Clinical trial NCT04164758
Conditions: Parkinson's Disease
Sponsor: ACADIA Pharmaceuticals Inc.
Start date: 2019-10-23; Completion date: 2020-09-25
Enrollment: 11 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a pilot study to explore the effects of pimavanserin and low-dose quetiapine in subjects with Parkinson's disease with neuropsychiatric symptoms.

Detailed description:

Arms: arm 1: Pimavanserin 34 mg provided as 2 x 17 mg encapsulated tablets arm 2: Placebo encapsulated tablet arm 3: Immediate release Quetiapine encapsulated tablets
Interventions: intervention 1: Pimavanserin intervention 2: Placebo intervention 3: Quetiapine
Intervention descriptions: intervention 1: Pimavanserin 34 mg (provided as 2×17 mg encapsulated tablets) administered orally as a single dose once daily intervention 2: Placebo (provided as 2 × placebo encapsulated tablets) administered orally as a single dose once daily intervention 3: Quetiapine 25 mg (provided as 1×25 mg quetiapine encapsulated tablet and 1 × placebo encapsulated tablet), OR 50 mg (provided as 2×25 mg quetiapine encapsulated tablets), OR 100 mg (provided as 2×50 mg quetiapine encapsulated tablets) administered orally as a single dose once daily

Protocol documents:
Prot_000.pdf: 
Official Title: A Pilot Randomized, Double-blind, Placebo-controlled Study to 
Evaluate Safety and Daytime Sedation in Subjects With Parkinson’s Disease With 
Neuropsychiatric Symptoms Treated With Pimavanserin or Low-Dose Quetiapine 
NCT Number: NCT04164758 
Document Date: 31 Jan 2020 


 
    
Confidential and Proprietary Information of ACADIA Pharmaceuticals Inc. 
Page 1 of 78 
 
 
 
CLINICAL STUDY PROTOCOL 
 
A Pilot Randomized, Double-blind, Placebo-controlled Study to Evaluate 
Safety and Daytime Sedation in Subjects With Parkinson’s Disease With 
Neuropsychiatric Symptoms Treated With Pimavanserin or Low-Dose 
Quetiapine 
 
Protocol Number: ACP-103-056 
Amendment 3 
 
Original Protocol Date: 04 October 2018 
Protocol Amendment 1 Date: 14 January 2019 
Protocol Amendment 2 Date: 22 April 2019 
Protocol Amendment 3 Date: 31 January 2020 
 
 
Protocol Template Version 1.0 
Confidentiality Statement 
This protocol is the confidential information of ACADIA Pharmaceuticals Inc. and is intended solely for the 
guidance of the clinical investigation. This protocol may not be disclosed to parties not associated with the 
clinical investigation or used for any purpose without the prior written consent of ACADIA Pharmaceuticals 
Inc. 


Study: ACP-103-056 
 
Final Version: 1.0 
Clinical Study Protocol Amendment 3 
 
Date: 31 January 2020 
 
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SPONSOR SIGNATURE PAGE 
Title: A Pilot Randomized, Double-blind, Placebo-controlled Study to Evaluate Safety and 
Daytime Sedation in Subjects With Parkinson’s Disease With Neuropsychiatric Symptoms 
Treated With Pimavanserin or Low-Dose Quetiapine 
 
ACADIA President: 
 
President 
ACADIA Pharmaceuticals Inc. 
 
 
   
See appended electronic signature page 
 
 
Signature 
 Date 
ACADIA Study Lead: 
 
Executive Director, Clinical Research 
ACADIA Pharmaceuticals Inc. 
 
 
  
 
See appended electronic signature page 
 
 
Signature 
 Date 
ACADIA Medical Affairs Lead: 
 
Executive Director, Medical Affairs 
ACADIA Pharmaceuticals Inc. 
 
