the ICF planned for use will 
be reviewed by the Sponsor or designee for acceptability and must be submitted by the 
Investigator or designee together with the protocol, to the appropriate IRB/EC for review and 
approval prior to the start of the study at that investigational site. Consent forms must be in a 
language fully comprehensible to the prospective subject. The Investigator must provide the 
Sponsor or designee with a copy of the IRB/EC letter approving the protocol and the ICF 
before the study drug supplies will be shipped and the study can be initiated. 
The consent form must be revised if new information becomes available during the study that 
may be relevant to the subject. Any revision must be submitted to the appropriate IRB/EC for 
review and approval in advance of use. 
12.3.1 
Consent and Other Informational Documents Provided to Subjects 
The subject must be given a copy of the signed informed consent and the original maintained 
in the designated location at the site. 
12.3.2 
Consent Procedures and Documentation 
It is the Investigator or designee’s responsibility to obtain written informed consent from the 
subject after adequate explanation of the aims, methods, anticipated benefits, and potential 


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hazards of the study. The subject must be given ample time to decide about study 
participation and opportunity to inquire about details of the study. The IRB/EC-approved 
consent form must be personally signed and dated by the subject and by the person who 
conducted the informed-consent discussion. The Investigator or appropriate site personnel 
must document the details of obtaining informed consent in the subject’s study documents. 
Copies of signed forms must be given to the signatories and original forms must be 
maintained in the designated location at the site. 
13 PUBLICATION PLAN 
All publication rights are delineated in the Clinical Study Agreement and/or other separate 
agreements with the Investigator and/or Institution, as applicable. 
14 CONFLICT OF INTEREST POLICY 
14.1 Finance, Insurance, and Indemnity 
Arrangements for finance, insurance and indemnity are delineated in the Clinical Study 
Agreement and/or other separate agreements with the Investigator and/or Institution, as 
applicable. 
 
 


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15 LITERATURE REFERENCES 
Brayfield A. Mirtazapine. In: Brayfield A, ed. Martindale: The Complete Drug Reference. 
38th ed. London, UK: Pharmaceutical Press. 2014. 
Chandler GM, Iosifescu DV, Pollack MH, Targum SD, Fava M. Validation of the 
Massachusetts General Hospital Antidepressant Treatment History Questionnaire (ATRQ). 
CNS Neurosci Ther. 2010;16(5):322-325. 
Fava M, Davidson KG. Definition and epidemiology of treatment-resistant depression. 
Psychiatr Clin North Am. 1996;19:179-200. 
Fava M. Diagnosis and definition of treatment-resistant depression. Biol Psychiatry. 
2003;53:649-659. 
Folstein MF, Folstein SE, McHugh PR. “Mini-Mental state”: A practical method for grading 
the cognitive state of patients for the clinician. J Psychiatr Res.1975;12(3):189-198. 
Goetz CG, Fahn S, Martinez-Martin P, et al. Movement Disorder Society-sponsored revision 
of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Process, format, and 
clinimetric testing plan. Movement Disorders. 2007;22 (1):41–47. 
Goodarzi Z, Mrklas KJ, Roberts DJ, Jette N, Pringsheim T, Holroyd-Leduc J. Detecting 
depression in Parkinson disease: A systematic review and meta-analysis. Neurology. 
2016;87(4):426-437. 
Guy W. Clinical Global Impressions. In: ECDEU Assessment Manual for 
Psychopharmacology – Revised (DHEW publication number ADM 76-338). Rockville, MD: 
US Department of Health, Education, and Welfare. 1976;218-222. 
Hamilton M. A rating scale for depression. J. Neurol. Neurosurg. Psychiat. 1960;(23):56. 
Kind P. The EuroQol instrument: An index of health related quality of life. In: Spiker B, ed. 
Quality of Life and PharmacoEconomics in Clinical Trials. 2nd ed. Philadelphia, PA: 
Lippincott-Raven Publishers; 1996. 
Liu J, Dong J, Wang L, Su Y, Yan P, Sun S. Comparative efficacy and acceptability of 
antidepressants in Parkinson's disease: a network meta-analysis. PLoS One. 
2013;8(10):e76651. 
Marinus J, Visser M, van Hilten JJ, Lammers GJ, Stiggelbout AM. Assessment of sleep and 
sleepiness in Parkinson disease. Sleep. 2003;26(8):1049-1054. 


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Marsh L, McDonald WM, Cummings J, Ravina B; NINDS/NIMH Work Group on 
Depression and Parkinson's Disease. Provisional diagnostic criteria for depression in 
Parkinson's disease: report of an NINDS/NIMH Work Group. Mov Disord. 
2006;21(2):148-158. 
Marsh L. Depression and Parkinson's disease: current knowledge. Curr Neurol Neurosci Rep. 
2013;(12):409. 
Mehta MA, Manes FF, Magnolfi G, Sahakian BJ, Robbins TW. Impaired set-shifting and 
dissociable effects on tests of spatial working memory following the dopamine D2 receptor 
antagonist sulpiride in human volunteers. Psychopharmacology (Berl). 2004;176(3-4):331-
342. 
Menza M, Dobkin RD, Marin H, Mark MH, Gara M, Buyske S, Bienfait K, Dicke A. The 
impact of treatment of depression on quality of life, disability and relapse in patients with 
Parkinson's disease. Mov Disord. 2009;24(9):1325-1332. 
Moonen AJ, Wijers A, Leentjens AF, et al. Severity of depression and anxiety are predictors 
of response to antidepressant treatment in Parkinson's disease. Parkinsonism Relat Disord. 
2014;20(6):644-646. 
Peretti CS, Danion JM, Kauffmann-Muller F, Grangé D, Patat A, Rosenzweig P. Effects of 
haloperidol and amisulpride on motor and cognitive skill learning in healthy volunteers. 
Psychopharmacology (Berl). 1997;131(4):329-338. 
Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry. 2011;168(12):1266-1277. 
Rocha FL, Murad MG, Stumpf BP, Hara C, Fuzikawa C. Antidepressants for depression in 
Parkinson's disease: systematic review and meta-analysis. J Psychopharmacol. 
2013;27(5):417-423. 
Roth BL, Kroeze WK, Patel S, Lopez E. The multiplicity of serotonin receptors: uselessly 
diverse molecules or an embarrassment of riches? Neuroscientist. 2000;6:252-262. 
Rush AJ, Kraemer HC, Sackeim HA, et al. Report by the ACNP Task Force on Response and 
Remission in Major Depressive Disorder. Neuropsychopharmacology. 2006;31:1841-1853. 
Saeedi H, Remington G, Christensen BK. Impact of haloperidol, a dopamine D2 antagonist, 
on cognition and mood. Schizophr Res. 2006;85(1-3):222-231. 


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Schotte A, Janssen PF, Gommeren W, et al. Risperidone compared with new and reference 
antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology. 
1996;124(1-2):57-73. 
US Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for 
Industry and Investigators: Safety Reporting Requirements for INDs and BA/BE Studies. 
Rockville, MD: US Dept of Health and Human Services; 2012. 
Vanover KE, Weiner DM, Makhay M, et al. Pharmacological and behavioral profile of N-(4-
fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl) 
carbamide (2R,3R)-dihydroxybutanedioate (2:1) (ACP-103), a novel 5-
hydroxytryptamine(2A) receptor inverse agonist. J Pharmacol Exp Ther. 2006;317(2):910-
918. 
Wang PS, Schneeweiss S, Avorn J, et al. Risk of death in elderly users of conventional vs. 
atypical antipsychotic medications. N Engl J Med. 2005;353(22):2335-2341. 
Weintraub D, Morales KH, Moberg PJ, et al. Antidepressant studies in Parkinson's disease: a 
review and meta-analysis. Mov Disord. 2005;20(9):1161-1169. 
Wikström HV, Mensonides-Harsema MM, Cremers TI, Moltzen EK, Arnt J. Synthesis and 
pharmacological testing of 1,2,3,4,10,14b-hexahydro-6-methoxy-2-
methyldibenzo[c,f]pyrazino[1,2-a]azepin and its enantiomers in comparison with the two 
antidepressants mianserin and mirtazapine. J Med Chem. 2002;45(15):3280–3285. 
Xie CL, Wang XD, Chen J, Lin HZ, Chen YH, Pan JL, Wang WW. A systematic review and 
meta-analysis of cognitive behavioral and psychodynamic therapy for depression in 
Parkinson's disease patients. Neurol Sci. 2015;36(6):833-843. 
 
 


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16 APPENDICES 
Appendix A  Prohibited and Restricted Medications 
Subjects taking prohibited medications at study entry will not be eligible for the study. 
Subjects 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 
Medicationa 
Prohibition/restrictions 
Antipsychotics other than 
pimavanserin 
PROHIBITED 
 
All in class 
 
Must be washed out 2 weeks or 
5 half-lives (whichever is longer) 
prior to Baseline 
 
All antipsychotics are prohibited 
Anticholinergics 
PROHIBITED 
 
Centrally acting 
anticholinergics 
o 
benztropine 
o 
biperiden 
o 
trihexiphenidyl 
o 
oral diphenhydramine 
 
Centrally acting anticholinergic 
medications are prohibited and 
should be washed out and 
discontinued at least 2 weeks or 
5 half-lives (whichever is longer) 
prior to Baseline 
UNRESTRICTED 
 
Peripherally acting 
anticholinergics 
 
Topical diphenhydramine 
 
Peripherally acting anticholinergic 
medications and topical 
diphenhydramine are allowed 
without restriction 
Anticonvulsant and mood 
stabilizers 
PROHIBITED 
 
carbamazepine 
 
lamotrigine 
 
lithium 
 
phenytoin 
 
Must be washed out prior to 
Baseline or for 5 half-lives of the 
drug 
 
Prohibited throughout the study 
RESTRICTED 
 
valproate 
 
Valproate may be used if dose 
unchanged for at least 4 weeks prior 
to Baseline and dose should be 
expected to remain unchanged until 
the subject’s final visit. 
Antidepressants other than 
background therapy 
PROHIBITED 
 
mirtazapine 
 
nefazadone 
 
fluvoxamine 
 
Prohibited throughout the study 
 
Must be discontinued at least 2 
weeks or 5 half-lives (whichever is 
longer) prior to the Baseline visit 


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Medication Class 
Medicationa 
Prohibition/restrictions 
 
mianserin 
 
trazodone 
 
amitriptyline 
 
nortriptyline 
 
imipramine 
 
trimipramine 
 
desipramine 
 
clomipramine 
RESTRICTED 
Restricted due to potential 
for QT prolongation are the 
following: 
 
citalopram 
 
escitalopram 
 
venlafaxine 
 
 
Current treatment with an 
antidepressant is not required. 
However, if the subject is taking 
one of the permitted 
antidepressants on the left, the 
dose must be unchanged for at 
least 4 weeks prior to Baseline 
and should be expected to 
remain unchanged until the 
subject’s final visit 
 
Citalopram is restricted to a 
maximum dose of 20 mg/day. 
Escitalopram is restricted to a 
maximum dose of 10 mg/day. 
Venlafaxine is restricted to a 
maximum dose of 225 mg/day. 
 
Citalopram, escitalopram, and 
venlafaxine are prohibited in 
subjects with the following ECG 
results at Screening:  
o 
QTcF >425 ms, if QRS duration 
<120 ms 
o 
QTcF >450 ms, if QRS duration 
≥120 ms 
 


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Medication Class 
Medicationa 
Prohibition/restrictions 
Anxiolytics 
PROHIBITED 
 
chlordiazepoxide 
 
diazepam 
 
flurazepam 
 
Prohibited at Baseline and 
throughout the study 
RESTRICTED 
 
alprazolam 
 
clonazepam 
 
lorazepam 
 
oxazepam 
 
temazepam 
 
midazolam 
 
triazolam 
 
Short- or medium-acting 
benzodiazepine may be used. 
Reasonable efforts should be made 
to use minimum dose necessary for 
symptom management. 
 
May not be used within 12 hours 
prior to an assessment visit 
Stimulants 
PROHIBITED 
 
methylphenidate 
 
modafinil 
 
armodafinil 
 
Prohibited at Baseline and 
throughout the study 
Non-stimulant ADHD 
medications 
PROHIBITED 
 
atomoxetine 
 
guanfacine 
 
Prohibited at Baseline and 
throughout the study 
Serotonin antagonists  
PROHIBITED 
 
cyproheptadine 
 
fluvoxamine 
 
mianserin 
 
mirtazapine 
 
nefazodone 
 
trazodone 
 
Prohibited throughout the study 
 
Must be discontinued 5 half-lives 
prior to the Baseline visit 
Antiarrhythmic drugs 
PROHIBITED 
 
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 
 
clarithromycin 
 
erythromycin 
 
levofloxacin 
 
moxifloxacin 
 
pentamidine 
 
Clarithromycin, erythromycin, 
levofloxacin, moxifloxacin, and 
pentamidine are prohibited at 
study entry and throughout the 
study 


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Medication Class 
Medicationa 
Prohibition/restrictions 
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 Principal 
Investigator (PI). 
 
Artenimol/piperaquine, bedaquiline, 
gemifloxacin, norfloxacin, 
ofloxacin, quinine, and 
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 
Herbal and nutritional 
supplements 
PROHIBITED 
 
St. John’s wart 
 
S-adenosylmeththionine  
(SAM-E) 
 
valerian root 
 
melatonin 
 
L-tryptophan 
 
Prohibited at Baseline and 
throughout the study 
a 
Medications within each class include but are not limited to the examples listed in this table. 


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Appendix B Prohibited and Restricted Concomitant Medications: Inhibitors and 
Inducers of Cytochrome P450 Enzyme 3A4 
The information presented here is intended to provide guidance and does not constitute an 
exhaustive list of strong CYP 3A4 enzyme (CYP3A4) inhibitors and inducers. Any questions 
should be discussed with the Medical Monitor or appropriate designee.  
Subjects who take prohibited concomitant medications during the study 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 the Sponsor/Medical Monitor with 
medical input from the Investigator, and will be documented. If allowed to remain in the 
study, this will be reported as a major protocol deviation and not a waiver. 
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 juice
a  
Indinavir (Crixivan®)  
Itraconazole (Sporanox®)  
Ketoconazole (Nizoral®) 
Lopinavir and ritonavir (Kaletra®) 
Mibefradil (Posicor®) 
Nefazodone (Serzone®)  
Nelfinavir (Viracept®)  
Posaconazole (Noxafil®) 
Quinupristin (Synercid®) 
Rritonavir (Norvir®, part of 
Viekira Pak™)  
Saquinavir (Invirase®) 
Telaprevir (Incivek®) 
Telithromycin (Ketek®) 
Voriconazole (Vfend®) 
MODERATE 
INHIBITORS 
Amprenavir (Agenerase®) 
Aprepitant (Emend®) 
Atazanavir (Reyataz®) 
Ciprofloxacin (Cipro®) 
Darunavir/Ritonavir 
(Prezista®/Ritonavir) 
Diltiazem 
Erythromycin (Erythrocin® 
Lactobionate) 
Fluconazole (Diflucan®) 
Fosamprenavir (Lexiva®) 
Grapefruit juicea 
Imatinib (Gleevec®) 
Verapamil (Calan®) 


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STRONG 
INDUCERS 
Avasimibe 
Carbamazepine (Tegretol®) 
Phenobarbital (Luminal®, 
Solfoton®) 
Phenytoin (Dilantin®)  
Rifampin (Rifadin®, Rifadin® IV, 
Rimactane®) 
St. John's Wort 
MODERATE 
INDUCERS 
Bosentan (Tracleer®) 
Efavirenz (Sustiva®) 
Etravirine (Intelence®) 
Modafinil (Provigil®) 
Nafcillin (Unipen®, Nallpen®) 
a 
The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-
dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain 
preparation was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when another 
preparation was used (e.g., low dose, single strength). (FDA Drug Development and Drug Interactions 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabelin
g/ucm093664.htm#classInhibit). 
 

SAP_001.pdf: 
Official Title: An Open-label, 8-Week Study of Safety and Efficacy of Pimavanserin 
Treatment in Adults with Parkinson’s Disease and Depression 
NCT Number: NCT03482882 


 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Protocol No.: 
ACP-103-048 
Protocol Title: 
An Open-label, 8-Week Study of Safety and Efficacy of 
Pimavanserin Treatment in Adults with Parkinson’s 
Disease and Depression 
Drug: 
Pimavanserin 
Sponsor:  
ACADIA Pharmaceuticals Inc. 
 
  
Version No. and Date 
Version 2.0, 31 January 2019 
 
 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
 


Protocol ACP-103-048 
Statistical Analysis Plan 
SIGNATURE/APPROVAL PAGE 
AUTHOR 
Associate Director, Biostatistics 
ACADIA Pharmaceuticals Inc. 
APPROVERS 
Vice President, Biometrics 
ACADIA Pharmaceuticals Inc. 
Date 
Date 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Version 2.0 
31 January 2019 
Page 2 of40 


Protocol ACP-103-048 
Version 2.0 
Statistical Analysis Plan 
31 January 2019 
 
Page 3 of 40 
 
 
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
TABLE OF CONTENTS 
TABLE OF CONTENTS ........................................................................................................... 3 
LIST OF TABLES ..................................................................................................................... 6 
LIST OF FIGURES ................................................................................................................... 6 
ABBREVIATIONS .................................................................................................................... 7 
1 INTRODUCTION ............................................................................................................... 8 
2 OBJECTIVES ...................................................................................................................... 8 
2.1 
Primary Objective ............................................................................................................ 8 
2.2 
Secondary Objectives ...................................................................................................... 8 
2.3 
Safety Objectives ............................................................................................................. 8 
3 STUDY DESIGN ................................................................................................................. 8 
3.1 
General Study Design ...................................................................................................... 8 
3.2 
Schedule of Assessments ............................................................................................... 11 
3.3 
Randomization ............................................................................................................... 13 
3.4 
Blinding ......................................................................................................................... 13 
3.5 
Determination of Sample Size ....................................................................................... 13 
4 ANALYSIS SETS .............................................................................................................. 13 
4.1 
Safety Analysis Set ........................................................................................................ 13 
4.2 
Full Analysis Set ............................................................................................................ 13 
5 DATA HANDLING CONVENTIONS .............................................................................. 13 
5.1 
General Data Reporting Conventions ............................................................................ 14 
5.1.1 
Continuous Variables ................................................................................................. 14 
5.1.2 
Categorical Variables ................................................................................................. 14 
5.1.3 
Statistical Tests .......................................................................................................... 14 
5.1.4 
Conversion of Days to Months .................................................................................. 14 
5.2 
Derived Variables........................................................................................................... 14 
5.2.1 
Hamilton Depression Rating Scale 17-Items (HAMD-17) ....................................... 14 
5.2.2 
Clinical Global Impression – Severity (CGI-S) Scale ............................................... 15 
5.2.3 
Clinical Global Impression– Improvement (CGI-I) Scale ........................................ 15 
5.2.4 
Scale for Outcomes in Parkinson’s Disease (SCOPA) – Sleep Scale ........................ 16 
5.2.5 
EQ-5D-5L Proxy Version 1 ....................................................................................... 16 
5.2.6 
Columbia-Suicide Severity Rating Scale (C-SSRS) ................................................. 17 


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Statistical Analysis Plan 
31 January 2019 
 