 
  
 
See appended electronic signature page 
 
 
Signature 
 Date 
 
 


Signature Page for ACP-103-056 Protocol Amendment 3
Signature Page for ACP-103-056 Protocol Amendment 3
Approve
03-Feb-2020 17:30:26 GMT+0000
Approve
airs
03-Feb-2020 17:38:43 GMT+0000
Approve
03-Feb-2020 19:55:40 GMT+0000


Study: ACP-103-056 
 
Final Version: 1.0 
Clinical Study Protocol Amendment 3 
 
Date: 31 January 2020 
 
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DECLARATION OF INVESTIGATOR 
I confirm that I have read the above protocol. I understand it, and I will work according to the 
moral, ethical, and scientific principles governing clinical research as set out in the principles 
of Good Clinical Practice, as required by International Council for Harmonisation (ICH) of 
Technical Requirements for Pharmaceuticals for Human Use Guideline E6 and as described 
in the United States (US) Code of Federal Regulations (CFR) 21 CFR parts 50, 54, 56, 312, 
and according to applicable local requirements. 
Confidentiality Statement 
The confidential information in this document is provided to you as a Principal Investigator 
or Consultant for review by you, your staff, and the applicable institutional review 
board/ethics committee (IRB/EC). 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-103-056 
 
Final Version: 1.0 
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Date: 31 January 2020 
 
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PROTOCOL SYNOPSIS 
Protocol Number 
ACP-103-056 
EudraCT Number 
Not applicable 
Protocol Title 
A Pilot Randomized, Double-blind, Placebo-controlled Study to 
Evaluate Safety and Daytime Sedation in Subjects With Parkinson’s 
Disease With Neuropsychiatric Symptoms Treated With Pimavanserin 
or Low-Dose Quetiapine 
Name of 
Investigational 
Product 
Pimavanserin tablets 
Phase of 
Development 
2 
Sponsor 
ACADIA Pharmaceuticals Inc. 
 
 
Study Rationale 
This is a pilot, hypothesis-generating study to explore the effects of pimavanserin and low-dose 
quetiapine in subjects with Parkinson’s disease that will be used to guide the design of future 
studies. 
Primary Objectives 
• To assess the safety and tolerability of 
pimavanserin and low-dose quetiapine 
compared to placebo in subjects with 
Parkinson’s disease  
Primary Endpoint 
• Treatment-emergent adverse events 
(TEAEs) 
Exploratory Objectives 
• To explore the sensitivity of 
assessments/instruments that are novel for 
evaluating the experience of subjects with 
Parkinson’s disease with respect to 
sedation/sleep, cognition, and other non-
motor symptoms 
• To explore the effects of pimavanserin and 
low-dose quetiapine compared to placebo 
in subjects with Parkinson’s disease on: 
o Daytime sleepiness 
o Nighttime sleep 
Exploratory Endpoints 
• Measures related to daytime sedation: 
o Karolinska Sleepiness Scale (KSS) 
o Sleep-Related Impairment Scale 
o Nighttime Sleep Scale 
o Sleep/wake cycle and nighttime and 
daytime activity as measured by 
actigraphy via a wearable instrument 
• Measures of cognition: 
o Patient-Reported Outcomes 
Measurement Information System 
(PROMIS®) Cognition Assessment 


Study: ACP-103-056 
 
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Date: 31 January 2020 
 
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o Cognition 
o Other non-motor symptoms 
o Treatment satisfaction 
o Safety and tolerability 
o Trail Making Test (TMT) Parts A and B  
o Hopkins Verbal Learning Test-Revised 
(HVLT-R) 
• Measures of other nonmotor symptoms: 
o Parkinson’s Disease Non-motor 
Symptoms (PD NMS) Questionnaire 
o Patient Global Impression-
Improvement (PGI-I) 
o Clinical Global Impression-
Improvement (CGI-I) 
• Patient and Informant Satisfaction 
Question 
• Other measures of safety and tolerability: 
o Movement Disorders Society-Unified 
Parkinson’s Disease Rating Scale 
(MDS-UPDRS) Part III (motor 
examination)  
o Columbia-Suicide Severity Rating 
Scale (C-SSRS) score 
Number of Study 
Sites 
Approximately 23 sites within the United States will participate in this 
study. 
Number of Subjects 
Planned 
Up to 60 subjects with Parkinson’s disease will be randomized in a 
1:1:1 ratio to pimavanserin, quetiapine, or placebo. Up to 
approximately 120 subjects will be screened. A maximum of 20% of 
subjects across treatment groups (12 subjects) will be replaced. 
Test Product, Dose, 
and Administration 
Pimavanserin 34 mg (provided as 2×17 mg encapsulated tablets), 
immediate release quetiapine 25 mg (provided as 1×25 mg quetiapine 
encapsulated tablet and 1×placebo encapsulated tablet), 50 mg 
(provided as 2×25 mg quetiapine encapsulated tablets), 100 mg 
(provided as 2×50 mg quetiapine encapsulated tablets), or matching 
placebo (2×placebo encapsulated tablets). Capsules will be 
administered orally as a single dose once daily. 
All study drugs will be encapsulated in order to maintain the blind. 
Study Design 
This pilot study will provide data to inform and appropriately design 
future studies. This study will be conducted as a multicenter, 
randomized, double-blind, placebo and active-control, parallel-group 
pilot study in subjects with Parkinson’s disease. 