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5.2.7 
Movement Disorders Society-Unified Parkinson’s Disease Rating Scale Part III .... 17 
5.2.8 
Mini-Mental State Examination (MMSE) ................................................................. 18 
5.3 
Analysis Visit Windows ................................................................................................. 18 
5.3.1 
Unscheduled Assessments ......................................................................................... 19 
5.3.2 
Multiple Measurements within Visit Windows ......................................................... 19 
5.4 
Data Handling Conventions........................................................................................... 19 
5.4.1 
Missing or Incomplete Dates for Prior or Concomitant Medications ....................... 20 
5.4.2 
Missing or Incomplete Dates for Adverse Events ..................................................... 20 
5.4.3 
Missing Severity Assessment for Adverse Events ..................................................... 20 
5.4.4 
Missing Relationship to Study Drug for Adverse Events .......................................... 20 
5.4.5 
Character Values of Clinical Laboratory Variables.................................................... 21 
6 SUBJECT DISPOSITION ................................................................................................. 21 
7 PROTOCOL DEVIATIONS .............................................................................................. 21 
8 DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS .......................... 22 
8.1 
Demographics ................................................................................................................ 22 
8.2 
Disease Characteristics at Baseline ............................................................................... 22 
9 MEDICAL HISTORY ....................................................................................................... 23 
10 PRIOR, CONCOMITANT AND POST-TREATMENT MEDICATION .......................... 23 
11 EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE ................................... 24 
11.1 Exposure to Study drug ................................................................................................. 24 
11.2 Measurement of Study Drug Compliance ..................................................................... 24 
12 EFFICACY ANALYSES ................................................................................................... 24 
12.1 Efficacy Variables .......................................................................................................... 25 
12.1.1 
Primary Efficacy Endpoint ........................................................................................ 25 
12.1.2 
Secondary Efficacy Endpoints ................................................................................... 25 
12.2 Adjustment for Covariates ............................................................................................. 25 
12.3 Handling of Missing Data .............................................................................................. 25 
12.4 Multiple Comparisons / Multiplicity ............................................................................. 26 
12.5 Examination of Subgroups ............................................................................................ 26 
13 METHODS OF EFFICACY ANALYSES ........................................................................ 26 
13.1 Primary Efficacy Analysis ............................................................................................. 26 
13.1.1 
Primary Analysis using MMRM in the Full Analysis Set ......................................... 26 
13.1.2 
LOCF Paired T-test for HAMD-17 ............................................................................ 27 


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13.1.3 
Secondary Efficacy Analyses .................................................................................... 27 
13.1.4 
Change from Baseline to Weeks 2, 4, and 6 in HAMD-17 Total Score .................... 28 
13.1.5 
HAMD-17 Responder Analysis ................................................................................. 28 
13.1.6 
CGI-S ......................................................................................................................... 28 
13.1.7 
CGI-I .......................................................................................................................... 28 
13.1.8 
SCOPA ....................................................................................................................... 28 
13.1.9 
EQ-5D-5L .................................................................................................................. 29 
13.1.10 LOCF ANCOVA for Continuous Efficacy Variables ................................................ 30 
14 SAFETY ANALYSES ....................................................................................................... 30 
14.1 Adverse Events .............................................................................................................. 31 
14.2 Clinical Laboratory Variables ........................................................................................ 31 
14.3 Vital Signs ...................................................................................................................... 35 
14.4 Electrocardiogram ......................................................................................................... 36 
14.5 Physical Examination and Neurological Examination .................................................. 37 
14.6 Other Safety Variables ................................................................................................... 38 
14.6.1 
MMSE ....................................................................................................................... 38 
14.6.2 
MDS-UPDRS Part III ................................................................................................ 38 
14.6.3 
Suicidality .................................................................................................................. 38 
15 CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES ........ 39 
16 DATA MONITORING/REVIEW COMMITTEE ............................................................. 39 
17 COMPUTER METHODS ................................................................................................. 39 
18 CHANGES TO ANALYSES SPECIFIED IN PROTOCOL ............................................. 39 
19 APPENDICES ................................................................................................................... 40 
19.1 Summary of Version Changes ....................................................................................... 40 
 


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LIST OF TABLES 
Table 1 
Schedule of Events and Assessments............................................................... 11 
Table 2 
Analysis Visit Windows ................................................................................... 19 
Table 3 
Clinical Laboratory Assessments ..................................................................... 32 
Table 4 
Criteria for Potentially Clinically Important Laboratory Values – 
Hematology and Chemistry ............................................................................. 34 
Table 5 
Criteria for Potentially Clinically Important Laboratory Values - 
Urinalysis ......................................................................................................... 35 
Table 6 
Criteria for Potentially Clinically Important Vital Signs ................................. 36 
Table 7 
Criteria for Potentially Clinically Important ECG Values ............................... 37 
 
LIST OF FIGURES 
Figure 1 
Schematic of Study Design .............................................................................. 10 
 


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ABBREVIATIONS 
ADS 
analysis dataset specification 
AE 
adverse event 
ANCOVA 
analysis of covariance 
ATC 
Anatomical Therapeutic Chemical 
BMI 
body mass index 
CGI-I 
Clinical Global Impression – Improvement scale 
CGI-S 
Clinical Global Impression – Severity scale 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DPD 
depression in Parkinson’s disease 
DS 
daytime sleepiness 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EOS 
end-of-study 
ET 
early termination 
HAMD-17 
Hamilton Depression Rating Scale-17 items 
LOCF 
last observation carried forward 
MGH ATRQ 
Massachusetts General Hospital Antidepressant Treatment Questionnaire 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model for repeated measures 
MSEC 
Milliseconds 
NS 
nighttime Sleep 
OC 
observed cases 
PCI 
potentially clinically important 
PT 
preferred term 
QoL 
Quality of Life 
QTcB 
QT interval corrected for heart rate using Bazett’s formula 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCOPA 
Scale for Outcomes in Parkinson’s Disease 
SD 
standard deviation 
SE 
standard error 
SI 
Système International 
SOC 
system organ class 
SNRI 
selective norepinephrine inhibitor 
SSRI 
serotonin reuptake inhibitor 
TEAE   
treatment-emergent adverse event 
VAS 
visual analog scale 
 


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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 Amendment 2 of the final study 
protocol dated 08 January 2019. Specifications for tables, figures, and listings are contained 
in separate documents.  
2 OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to assess the efficacy of pimavanserin for the treatment 
of depression in adults with Parkinson’s disease (PD). 
2.2 
Secondary Objectives 
The secondary objectives of this study are to explore the efficacy of pimavanserin in the 
following domains: 
 Clinician’s global assessment of treatment benefits 
 Nighttime sleep and daytime sleepiness 
 Quality of life (QoL) 
2.3 
Safety Objectives 
The safety objectives of the study are to assess the safety of pimavanserin for the treatment of 
depression in adults with PD.  
3 STUDY DESIGN 
3.1 
General Study Design 
This study will be conducted as a Phase 2, 8-week, open-label, single arm, multi-center, 
outpatient study in subjects with PD and depression. Subjects can receive treatment as either 
a monotherapy (pimavanserin 34 mg alone), or adjunctively (pimavanserin 34 mg plus an 
antidepressant) if depression is inadequately controlled with  current therapy. 
Approximately 20 sites in the U.S will participate in this study. Subjects will participate in 
the study for up to 13 weeks, consisting of a screening period of up to 3 weeks, followed by a 
treatment period of approximately 8 weeks, and a 2-week safety follow-up (telephone call).  
On the first day of the treatment phase (Baseline), eligible subjects will be enrolled and 
receive the first dose of adjunctive pimavanserin 34 mg per day. The remaining study 


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medication will be provided to the subjects to take home with instruction to take the 
medication at approximately the same time each day.  
Clinic visits occurring after Baseline will be conducted at Weeks 2, 4, 6, and 8 (End-of-Study 
[EOS]/Early Termination [ET] visit). 
Figure 1 illustrates the study design. 
 


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Figure 1 
Schematic of Study Design 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
Screening 3 weeks 
8 Weeks Open Label 
34 mg pimavanserin 
2 Week Safety 
Follow-up 
Screening 
Baseline 
Week 2 
Week 4 
Week 6 
Week 8 
End of Study 
Week 10 


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3.2 
Schedule of Assessments 
The schedule of events and assessments for the study is presented in Table 1. 
Table 1 
Schedule of Events and Assessments 
 
 
Screening 
Baseline 
Week 2 
Week 4 
Week 6 
 EOT 
Week 8g 
Safety 
Follow-up 
Week 10 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Study Day(s) 
-21 to -1 
1 
12 to 18 
26 to 32 
40 to 46 
54 to 60 
68 to 74 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/exclusion assessment 
X 
X 
 
 
 
 
 
MGH ATRQa 
X 
 
 
 
 
 
 
Medical history and demographics 
X 
 
 
 
 
 
 
Weight, height, BMI 
X 
Xf 
 
 
 
Xf 
 
Physical and neurological examination 
X 
 
 
 
 
X 
 
12-lead ECG
b
 
X 
X 
X 
 
 
X 
 
Vital signsc 
X 
X 
X 
X 
X 
X 
 
Clinical laboratory testsd 
X 
X 
 
 
 
X 
 
Screen for drugs of abuse 
X 
X 
 
 
 
 
 
Pregnancy test
e
 
X 
X 
 
 
 
X 
 
HAMD-17 
X 
X 
X 
X 
X 
X 
 
C-SSRS 
X 
X 
X 
X 
X 
X 
 
MMSE 
X 
X 
 
X 
 
X 
 
CGI-I 
 
 
X 
X 
X 
X 
 
CGI-S 
 
X 
X 
X 
X 
X 
 
SCOPA 
 
X 
 
X 
 
X 
 
EQ-5D-5L 
 
X 
 
X 
 
X 
 
UPDRS Part III 
 
X 
 
X 
 
X 
 
Dispense study drug 
 
X 
 
X 
 
 
 


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Study drug accountability 
 
 
X 
X 
X 
X 
 
Phone Follow-Up 
 
 
 
 
 
 
X 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
AE assessment 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: AE=adverse event; BMI=body mass index; C-SSRS=Columbia Suicide Severity Rating Scale; CGI-I=Clinical Global Impression–Improvement; 
CGI-S=Clinical Global Impression–Severity; ECG=electrocardiogram; EOT-end of treatment; EQ-5D-5L-5L=EuroQol 5 dimensions-5 levels; HAMD-
17=Hamilton Depression Scale–17 Item; MGH ATRQ=Massachusetts General Hospital Antidepressant Treatment Questionnaire; MMSE=Mini-Mental State 
Exam; SCOPA=Sleep Scales for Outcomes in Parkinson’s Disease-Sleep ; UPDRS Part III=Unified Parkinson's Disease Rating Scale Part III. 
Notes: 
a 
Applicable only to subjects who are currently taking an antidepressant.  
b 
12-lead ECG at Screening is to be completed in triplicate within a 3 minute period. The ECG may be repeated once at Screening in consultation with the 
Medical Monitor. Single ECG recordings are to be collected at subsequent visits. ECGs can be performed any time before blood sampling or at least 
30 minutes after blood sampling during clinic visits  
c 
Vital signs (sitting or supine [at least 3 minutes] blood pressure, pulse rate, oral temperature, and respiratory rate) will be performed at Screening and each 
study visit. 
d 
Thyroid-stimulating hormone (TSH) will only be assessed at Screening. TSH will not be analyzed as part of the chemistry serum testing at other study visits. 
e 
Applicable only to women of childbearing potential. A serum pregnancy test is performed at Screening and a urine pregnancy test at Baseline and Week 8. 
f 
Only weight will be measured after Screening. 
g 
Subject terminating early should at a minimum complete assessments of safety (vital signs, ECG, AEs, clinical laboratories, C-SSRS) and, if possible, 
complete all Week 8 assessments. 
 
 
 
 


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3.3 
Randomization 
Not applicable. 
3.4 
Blinding 
This is an open-label study. Subjects, site staff, and the sponsor will be aware that the subject 
is being treated with a 34 mg dose of pimavanserin. 
3.5 
Determination of Sample Size 
The initial sample size calculation was based on a standard deviation of 8.0 and a dropout 
rate of 10%. An interim review of the statistical assumptions was conducted after 9 subjects 
completed the Week 8 visit, and the sample size was recalculated. The standard deviation in 
HAMD-17 total score change from Baseline to Week 8 was observed to be lower, and the 
dropout rate higher, than the initial assumptions. Therefore, the  sample size has been 
recalculated as follows. 
Assuming the standard deviation for the change in HAMD-17 total score from Baseline to 
Week 8 is 6.0 points, 34 evaluable subjects will provide 80% power to detect a minimum 
mean reduction of 3 points from Baseline to Week 8 at a significance level of 0.05 using a 
2-sided paired t-test. 
Adjusting for a potential non-evaluable rate of up to 15%, approximately 40 subjects will be 
enrolled. 
4 ANALYSIS SETS 
4.1 
Safety Analysis Set 
The Safety Analysis Set will consist of a subset of enrolled subjects who received at least one 
dose of study drug (pimavanserin). 
4.2 
Full Analysis Set 
The Full Analysis Set will consist of a subset of subjects in the Safety Analysis Set who have 
both a Baseline value and at least one post-Baseline value for the HAMD-17 total score. 
5 DATA HANDLING CONVENTIONS 
All data collected in the study will be listed.  


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5.1 
General Data Reporting Conventions 
5.1.1 
Continuous Variables 
For continuous variables, the following summary statistics will be provided:  number of 
subjects, mean, standard error of the mean (SE), standard deviation (SD), minimum, 
maximum, and median. Unless specified otherwise, means, medians, and confidence 
intervals (CIs) will be presented to one more decimal place than the raw data, and the 
standard deviations and standard errors will be presented to 2 more decimal places than the 
raw data. 
5.1.2 
Categorical Variables 
For categorical variables, summaries will include the number and percentage of subjects in 
each category, using the number of subjects with non-missing values as the denominator for 
the percentages (unless otherwise specified). Categories with zero counts will not have zero 
percentages displayed. Percentages will be presented to 1 decimal place.  
5.1.3 
Statistical Tests 
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 (CIs) will be 2-sided 
95% CIs. P-values will generally be presented to 4 decimal places; p-values less than 0.0001 
will be presented as <0.0001. 
5.1.4 
Conversion of Days to Months 
When converting number of days to months, it will be calculated as the number of days 
divided by 365.25 and then multiplied by 12. When converting number of days to years, it 
will be calculated as the number of days divided by 365.25. 
5.2 
Derived Variables 
In general, the total scores and subscores for assessment scales will be derived within the 
analysis datasets. In the event that total scores and/or subscores are also collected on the 
electronic case report form (eCRF), the derived values will be used for all analyses. Both the 
raw and derived scores will be presented in listings. 
5.2.1 
Hamilton Depression Rating Scale 17-Items (HAMD-17) 
The HAMD-17 is assessed at Screening, Baseline, Weeks 2, 4, 6, and Week 8/ET visits. 
The HAMD-17 is a 17-item clinician-administered questionnaire used to provide an 
indication of depression, and as a guide to evaluate recovery (Hamilton, 1960). The 


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questionnaire assesses symptoms over the past week (7 days). The questionnaire is designed 
for adults to rate the severity of, and change in, depressive symptoms by probing mood, 
feelings of guilt, suicide ideation, insomnia, agitation or retardation, anxiety, weight loss, and 
somatic symptoms. Each item on the questionnaire is scored on a 3- or 5-point scale, 
depending on the item, and the total score is compared to the corresponding descriptor. The 
HAMD-17 total score can range from a minimum of 0 to a maximum of 52. A score of 0-7 is 
considered normal. Scores of 14 or higher indicate moderate, severe, or very severe 
depression. 
If more than 3 items are missing, the total score will be set to missing. If 3 or fewer items are 
missing, then missing items will be imputed as follows: 
 Items using a 3-point scale (4, 5, 6, 12, 13, 14, 16, and 17): missing values will be 
imputed using the arithmetic mean of the non-missing items that are also scored on a 
3-point scale, then rounded to the nearest integer 
 Items using a 5-point scale (1, 2, 3, 7, 8, 9, 10, 11, and 15): missing values will be 
imputed using the arithmetic mean of the non-missing items that are also scored on a 
5-point scale, then rounded to the nearest integer 
5.2.2 
Clinical Global Impression – Severity (CGI-S) Scale  
The CGI-S is assessed at Screening, Baseline, Weeks 2, 4, 6, and 8/ET visits. 
The CGI-S is a clinician-rated, 7-point scale that is designed to rate the severity of the 
subject's depression at the time of assessment using Investigator’s judgment and past 
experience with subjects who have the same disorder (i.e., depression in Parkinson’s disease). 
The 7-point scores are: 1=normal, not ill; 2=minimally ill; 3=mildly ill; 4=moderately ill; 
5=markedly ill; 6=severely ill; 7=among the most severely ill.  
Missing CGI-S scores will not be imputed. 
5.2.3 
Clinical Global Impression– Improvement (CGI-I) Scale  
The CGI-I is assessed at Weeks 2, 4, 6, and 8/ET visits. 
The CGI-I is a clinician-rated, 7-point scale that is designed to rate the improvement in the 
subject’s depression at the time of assessment, relative to the symptoms at Baseline. The 7-
point scores are: 1=very much improved; 2=much improved; 3=minimally improved; 4=no 
change; 5=minimally worse; 6=much worse; 7=very much worse.   
Missing CGI-I scores will not be imputed. 


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5.2.4 
Scale for Outcomes in Parkinson’s Disease (SCOPA) – Sleep Scale 
The SCOPA-Sleep scale is assessed at Baseline, Week 4, and Week 8/ET visits. 
The SCOPA-Sleep was developed for research in Parkinson’s disease to evaluate both 
nighttime sleep (NS) and daytime sleepiness (DS). The SCOPA-Sleep scale consists of 
3 subscales, SCOPA-NS, SCOPA-DS, and one additional question that evaluates overall 
sleep quality. For each subscale, the time frame is the preceding month. 
The SCOPA-NS subscale addresses problems in nighttime sleep and consists of 5 items: 
sleep initiation, sleep fragmentation, sleep efficiency, sleep duration, and early wakening. 
Each item has 4 response options (ranging from 0=not at all, to 3=a lot) such that the 
minimum score is 0 and the maximum score is 15, with higher scores indicating more severe 
NS problems. 
The SCOPA-DS subscale addresses problems in daytime sleepiness and consists of 6 items: 
how often the subject 1) fell asleep unexpectedly,  2) fell asleep peacefully, 3) fell asleep 
watching TV/reading, 4) fell asleep while talking to someone, 5) had difficulty staying 
awake, and 6) whether falling asleep in the daytime was considered a problem. Each item has 
4 response options (ranging from 0=never, to 3=often). Therefore, possible SCOPA-DS 
subscale scores can range from 0 to 18, with higher scores indicating more severe DS 
problems.  
If only one SCOPA-NS item is missing, then the subscale score will be imputed by replacing 
the missing item with the mean (rounded to the nearest integer) of the non-missing items for 
a given subject and timepoint. If more than 1 item is missing, then the subscale total score 
will remain missing. The same imputation algorithm will be applied to the SCOPA-DS 
subscale. 
Global sleep quality is assessed using a single-item 7-point scale (1=slept very well to 
7=slept very badly). This item will not be included in the SCOPA-DS or SCOPA-NS total 
scores. Missing values for the global sleep quality items will not be imputed. 
5.2.5 
EQ-5D-5L Proxy Version 1 
The EQ-5D-5L questionnaire is assessed at Baseline, Week 4, and Week 8/ET. 
The EQ-5D-5L is a standardized measure of health status that provides a simple, generic 
measure of health for clinical and economic appraisal. In this study, Proxy Version 1 will be 
administered, in which the caregiver (the proxy) is asked to rate the subject’s health-related 
quality of life in his/her (the proxy’s) opinion. This questionnaire consists of 2 components – 
the EQ-5D-5L descriptive system and the EQ-5D-5L Visual Analogue scale (EQ-5D-5L 
VAS). 


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The descriptive system consists of 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each dimension has 5 levels (responses): no 
problem (1), slight problems (2), moderate problems (3), severe problems (4), and extreme 
problems (5). The digits for the 5 dimensions are combined into a 5-digit code that describes 
the subject’s health state. 
The EQ-5D-5L VAS records the subject’s health on a vertical visual analogue scale, where 
the upper endpoint is labeled “The best health you can imagine” and is numbered 100, while 
the lower endpoint is labeled “The worst health you can imagine” and is numbered 0. The 
EQ-5D-5L VAS will be treated as a continuous endpoint. 
Missing values will not be imputed for either the descriptive system or EQ-5D-5L VAS. 
5.2.6 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is assessed at Screening, Baseline, Weeks 2, 4, 6, and 8/ET visits. 
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 Baseline, Week 2, 
Week 4, Week 6, and Week 8/ET.  
The C-SSRS monitors changes in suicidal thinking and behavior over time in order to 
determine risk. Four constructs are measured: the severity of ideation, the intensity of 
ideation, behavior, and lethality. 
There are 5 questions about suicidal ideation: wish to be dead; non-specific active suicidal 
thoughts; active suicidal ideation with any methods (not plan) without intent to act; active 
suicidal ideation with some intent to act, without specific plan; active suicidal ideation with 
specific plan and intent. If a subject answers “yes” to any of these 5 questions, this subject 
will be counted as having suicidal ideation. 
There are 5 questions about suicidal behavior: suicide, actual attempt; interrupted attempt; 
aborted attempt; preparatory acts or behavior. If a subject answers “yes” to any of these 
4 questions, this subject will be counted as having suicidal behavior. 
Missing values will not be imputed.  
5.2.7 
Movement Disorders Society-Unified Parkinson’s Disease Rating Scale Part III 
The Movement Disorders Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) 
Part III (motor examination) will be assessed at Baseline, Week 4, and Week 8/ET. 
The MDS-UPDRS Part III is used to assess motor signs of PD and consists of 33 individual 
items based on 18 domains, due to left, right, and other body distributions. Each item has 