Study: ACP-103-056 
 
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The study will have 3 periods: 
• Screening period (7-28 days) 
• Double-blind treatment period (4 weeks) 
• Safety follow-up period (30 [±4] days) 
The study design schema is provided in Figure S–1.  
Screening Period (7-28 Days) 
During the Screening period, subjects will be assessed for study 
eligibility, the ability to swallow a test capsule (i.e., placebo), and 
prohibited medications will be discontinued. Only those subjects who 
are able to swallow the test capsule at the Screening visit and who 
meet all inclusion and no exclusion criteria will be eligible for the 
study.  
A wearable instrument (i.e., actigraph) will be used to continuously 
evaluate activity and sleep of subjects during the study. Training on the 
handheld device and actigraph may be done on the first day of 
Screening but must take place at least 7 days before the Baseline visit. 
Baseline data for the handheld device and actigraph will be collected 
during the 7-day period before the Baseline visit.  
Subjects who screen fail will be allowed to rescreen within 3 months 
with agreement of the Sponsor’s Medical Monitor. A subject may be 
rescreened up to two times. 
Investigators should not withdraw 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 and in 
consultation with the treating physician. 
Double-blind Treatment Period (4 Weeks) 
The Baseline visit (Visit 2) may occur after screening procedures are 
completed, subject eligibility has been confirmed, and no earlier than 
7 days after the subject has been given the wearable device. At the 
Baseline visit (Visit 2), eligible subjects will be randomized in a 
1:1:1 ratio to pimavanserin 34 mg, quetiapine 25 mg, or matching 
placebo.  
Subjects who are randomized to the quetiapine treatment group will 
begin dosing at 25 mg. At Week 1 (Visit 3), Week 2 (Visit 4) and 
Week 3 (Visit 5), the Investigator will be encouraged to increase the 
dose of blinded study drug, consistent with 50-100 mg quetiapine, 
based on the Investigator’s assessment of clinical response  
(Figure S–2). Dose adjustments will be implemented through 
interactive response technology (IRT) system. In actuality, only the 
dose of quetiapine would be increased (to 50 mg at Week 1 and then 
optionally to 100 mg at Week 2 or Week 3); the pimavanserin dose will 