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5 possible responses (0, 1, 2, 3, and 4) with 0 being normal and 4 severe. The total score will 
be derived as the sum of the 33 item scores; thus, the total score has a potential range from 
0 to 132, with higher scores indicating more severe extrapyramidal symptoms. 
If 6 or fewer items are missing, then the total score for a given subject and timepoint will be 
imputed as the mean of the non-missing items multiplied by 33 and rounded to the nearest 
integer. If more than 6 items are missing, the total score will not be derived. 
In addition, the MDS-UPDRS Part III assesses motor signs with the Hoehn and Yahr Stage 
on a 6-point scale, where asymptomatic is scored 0 and wheelchair bound or bedridden is 
scored 5. Missing values for Hoehn and Yahr Stage will not be imputed.  
5.2.8 
Mini-Mental State Examination (MMSE) 
The MMSE is assessed at Screening, Baseline, Week 4, and Week 8/ET. 
The MMSE is a 30-item questionnaire that includes simple questions and problems in the 
following areas: time and place of testing, repeating lists of words, arithmetic, language use 
and comprehension, and copying or drawing.  
Each of the 30 items has 2 possible values, 0 (incorrect) or 1 (correct). The MMSE total score 
will be derived as the sum of the 30 item scores, thus the total score has a potential range of 
0 to 30. Lower scores indicate more severe cognitive impairment. 
If 6 or fewer items are missing, then the total score for a given subject and timepoint will be 
imputed as the mean of the non-missing items multiplied by 30 and rounded to the nearest 
integer. If more than 6 items are missing, the total score will not be derived. 
5.3 
Analysis Visit Windows  
Baseline will be defined as the last non-missing result, including results from repeated and 
unscheduled measurements, before dosing.  
Efficacy and safety assessments will be summarized by analysis visit as shown in Table 2 
below. 


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Table 2 
Analysis Visit Windows 
Analysis Visit 
Name 
Study Visit 
Target Study 
Day1 
Study Day Interval 
Baseline  
Visit 2 (Baseline) 
1 
≤1 
Week 2 
Visit 3 (Week 2) 
15 
2 to 21 
Week 4 
Visit 4 (Week 4) 
29 
22 to 35 
Week 6 
Visit 5 (Week 6) 
43 
36 to 49 
Week 8 
Visit 6 (Week 8/ET) 
57 
50 to 63 
Follow-up 
Visit 7 (Week 
10/Safety Follow-up) 
71 
≥64 
1 
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). 
 
5.3.1 
Unscheduled Assessments 
Both scheduled and unscheduled assessments, including the assessments at ET visits, will be 
considered for planned timepoint analyses. All assessments will be presented in data listings. 
5.3.2 
Multiple Measurements within Visit Windows 
If more than one assessment falls within a given window, then the assessment closest to the 
target study day will be selected for the by-visit summaries. If two assessments are 
equidistant from the target day, then the chronologically last assessment will be used. 
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 analysis where the most extreme values should be selected (e.g., overall post-
baseline minimum, overall post-baseline maximum, and potentially clinically important 
values), all non-missing post-Baseline values will be considered, regardless of whether the 
value is selected for the by-visit summaries. All results will be presented in data listings. 
When the 12-lead electrocardiogram (ECG) is collected in triplicate, the average of the 
triplicate parameter values will be considered as one assessment for the summaries.  
5.4 
Data Handling Conventions 
If the last dose date of study drug is missing for a subject who completed or discontinued 
from the study, then the last study drug return date will be used in the calculation of treatment 
duration. If the study drug return dates are all missing (e.g., the subject never returned any 


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study drug), then the ET/EOS date (excluding follow-up visit) will be used in the calculation 
of treatment duration. For the incomplete last dose date of the study drug, the imputation 
algorithms will be detailed in the analysis dataset specification (ADS) document. The missing 
or incomplete dates will be displayed in the data listings as reported on the eCRF rather than 
the imputed dates. 
For any data summarization that occurs before final database lock, if a subject is still 
ongoing, then that subject’s last dose date will be imputed using the database extract date.
5.4.1 
Missing or Incomplete Dates for Prior or Concomitant Medications 
Missing or incomplete medication start or end dates will be imputed for the purpose of 
determining whether the medications are taken concomitantly (see Section 10 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 ADS document. The missing 
or incomplete dates will be displayed in the data listings as reported on the eCRF rather than 
the imputed dates. 
5.4.2 
Missing or Incomplete Dates for Adverse Events 
Missing or incomplete adverse event (AE) start dates will be imputed for the purpose of 
determining whether the AEs are treatment-emergent (see Section 14.1 for definition). When 
the chronological order of an AE onset relative to the study drug treatment period is unclear 
due to missing or incomplete date(s), the AE will be considered as treatment-emergent. The 
imputation algorithms will be detailed in the ADS document. The missing or incomplete 
dates will be displayed in the data listings as reported on the eCRF rather than the imputed 
dates. 
5.4.3 
Missing Severity Assessment for Adverse Events 
If the severity is missing for an AE starting on or after the date of the first dose of study drug, 
then a severity of “Severe” will be assigned. The imputed values for severity assessment will
be used for incidence summaries, and the actual values will be used in data listings. 
5.4.4 
Missing Relationship to Study Drug for Adverse Events 
If the relationship to study drug is missing for an AE starting on or after the date of the first 
dose of study drug, a causality of “Related” will be assigned. The imputed values for
relationship to study drug will be used for incidence summaries, and the actual values will be 
presented in data listings. 
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5.4.5 
Character Values of Clinical Laboratory Variables  
If the reported value of a clinical laboratory variable cannot be used in a statistical analysis 
due to, for example, a character string reported for a numeric variable, an appropriately 
determined coded value may be used in the statistical analysis. The coding algorithms will be 
detailed in ADS document. The actual values as reported in the database will be presented in 
data listings. 
6 SUBJECT DISPOSITION 
For subjects who participate in the screening phase but are not enrolled in the study (i.e., 
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.   
The number of sites that screened at least 1 subject, number of sites that enrolled at least 
1 subject, number of subjects screened, and number of unique subjects screened will be 
summarized by site and overall. In addition, the number of subjects enrolled at each site will 
also be tabulated by analysis set. 
For enrolled subjects, the number and percentage of subjects in Safety Analysis Set and Full 
Analysis Set will be summarized. A listing will be provided displaying all subjects excluded 
from the Safety and Full Analysis Sets, and will include reason(s) for exclusion.  
Within each analysis set, the number and percentage of subjects who completed the study or 
discontinued (all discontinued and by discontinuation reason) will also be summarized. 
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. 
A summary of the number and percentage of subjects with major protocol deviations for each 
deviation category will be presented for the Safety Analysis Set. A listing of protocol 
deviations by site and subject will also be provided. 


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8 DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
8.1 
Demographics 
Demographics will be summarized for the Safety Analysis Set and the Full Analysis Set using 
descriptive statistics. Variables include age, sex, primary race (subjects of multi-racial 
background can only identify/select one primary race on eCRF, or choose “other” and 
specify), ethnicity, height (cm), weight (kg), body mass index (BMI), Baseline living 
situation category, and Baseline caregiver category.  
The reported age will be calculated relative to the subject’s age at the informed consent date. 
Age and BMI will be presented as both continuous and categorical variables. Age categories 
will be presented as <70 and ≥70 years old. BMI categories will be presented as <25, ≥25 to 
<30, and ≥30. 
A listing of subject living situation and caregiver information will be provided. 
8.2 
Disease Characteristics at Baseline 
Disease characteristics at Baseline will be summarized for the Safety Analysis Set and the 
Full Analysis Set using descriptive statistics. Variables include Baseline HAMD-17 total 
score, Baseline CGI-S, Baseline MMSE total score, Baseline SCOPA-NS score, Baseline 
SCOPA-DS score, Baseline SCOPA global sleep quality, and Baseline MDS-UPDRS Part III 
total score. 
Baseline HAMD-17 total score, Baseline CGI-S, Baseline SCOPA global sleep quality, and 
Baseline MMSE total score will be presented as continuous and categorical variables. The 
categories will be displayed as follows: 
 Baseline HAMD-17 total score: <24 and ≥24  
 Baseline CGI-S:  normal (1) to among the most extremely ill (7)  
 Baseline SCOPA global sleep quality: very well (1) to very badly (7) 
 Baseline MMSE total score: <25 and ≥25  
PD and DPD disease history will include the following variables:  
 Age (years) at onset of PD  
 Duration (years) of PD  
 Age (years) at onset of DPD  
 Duration (years) of DPD  


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 Time (years) since first antidepressant treatment  
 Current background antidepressant  medication 
 Duration (months) of current background antidepressant medication 
 Ever had suicidal ideation or behavior (yes or no) 
 Had suicidal ideation or behavior within past 6 months (yes or no) 
Informed consent date will be used as the reference date for calculating the durations listed 
above. 
The Massachusetts General Hospital (MGH) Antidepressant Treatment Response 
Questionnaire (ATRQ) is assessed at the Screening visit for subjects who are taking an 
SSRI/SNRI (i.e. adjunctive treatment). It is a clinician-assisted questionnaire used to 
determine response to antidepressant therapy. Drug type, generic name, drug taken during 
this current episode of depression (Yes/No), dose, and took at least this dose for at least 4 
weeks (Yes/No), and the percentage of improvement in depression will be listed. 
In addition, for all subjects lifetime antidepressant use and response will be collected, 
including start and stop dates, dose, units, and response (≤25%, 26% to <50%, 50% to <75%, 
and 75% to 100%). These data will only be listed. 
9 MEDICAL HISTORY 
Medical and surgical history data will be coded using 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 (PT) for the Safety Analysis Set and Full 
Analysis Set. A subject will be counted only once per SOC or per PT for the summary. 
A listing of the SOC, PT, body system, verbatim term for the medical history condition/event, 
start and stop dates (when available), and an indicator for whether or not the condition is 
ongoing will be provided. 
10 PRIOR, CONCOMITANT AND POST-TREATMENT MEDICATION 
Summaries of prior, concomitant, and post-treatment medications will be provided for the 
Safety Analysis Set. 
For a subject, a prior medication is defined as any medication with the start and stop dates 
prior to the date of the first dose of study drug. A Concomitant medication is defined as any 
medication with a start date prior to the date of the first dose of study drug and continuing 
after the first dose of study drug or with a start date between the dates of the first and last 