Study: ACP-103-056 
 
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remain fixed at 34 mg per day throughout the study (Figure S–2).  
Subjects for whom the Investigator does not increase the dose of 
blinded study drug consistent with 50 mg quetiapine at Week 1 
(Visit 3) will be withdrawn from the study and replaced. A maximum 
of 12 subjects across treatment groups (20%) will be replaced for this 
and only this reason. 
Assessments in the clinic will be conducted at Weeks 0 (Baseline), 
1, 2, 3 and 4/end of treatment (EOT). Assessments on the handheld 
device will be collected from Baseline to Week 4/EOT on a regular 
basis (see Table S–2). 
Subjects will be provided standard of care treatment per investigator 
judgment for 3 months following their completion of the double-blind 
treatment period.  
Safety Follow-up Period (30 Days) 
A follow-up safety assessment telephone call will be conducted 
30 (±4) days after the last dose of study drug. 
The schedule of events and assessments is provided in Table S–1. 
Study Duration 
The duration of participation for individual study subjects will be 
approximately 12 weeks, consisting of a screening period of up to 
4 weeks, a 4-week, double-blind treatment period, and a safety 
follow-up period of 30 (±4) days (Figure S–1).  
The study completion date is defined as the date the final subject, 
across all sites, completes their final protocol-defined assessment 
(Note: this includes the safety follow-up telephone call). If the study is 
terminated for any reason, subjects remaining in the study will return 
to standard of care. 
Main Criteria for 
Inclusion and 
Exclusion 
To be eligible for this study, subjects must meet all of the inclusion 
criteria and none of the exclusion criteria. 
Inclusion Criteria: 
1. Male or female subjects 50 to 85 years of age, inclusive, at 
Screening and Baseline 
2. Can understand the nature of the trial and protocol 
requirements and provide written informed consent 
3. Is able to demonstrate the ability to complete subject-reported 
outcome measures on a handheld device, is willing to wear a 
data capture instrument (e.g., an actigraph), and can be reliably 
rated on assessment scales (in the opinion of the Investigator) 
4. Can designate an “informant” (a relative, housemate, or friend) 
who the subject agrees can provide reliable information on the 
subject’s well-being and is willing to attend clinic visits with 
the subject 


Study: ACP-103-056 
 
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5. Is able to swallow the test capsule without difficulty during the 
Screening visit  
6. Has a Mini-Mental State Examination (MMSE) score ≥19 
7. Has a diagnosis of idiopathic Parkinson’s disease, without any 
other known or suspected cause of parkinsonism, according to 
the UK Parkinson’s Disease Society Brain Bank Clinical 
Diagnostic Criteria (Hughes et al. J Neurol Neurosurg 
Psychiatry. 1992;55:181-184). Initial diagnosis of PD must 
have been made more than 1 year prior to Screening. 
8. [Inclusion criterion eliminated] 
9. Has at both Visit 1 (Screening) and Visit 2 (Baseline), a CGI-S 
score of ≥3 on at least one of the following non-motor 
neuropsychiatric symptoms that warrant treatment with an 
antipsychotic agent based on Investigator judgement. Such 
symptoms do not need to be the same at Screening and 
Baseline, and all symptoms should be assessed at both 
Screening and Baseline. 
a. Delusions 
b. Hallucinations 
c. Depression/Dysphoria 
d. Apathy/Indifference 
e. Disinhibition 
f. Irritability/Lability 
10. If the subject is on anti-Parkinsonian medication, they must be 
on a stable regimen for 1 month prior to Baseline and not 
planning (at the time of the Baseline visit) to make a major 
change in dose(s)  
11. If the subject has had stereotaxic surgery for subthalamic 
nucleus deep brain stimulation, they must be at least 6 months 
post-surgery. The stimulator settings must have been stable for 
at least 1 month prior to the Baseline visit and are expected to 
remain stable during the trial.  
12. If the subject is female, she must not be pregnant or 
breastfeeding. She must also be of non-childbearing potential 
(defined as either surgically sterilized or at least 1 year 
postmenopausal) or must agree to use a clinically acceptable 
method of contraception or be abstinent for at least 1 month 
prior to the Baseline visit, during the study, and 41 days 
following completion of double-blind treatment. 
If intercourse does occur, an acceptable method of birth control 
is required. 
Acceptable methods of birth control include the following: 
• Condom, diaphragm, or cervical cap with spermicide 