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doses of study drug, inclusive. Any medication with a start date after the date of the last dose 
of study drug will be considered as post-treatment medication. Prior, concomitant, and post-
treatment medications will be summarized separately. Medications will be coded using the 
World Health Organization Drug Dictionary, version March 2017 or newer. The number and 
percentage of subjects taking each drug class (Anatomical Therapeutic Chemical Level 3) 
and medication PT will be tabulated. Multiple medication usage by a subject in the same 
category will be counted only once. 
Background antidepressant therapies will be tabulated by medication PT and dose level. 
11 EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE 
Summaries of exposure and compliance to study drug will be provided for the Safety 
Analysis Set and Full Analysis Set. 
11.1 Exposure to Study drug  
For each subject, the duration of exposure to study drug is calculated as follows: 
𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑒𝑥𝑝𝑜𝑠𝑢𝑟𝑒= 𝑙𝑎𝑠𝑡 𝑑𝑜𝑠𝑒 𝑑𝑎𝑡𝑒−𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 𝑑𝑎𝑡𝑒+ 1 
Duration of exposure will be summarized descriptively as both continuous and categorical 
variables. For the categorical presentation, the number and percentage of subjects in each of 
the following categories will be displayed: <1week (1 to 6 days), 1 to <2 weeks (7 to 
13 days), 2 to <4 weeks (14 to 27 days), 4 to <6 weeks (28 to 41 days), and >6 weeks 
(42 days or longer). A Kaplan-Meier curve of duration of exposure will also be presented.  
The pimavanserin dose levels are expressed as free base.  
11.2 Measurement of Study Drug Compliance 
Study drug compliance (in percentage) for a given subject is defined as follows: 
𝐶𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒= [𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑑𝑖𝑠𝑝𝑒𝑛𝑠𝑒𝑑−𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑟𝑒𝑡𝑢𝑟𝑛𝑒𝑑
2 × 𝑑𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑒𝑥𝑝𝑜𝑠𝑢𝑟𝑒
] × 100% 
Compliance will be summarized as both continuous and categorical variables. For categorical 
presentation, the number and percentage of subjects in each of the following categories will 
be presented: <80%, ≥80 to <120%, and ≥120%. 
12 EFFICACY ANALYSES 
All efficacy analyses will be performed on the Full Analysis Set. 


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12.1 Efficacy Variables 
12.1.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from Baseline to Week 8 in the HAMD-17 total 
score. 
12.1.2 Secondary Efficacy Endpoints 
Secondary efficacy endpoints are the following: 
 Change from Baseline in HAMD-17 total score at Weeks 2, 4, and 6 
 Proportion of  responders (defined as ≥50% reduction from Baseline in HAMD-17 
total score) 
 CGI-I score  
 Change from Baseline in CGI-S 
 Change from Baseline in SCOPA-NS 
 Change from Baseline in SCOPA-DS 
 Change from Baseline in EQ-5D-5L  
12.2 Adjustment for Covariates 
For continuous variables (except CGI-I) analyzed using the mixed model for repeated 
measures (MMRM) , the Baseline value of the endpoint being analyzed will be included as a 
covariate as described in Section 13. For CGI-I, the Baseline CGI-S score will be included as 
a covariate in the MMRM analysis. 
12.3 Handling of Missing Data 
Total scores that are missing, after any imputation of individual missing items as described in 
Section 5.2.1, will not be imputed. Analysis of covariance (ANCOVA) and EQ-5D 
categorical analyses will be performed using the last observation carried forward (LOCF) 
method of imputation for missing data. The LOCF method will carry forward the Baseline 
value if necessary. 
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 the study drug, the 
imputation algorithms will be detailed in the ADS document. The missing or incomplete 


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dates will be displayed in the data listings as reported on the eCRF rather than the imputed 
dates. 
For any data summarization that occurs before final database lock, if a subject is still 
ongoing, then that subject’s last dose date will be imputed using the database extract date. 
12.4 Multiple Comparisons / Multiplicity 
No adjustments of p-values for multiple comparisons will be performed. 
12.5 Examination of Subgroups 
The MMRM analysis described in Section 13.1.1 will be performed separately for the 
primary efficacy variable (HAMD-17 total score), and for CGI-S and CGI-I as described in 
Section 13.1.6 and Section 13.1.7, respectively, for each of the following subgroups: 
 treatment regimen (pimavanserin monotherapy or pimavanserin adjunctive therapy) 
 age group (<70 or  >70 years old) 
 sex (male or female) 
 primary race (white or non-white) 
 Baseline symptom severity measured by HAMD-17 total score (<24 or  >24)  
The LS mean changes with corresponding 95% CIs from the subgroups will also be 
graphically presented in forest plots for the above efficacy variables. 
13 METHODS OF EFFICACY ANALYSES 
13.1 Primary Efficacy Analysis  
The primary endpoint is the change from Baseline to Week 8 in the HAMD-17 total score. 
The primary analysis will be based on the Full Analysis Set.  
The null and alternative hypotheses for the primary endpoint are as follows: 
Let Δ be the mean change from Baseline to Week 8 in the HAMD-17 total score: 
The null hypothesis for the primary efficacy endpoint is:  
 
Δ = 0 
The alternative hypothesis for the primary efficacy endpoint is:          Δ ≠ 0 
13.1.1 Primary Analysis using MMRM in the Full Analysis Set 
The HAMD-17 total score will be analyzed using mixed model repeated measures (MMRM) 
in the Full Analysis Set. The dependent variable will be the change from Baseline in the 


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HAMD-17 total score. The independent variables in the model will include the following: 
visit (Week 2, Week 4, Week 6, and Week 8), Baseline-by-visit interaction, and the Baseline 
HAMD-17 total score as a continuous covariate. An unstructured covariance matrix will be 
used and the Kenward-Roger approximation will be used to adjust the denominator degrees 
of freedom. Least squares (LS) adjusted means will be estimated using observed cases (OC).  
 
 
 
        
   
 
        
   
 
        
 
        
 
 
In the event that the model fails to converge using the unstructured  covariance matrix, then 
the following covariance structures will be modeled in the order given: heterogeneous 
Toeplitz, heterogeneous compound symmetry, heterogeneous autoregressive(1), Toeplitz,  
compound symmetry, autoregressive(1), variance components. The first covariance structure 
that allows for convergence will be selected for the final model. 
Summary statistics for the HAMD-17 total score (observed and change from Baseline) will 
be presented for all visits from Baseline through Week 8. For change from Baseline values at 
each post-Baseline visit, LS means and standard errors (SE), the corresponding 95% 
confidence interval and p-value will also be presented. In addition, LS mean ± SE over time 
for the change from Baseline values will also be presented in line plots. 
The hypothesis testing will be performed based on the LS mean change at Week 8 and will be 
tested at an alpha level of 0.05 (2-sided).   
13.1.2 LOCF Paired T-test for HAMD-17 
A paired t-test using LOCF will be performed on the HAMD-17 total score change from 
Baseline at each post-baseline visit using the Full Analysis Set. Summary statistics for the 
HAMD-17 total score (observed and change from Baseline) will be presented for all visits 
from Baseline through Week 8. For change from Baseline values at each post-Baseline visit, 
95% confidence intervals and p-values will be presented. 
13.1.3 Secondary Efficacy Analyses 
The Full Analysis Set will be used for all secondary efficacy analyses. 


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13.1.4 Change from Baseline to Weeks 2, 4, and 6 in HAMD-17 Total Score 
See Section 13.1.1 for details of this analysis. 
13.1.5 HAMD-17 Responder Analysis 
For the HAMD-17 total score, a treatment response is defined as a ≥50% reduction from 
Baseline. 
At each timepoint the proportion of responders will be descriptively summarized including 
95% confidence intervals. Both OC, in which subjects with missing values at a given visit are 
excluded, as well as missing values imputed as non-responders will be presented.  
13.1.6 CGI-S 
The CGI-S score change from Baseline at each post-Baseline timepoint will be analyzed 
using an MMRM model similar to that used for the primary efficacy endpoint. The dependent 
variable will be the CGI-S score change from Baseline, and the independent variables in the 
model will include the following: visit (Weeks 2, 4, 6, and 8), Baseline CGI-S score 
(continuous covariate), and Baseline CGI-S score-by-visit interaction. 
13.1.7 CGI-I 
The CGI-I score at each post-Baseline timepoint will be analyzed using an MMRM model 
similar to that used for the primary efficacy endpoint. The dependent variable will be the 
CGI-I score, and the independent variables in the model will include the following: visit 
(Weeks 2, 4, 6, and 8), Baseline CGI-S score (continuous covariate), and Baseline CGI-S 
score-by-visit interaction. 
The CGI-I scores will also be dichotomized by combining scores of 1 or 2 (very much 
improved or much improved) into an “Improved” category, and all remaining scores into a 
“Not Improved” category. At each timepoint, the proportion of responders (very much 
improved or much improved) will be descriptively summarized including 95% confidence 
intervals. Both OC, in which subjects with missing values at a given visit are excluded, as 
well as missing values imputed as not improved, will be presented.  
The observed (un-dichotomized) scores, as well as dichotomized scores, will be descriptively 
summarized by visit.  
13.1.8 SCOPA 
13.1.8.1 
SCOPA-NS 
The SCOPA-NS score at each post-Baseline timepoint will be analyzed using an MMRM 
model similar to that used for the primary efficacy endpoint. The dependent variable will be 