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• Hormonal contraception, including oral, injectable, 
transdermal, or implantable methods 
• Intrauterine device (IUD) 
Exclusion Criteria: 
1. Has atypical parkinsonism (Parkinson’s plus, multiple system 
atrophy [MSA], progressive supranuclear palsy [PSP]), or 
secondary parkinsonism variants such as tardive or 
medication-induced parkinsonism 
2. Has undergone ablative procedures such as a pallidotomy, 
thalamotomy, or treatment with focused ultrasound  
3. Is in hospice, is receiving end-of-life palliative care, or is 
bedridden or confined to a wheelchair (as defined by spending 
>80% of the day in a wheelchair)  
4. Has neuropsychiatric symptoms that are primarily attributable 
to current delirium or substance abuse  
5. Has current evidence of an unstable neurological, 
cardiovascular, respiratory, gastrointestinal, renal, hepatic, 
hematologic, or other medical or psychiatric disorder, including 
cancer or malignancies that, in the judgment of the Investigator, 
would jeopardize the safe participation of the subject in the 
study or significantly interfere with the conduct or 
interpretation of the study 
6. Has a history of epilepsy 
7. Has atrial fibrillation unless adequately anticoagulated 
8. Has a history of myocardial infarction, unstable angina, acute 
coronary syndrome, or cerebrovascular accident within the last 
6 months prior to Visit 1 (Screening) 
9. Has any of the following: 
a. greater than New York Heart Association (NYHA) 
Class 2 congestive heart failure  
b. Grade 2 or greater angina pectoris (by Canadian 
Cardiovascular Society Angina Grading Scale)  
c. sustained ventricular tachycardia 
d. ventricular fibrillation 
e. torsades de pointes 
f. syncope due to an arrhythmia 
g. an implantable cardiac defibrillator 
10. Has a known history of a positive hepatitis B virus (HBV) or 
hepatitis C virus (HCV) test 


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11. Has a history of human immunodeficiency virus (HIV)  
12. Has a history of neuroleptic malignant syndrome or serotonin 
syndrome 
13. Has a known personal or family history of long QT syndrome 
or family history of sudden cardiac death 
14. Has any of the following electrocardiogram (ECG) results at 
the Screening or Baseline visit  
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 
If the mean QTcF value from the centrally read set of triplicate 
ECGs done at Screening is prolonged due to an identifiable 
cause, and it is medically appropriate to address that cause, a 
repeat set of triplicate ECGs may be performed during 
Screening at the discretion of the Medical Monitor.  
15. Has a heart rate as measured at Screening by the ECG machine 
<50 beats per minute (mean value from centrally read set of 
triplicate ECGs). If bradycardia is secondary to iatrogenic or 
treatable causes and these causes are treated, a heart rate 
assessment can be repeated during the screening period.  
16. Has major surgery planned during the screening through the 
end of the treatment or follow-up periods 
17. Requires treatment with a medication or other substance that is 
prohibited by the protocol 
18. Has a body mass index (BMI) <18.5 kg/m2 or >35 kg/m2 at 
Screening or Baseline or known unintentional clinically 
significant weight loss (i.e., ≥7%) over past 6 months  
19. The urine drug screen result at Visit 1 (Screening) or Visit 2 
(Baseline) indicates the presence of 
amphetamine/methamphetamine, barbiturates, cocaine, or 
phencyclidine (PCP). The presence of benzodiazepines, 
marijuana (THC), or opiates does not necessarily exclude the 
subject from the study. 
20. Is suicidal at Screening or Baseline as defined below: 
a. According to the C-SSRS, he or she must not be 


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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]) and 
must not have attempted suicide in the 2 years prior to 
Visit 1 (Screening); OR 
b. The subject is actively suicidal in the Investigator’s 
judgment 
21. Has participated in or is participating in a clinical trial of any 
investigational drug, device, or intervention, within 30 days or 
5 half-lives, whichever is longer, of Visit 2 (Baseline) 
22. Has previously been enrolled in any prior clinical study with 
pimavanserin  
23. Has previously or is currently taking pimavanserin 
24. Has taken an antipsychotic medication in the last 2 weeks or 
less than 5 half-lives (whichever is longer) prior to Baseline or 
is currently taking an antipsychotic medication  
25. Has a significant sensitivity or allergic reaction to 
pimavanserin, quetiapine or its excipients 
26. Is an employee or is a family member of an employee of 
ACADIA Pharmaceuticals Inc. 
27. Is judged by the Investigator or the Medical Monitor to be 
inappropriate for the study for any reason, including if the 
subject is judged to be a danger to self or others 
28. Has orthostatic hypotension at Screening or Baseline. A drop in 
systolic BP of ≥20 mm Hg, or in diastolic BP of ≥10 mm Hg, 
within 3 minutes of standing, or experiencing significant 
lightheadedness or dizziness after standing, along with a 
remarkable drop in BP as judged by the Investigator with 
agreement of the Sponsor’s Medical Monitor, is considered 
orthostatic hypotension. 
Sample Size 
Calculations 
This is a pilot study and is not powered for statistical significance. 
Statistical Methods 
Analysis Sets 
The Safety Analysis Set will consist of all subjects who have taken at 
least 1 dose of study drug. Safety analyses will be based on the Safety 
Analysis Set. 
The Exploratory Analysis Set will consist of randomized subjects in 
the Safety Analysis Set excluding subjects who were replaced due to 
no increase of the dose of blinded study drug consistent with 50 mg 