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the SCOPA-NS score change from baseline, and the independent variables in the model will 
include the following: visit (Weeks 4 and 8), Baseline SCOPA-NS score (continuous 
covariate), and Baseline SCOPA-NS score-by-visit interaction. 
13.1.8.2 
SCOPA-DS 
The SCOPA-DS score at each post-Baseline timepoint will be analyzed using an MMRM 
model similar to that used for the primary efficacy endpoint. The dependent variable will be 
the SCOPA-DS score change from Baseline, and the independent variables in the model will 
include the following: visit (Weeks 4 and 8), Baseline SCOPA-DS score (continuous 
covariate), and Baseline SCOPA-DS score-by-visit interaction. 
13.1.8.3 
SCOPA Global Sleep Quality 
The SCOPA global sleep quality score at each post-Baseline timepoint will be analyzed using 
an MMRM model similar to that used for the primary efficacy endpoint. The dependent 
variable will be the global sleep quality score change from Baseline, and the independent 
variables in the model will include the following: visit (Weeks 4 and 8), Baseline global sleep 
quality score (continuous covariate), and Baseline global sleep quality score-by-visit 
interaction. 
13.1.9 EQ-5D-5L  
13.1.9.1 
EQ-5D-5L Descriptive System 
For each EQ-5D-5L dimension the proportion of subjects reporting no, slight, moderate, 
severe, and extreme/unable to perform activity will be summarized descriptively at each 
timepoint (Baseline, Week 4, and Week 8), using both OC and LOCF analysis methods.  
Change from Baseline in EQ-5D-5L health state will be assessed with the Pareto 
classification of health change (PCHC) method. By using this methodology, at each post-
Baseline visit (Week 4 and Week 8), each EQ-5D-5L health state will be classified into one of 
four categories, relative to the Baseline health state: 
 Improved = improved on at least one dimension and not worsened on any other 
dimension 
 Mixed = improved on at least one dimension and worsened on at least one other 
dimension 
 No change = no changes in any dimension 
 Worsened = deterioration on at least one dimension and no improvement on any other 
dimension 


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The proportion of subjects in each PCHC category will be summarized descriptively at 
Week 4 and Week 8, using both OC and LOCF analysis methods.  
13.1.9.2 
EQ-5D-5L VAS 
EQ-5D-5L VAS score change from Baseline at each post-Baseline timepoint will be analyzed 
by using an MMRM model similar to that used for the primary efficacy endpoint. The 
dependent variable will be the EQ-5D-5L VAS change from Baseline, and the independent 
variables in the model will include the following: visit (Weeks 4 and 8), Baseline EQ-5D-5L 
VAS score (continuous covariate), and Baseline EQ-5D-5L VAS score-by-visit interaction. 
13.1.9.3 
EQ-5D-5L Index Scores 
Since a United States value set to map EQ-5D-5L health states to preference weights (i.e., 
index values) is not yet available, the EQ-5D-5Lindex scores will be derived from EQ-5D-3L 
values. This procedure entails using a crosswalk dataset to map health states from the 5L 
system to the 3L system, and then applying EQ-5D-5L-3L weights from the US general 
population to obtain the index scores. The SAS software program to assign each health state 
to its corresponding index score was obtained from the EuroQol Research Foundation. 
The EQ-5D-5L index score change from Baseline at each post-Baseline timepoint will be 
analyzed using an MMRM model similar to that used for the EQ-5D-5L VAS.  
13.1.10 LOCF ANCOVA for Continuous Efficacy Variables 
For each of the continuous secondary efficacy endpoints (HAMD-17, CGI-S, CGI-I, SCOPA-
NS, SCOPA-DS, SCOPA global sleep quality, EQ-5D-5L VAS, EQ-5D-5L index scores), 
ANCOVA using LOCF will be performed at each post-baseline visit, similar to that described 
in Section 13.1.2. 
To assess whether there is a linear correlation between the HAMD-17 total score change from 
Baseline and CGI-I rating, the HAMD-17 total score change from Baseline will also be 
summarized by CGI-I rating for all post-baseline visits.  The mean + SE HAMD-17 total 
score change from Baseline by CGI-I rating will also be plotted for Week 8OC. 
14 SAFETY ANALYSES 
The safety analysis will be performed based on the Safety Analysis Set using actual 
treatment. Safety variables include adverse events (AEs), clinical laboratory variables, vital 
signs, body weight, BMI, physical examinations, electrocardiogram (ECG), C-SSRS, MMSE, 
and MDS-UPDRS Part III variables. 


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14.1 Adverse Events  
All Adverse events (AEs) will be coded using MedDRA version 19.0 or newer. 
An AE (classified by PT) will be considered a treatment-emergent AE (TEAE) if started after 
first study drug dose administration and no later than last study drug dose date + 30. AEs 
reported on Day 1 based on pre-dose findings (e.g., clinically significantly abnormal vital 
signs, laboratory test results, or electrocardiogram parameters) will not be considered as 
TEAEs.  
The event counts and the number and percentage of subjects reporting TEAEs will be 
tabulated by SOC and PT; and by SOC, PT, and maximum severity. If more than 1 AE occurs 
with the same PT for the same subject, the subject will be counted only once for that PT 
using the most severe occurrence for the summarization by severity to study drug. In 
addition, the event counts and the number and percentage of subjects with TEAEs classified 
by the Investigator as related to the study drug, with most frequently reported TEAEs (PTs 
reported by  5% of subjects), with treatment-emergent serious AEs (TESAEs), with fatal 
AEs (i.e., events that cause death), and with TEAEs leading to discontinuation of study drug 
will be summarized by SOC and PT. These tables will be sorted alphabetically by SOC and 
then by descending subject frequency for the PTs within each SOC. 
The event counts and the number and percentage of subjects with any TEAEs will also be 
tabulated by PT without SOCs and will be sorted by descending subject frequency. 
An AE listing by subject will display all events, including those which are not treatment-
emergent, and will include the verbatim term in addition to the MedDRA SOC and PT. This 
listing will also include all relevant eCRF data associated with the event: e.g., date of onset, 
date resolved, date of first dose, date of last dose, study dose level at AE onset, severity, 
frequency, outcome, relationship to study drug, action taken with study drug, and required 
therapy. When a date is presented, the study day associated with the date will also be 
displayed. Separate listings will be presented for subjects with SAEs, subjects with AEs 
leading to discontinuation, and subjects who died (if any). In these listings, an indicator for 
treatment-emergent events will also be included. 
14.2 Clinical Laboratory Variables 
Laboratory evaluations will be completed according to the schedule presented in Table 3 
below. 


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Table 3 
Clinical Laboratory Assessments 
Visit 
Testsa,b,c 
Screening 
Clinical chemistry serum (including HbA1c, TSH, free T4 
reflex), complete blood count, urinalysis, urine toxicity screen, 
and serum pregnancy test 
Baseline 
Clinical chemistry serum, complete blood count, urinalysis, urine 
toxicity screen, and urine pregnancy test 
Week 8/ET 
Clinical chemistry serum (including HbA1c), complete blood 
count, urinalysis, and urine pregnancy test 
a 
Pregnancy tests are only required for women of child-bearing potential. 
b 
An HbA1c test is only required at Screening and Week 8/ET. 
c 
TSH and free T4 reflex are only required at Screening. 
 
Hematology tests include the following: 
o Complete blood count (CBC) including: 
 
White blood cell (WBC) count 
 
Complete differential (relative and absolute) 
 
Hematocrit (Hct), hemoglobin (Hgb), red blood cells (RBC), platelets 
 
Reticulocyte count 
Serum chemistry 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 Glucose 
o Albumin (ALB), total protein 
o Prolactin 
o HbA1c 
o Lipid panel  
– Total cholesterol, high-density lipoprotein (HDL)-cholesterol, triglycerides, 
low-density lipoprotein(LDL)-cholesterol 
o Thyroid stimulating hormone (TSH) and reflex free thyroxine (T4) (TSH and T4 are 
collected only at Screening) 
 
Urinalysis tests include the following: 
o Color, clarity, blood, RBCs, WBCs, protein, glucose, ketones, specific gravity, pH, 
leukocyte esterase, nitrite, microscopic analysis 
Pregnancy tests include the following: 
o A serum pregnancy test will be performed at Screening for women of child-bearing 
potential 


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o A urine pregnancy test will be performed at Baseline and Week 8/ET for women of 
child-bearing potential 
All laboratory test results (including urine drug screen) are from a central laboratory and will 
be listed. The listings will include date and study day of collection. All units will be displayed 
in Système International [SI] units. Out-of-range values will be flagged in the data listings 
(e.g. ‘L’ or ‘H’). 
Clinical laboratory values for hematology, chemistry and urinalysis (specific gravity and pH) 
will be summarized by descriptive statistics at Baseline and Week 8 visits. The change from 
Baseline values will also be summarized at the Week 8 visit. 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 (e.g., 
blood, protein, glucose, and ketones), the number and percentage of subjects will be tabulated 
by category at Baseline and Week 8, and the denominator is the number of subjects with non-
missing values for the given parameter and visit.  
Laboratory values (except for those that were only assessed at Screening or Baseline) will 
also be summarized in shift tables to determine the number and percentage of subjects with 
values classified as below (low), within (normal), and above (high) normal ranges at Week 8, 
overall post-Baseline minimum, and overall post-Baseline maximum. For the by-visit shift 
summary, the denominator is the total number of subjects with non-missing values at 
Baseline and the given visit for the given parameter. 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. The denominator is the number of subjects with non-missing 
Baseline and at least one post-Baseline value for the given parameter. For hemoglobin, 
hematocrit, and uric acid, the shift summaries will be presented for each gender and for both 
genders combined. 
The number and percentage of subjects with potentially clinically important laboratory values 
(PCI) at Week 8 and overall post-Baseline will be summarized for selected parameters by 
Baseline status (All subjects and Within Normal Range). PCI criteria are listed in Table 4 and 
Table 5. For the overall post-Baseline summaries of PCI values, all post-Baseline values will 
be considered, including unscheduled and out of window values. Subjects with multiple PCI 
values for a given parameter will be counted only once for that parameter. For the by-visit 
summary, the numerator for the percentage is the total number of subjects with a 
post-Baseline PCI value for the given parameter and visit, and the denominator is the total 
number of subjects with non-missing values for the given parameter and visit. For the overall 
post-Baseline summary, the numerator for the percentage is the total number of subjects with 


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at least 1 post-Baseline PCI laboratory value for the given parameter, and the denominator is 
the number of subjects with at least 1 post-Baseline laboratory value for the given parameter. 
Subjects with any 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 
% 
<30 
>50 (F) 
>55 (M) 
L/L 
<0.3 
>0.5 (F) 
>0.55 (M) 
Leukocyte (White 
Blood Cell Count) 
x 103/µL 
≤2.8 
≥15 
x 109/L 
≤2.8 
≥15 
Neutrophils 
x 103/µL 
≤1.5 
No upper 
limit 
x 109/L 
≤1.5 
No upper 
limit 
Platelet Count 
x 103/µL 
≤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 
 
 
 
 
 
 
 
Sodium 
mEq/L 
≤125 
≥155 
mmol/L 
≤125 
≥155 
Potassium 
mEq/L 
≤3.0 
≥5.5 
mmol/L 
≤3.0 
≥5.5 
Calcium, total 
mg/dL 
<8.0 
>11.0 
mmol/L 
<2.0 
>2.75 
Lactate 
Dehydrogenase 
(LDH) 
U/L 
No lower 
limit 
≥3 X ULN 
U/L 
No lower 
limit 
≥3 X ULN 
Alkaline 
Phosphatase 
U/L 
No lower 
limit 
≥3 X ULN 
U/L 
No lower 
limit 
≥3 X ULN 
Uric acid (male) 
mg/dL 
No lower 
limit 
≥10.5 
umol/L 
No lower 
limit 
≥624.75 
Uric acid (female) 
mg/dL 
No lower 
limit 
≥8.5 
umol/L 
No lower 
limit 
≥505.75 
Albumin 
g/dL 
≤2.6 
≥6.0 
g/L 
≤26 
≥60 
Total Protein 
g/dL 
≤5.0 
≥10.0 
g/L 
≤50 
≥100 
Chloride 
mEq/L 
≤85 
≥120 
mmol/L 
≤85 
≥120 
Glucose (random) 
mg/dL 
≤45.1 
≥200.0 
mmol/L 
≤2.48 
≥11 
Serum Creatinine 
mg/dL 
Not 
Applicable 
>1.5 ULN 
umol/L 
Not 
Applicable 
>1.5 ULN 
Triglycerides 
mg/dL 
Not 
>300 
mmol/L 
Not 
>3.39 


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Applicable 
Applicable 
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 
 
The pregnancy results (positive or negative) for female subjects will be presented in a listing. 
14.3 Vital Signs 
Vital signs are assessed at Screening, Baseline, and Weeks 2, 4, 6 and 8/ET visits. 
Vital signs including weight, height (only at Screening), and derived BMI will be 
summarized at Baseline and all post-Baseline visits using descriptive statistics. The change 
from Baseline values will also be summarized at each post-Baseline visit. 
Vital sign values will be considered PCI if they meet both the observed value criteria and the 
change from baseline criteria listed in Table 6. The number and percentage of subjects with 
post-Baseline vital signs that are PCI will be summarized 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 total number of subjects with a post-
Baseline PCI vital sign for the given parameter and visit, and the denominator is the total 
number of subjects with non-missing values for the given parameter and visit. For the overall 
post-Baseline summary, the numerator for the percentage is the total number of subjects with 
at least 1 post-Baseline PCI vital sign for the given parameter, and the denominator is the 
number of subjects with at least 1 post-Baseline vital sign for the given parameter. A listing 
of all subjects with any PCI values will be provided. 


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Table 6 
Criteria for Potentially Clinically Important Vital Signs 
Vital Sign 
Parameter 
Unit 
Criteriaa 
Observed Value 
And/Or 
Change Relative to Baseline 
Systolic blood 
pressure 
(supine or sitting) 
mmHg 
180 
And 
Increase of ≥20 
90 
And 
Decrease of ≥20 
Diastolic blood 
pressure (supine or 
sitting) 
mmHg 
105 
And 
Increase of ≥15 
50 
And 
Decrease of ≥15 
Pulse (supine or 
sitting) 
bpm 
120 
And 
Increase of ≥15 
50 
And 
Decrease of ≥15 
Weight 
kg 
Not Applicable 
Increase of ≥7% 
Decrease of ≥7% 
a 
A post-Baseline value is considered a PCI value if it meets both criteria for observed value and change from 
baseline. 
14.4 Electrocardiogram 
12-lead ECG assessments are performed at Screening, Baseline, Week 2 and Week 8/ET 
visits. ECGs will be completed in triplicate at Screening, and as a single tracing at all other 
timepoints. When ECG is collected in triplicate, the average of the triplicate will be 
considered as one assessment for the analyses. All tracings will be evaluated by a central 
reading laboratory. ECG data summaries will be performed using the centrally evaluated 
data, including the cardiologist’s interpretation. 
Observed values of ECG variables (heart rate, PR interval, RR interval, QRS interval, QT 
interval, and QTc intervals) and the changes from baseline at each assessment timepoint will 
be summarized by visit. QTc intervals include QTcB (Bazett’s formula) and QTcF 
(Fridericia’s formula).  
QTcF (msec) observed and change from Baseline values will also be classified into the 
following categories, and the number and percentage of subjects in each category will be 
summarized at each visit and for the overall post-baseline maximum: 
 Observed  
o ≤450, 451 to 480, 481 to 500, and  >500 
o >450 
o >480 
 Change from Baseline 
o ≤10, 11 to 30, 31 to 60, and >60 
o >30 


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Electrocardiogram variable values will be considered PCI if they meet or exceed the upper 
limit values listed in Table 7. The number and percentage of subjects with post-baseline PCI 
values will be summarized 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 and visit, and the denominator is the number of 
subjects with non-missing values for the given parameter and visit. For the overall post-
Baseline summary, the numerator for the percentage is the number of subjects with at least 
1 post-Baseline PCI ECG for the given parameter, and the denominator is the number of 
subjects with at least 1 post-Baseline ECG for the given parameter. A listing of all subjects 
with any PCI values 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 
msec 
>60 
 
For cardiologist’s interpretations, the number and percentage of subjects with ECG results 
that are determined as normal or abnormal will be summarized at scheduled visits. The 
overall post-baseline worst interpretation will also be summarized (i.e. if a subject has one or 
more ECG results that is/are considered as abnormal, this subject will be counted in the 
abnormal category). Cardiologist’s interpretations will also be summarized in a shift table to 
determine the number and percentage of subjects with ECG results classified as normal or 
abnormal at scheduled post-Baseline visits relative to the same classification at the Baseline 
visit. The shifts from Baseline to overall post-Baseline worst interpretation will also be 
presented. For the by-visit shift summary, the denominator is the number of subjects with 
non-missing cardiologist’s interpretation at Baseline and the given visit. For the summaries of 
shift from Baseline to the overall post-Baseline worst interpretation, the denominator is the 
number of subjects with non-missing Baseline and at least 1 post-Baseline cardiologist’s 
interpretation.  
14.5 Physical Examination and Neurological Examination 
A general physical examination, in addition to a neurological examination (cranial nerves, 
motor, sensory, reflexes, gait, and coordination), are performed at Screening and Week 8/ET 
visits. 


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Physical and neurological examination results (normal, abnormal, and not done) at Screening 
and Week 8 will be summarized descriptively by body/neurological system and visit. 
14.6 Other Safety Variables 
14.6.1 MMSE 
The MMSE total score will be summarized by timepoint (Baseline, Week 4, and Week 8) 
using descriptive statistics. The change from Baseline scores will also be summarized 
descriptively at Week 4 and Week 8. In addition, the MMSE total score change from Baseline 
be analyzed using an MMRM similar to the primary efficacy endpoint. The dependent 
variable will be the MMSE total score change from baseline, and the independent variables in 
the model will include the following: visit (Weeks 4 and 8), Baseline MMSE total score 
(continuous covariate), and Baseline MMSE total score-by-visit interaction. 
The individual item scores will be listed but not summarized. 
14.6.2 MDS-UPDRS Part III 
The MDS-UPDRS Part III total score will be summarized by timepoint (Baseline, Week 4, 
and Week 8) using descriptive statistics. The MDS-UPDRS Part III total score change from 
Baseline will be summarized descriptively at Week 4 and Week 8, and will also be analyzed 
using an MMRM similar to the primary efficacy endpoint. The dependent variable will be the 
MDS-UPDRS Part III total score change from baseline, and the independent variables in the 
model will include the following: visit (Weeks  4 and 8), Baseline MDS-UPDRS Part III total 
score (continuous covariate), and Baseline MDS-UPDRS Part III total score-by-visit 
interaction. 
The Hoehn and Yahr Stage will be summarized descriptively by visit as a categorical 
variable.  
The individual item scores and all remaining questions will be listed but not summarized. 
14.6.3 Suicidality 
The C-SSRS is assessed at Screening, Baseline, Weeks 2, 4, 6, and Week 8/ET visits. 
The event counts and the number and percentage of subjects in each suicide category at any 
post-Baseline timepoint (including unscheduled and out of window visits), will be 
summarized descriptively. Suicide categories will be defined as follows. 
 Suicidality: Subjects who report at least one post-Baseline occurrence of suicidal 
behavior or suicidal ideation  


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 Suicidal ideation: Subjects who report at least one post-Baseline occurrence of the 
following 
o wish to be dead 
o  non-specific active suicidal thoughts 
o active suicidal ideation with any methods (not plan) without intent to act 
o active suicidal ideation with some intent to act, without specific plan 
o active suicidal ideation with specific plan and intent 
 Suicidal behavior: Subjects who report at least one post-Baseline occurrence of the 
following 
o Preparatory acts or behavior 
o Aborted attempt 
o Interrupted attempt 
o Actual attempt  
o Suicide  
15 CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
Not applicable 
16 DATA MONITORING/REVIEW COMMITTEE 
Not applicable. 
17 COMPUTER METHODS  
Statistical analyses will be performed using Version 9.4 (or newer) of SAS software (SAS 
Institute Inc., Cary, NC, USA) 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. 
18 CHANGES TO ANALYSES SPECIFIED IN PROTOCOL 
Not applicable. 


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19 APPENDICES 
19.1 Summary of Version Changes   
Version No: 
Document History 
Description of Update 
Author(s) 
Version Date 
1.0 
Original version 
 
12 September 2018 
2.0 
Revised Section 3.5 due to 
sample size reduction per 
Protocol Amendment 2; and 
made update to Section 13.1.2 to 
use paired t-test (instead of 
ANCOVA) as per protocol. 
Updated primary objective to 
agree with Protocol Amendment 
2 (adjunctive treatment no longer 
restricted to SSRI/SNRI). 
Updated Section 12.1.2 to agree 
with Protocol Amendment 2 
(ANCOVA changed to t-test). 
 
 
31 January 2019