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quetiapine at Week 1 (Visit 3). Exploratory analyses will be based on 
the Exploratory Analysis Set.  
Primary Analysis 
Adverse events will be classified into standard terminology using the 
Medical Dictionary for Regulatory Activities. All adverse events (AEs) 
will be listed and TEAEs will be summarized by system organ class 
and preferred term. 
A TEAE is defined as an AE that occurs after the first dose of study 
drug and up to 30 days after the last dose of study drug. Summaries by 
maximum severity and by relationship will also be provided. Serious 
TEAEs, fatal AEs, and TEAEs leading to discontinuation will also be 
summarized. 
Exploratory Analyses 
The change from Baseline in the exploratory endpoints measured at 
scheduled visits including Trail Making Test Parts A and B, HVLT-R, 
and PD NMS Questionnaire will be summarized using a mixed model 
repeated measures (MMRM) model. The model will include effects for 
treatment group, visit, treatment-by-visit interaction, Baseline score, 
and Baseline score-by-visit interaction. CGI-I score will be analyzed 
using a similar MMRM model with the effects for treatment group, 
visit, treatment-by-visit interaction, Baseline CGI-S score, and 
Baseline CGI-S score-by-visit interaction. PGI-I score will be 
summarized using a MMRM model that will include effects for 
treatment group, visit, and treatment-by-visit interaction. The treatment 
comparisons will be based on the difference in least squares means at 
Week 4.  
Analysis of Ecological Momentary Assessment (EMA) and 
Actigraphy Data 
EMA Analyses 
EMA includes scales for nighttime sleep (Nighttime Sleep Scale), 
sleep impairment (Sleep-Related Impairment Scale), daytime 
sleepiness (Karolinska Sleepiness Scale [KSS]), cognition (Patient-
Reported Outcomes Measurement Information System [PROMIS®] 
Cognition Assessment), and satisfaction (Patient and Informant 
Satisfaction Question) collected on a handheld device multiple times 
per week with an initial baseline assessment collected during the 7-day 
period before the Baseline visit. The outcome and change from 
Baseline in EMA scales will be evaluated using an MMRM model. 
This model will include fixed effects of treatment, time of day, and day 
of visit, as well as the continuous fixed covariate of Baseline scores. 
All of these factors have naturally occurring interaction terms, which 
will also be included in analysis models.  


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Actigraphy Analyses 
Actigraphy data on physical activity will be collected continuously 
using a wearable device from at least one week before the Baseline 
visit through Week 4. Exploratory analyses will be used to see how the 
data should be collapsed into average values for each time of day, day, 
and week. The outcome and change from Baseline in actigraphy data 
will be evaluated using an MMRM model. This model will include 
fixed effects of treatment, time of day, and day of visit, as well as the 
continuous fixed covariate of Baseline scores. All of these factors have 
naturally occurring interaction terms, which will also be included in 
analysis models.  
Safety Analyses 
The serum clinical chemistry, hematology, and urinalysis results at 
each time point will be summarized by treatment group. Change from 
Baseline values will also be summarized. 
The number and percentage of subjects with potentially clinically 
important (PCI) post-Baseline laboratory values will be summarized 
by treatment group at each post-Baseline visit and overall 
post-Baseline for selected parameters. The PCI criteria will be 
specified in the statistical analysis plan. 
Vital signs and body weight at Baseline and each post-Baseline visit 
will be summarized by treatment group. Change from Baseline values 
will also be summarized. 
The results of the physical examinations at each visit will be tabulated 
by treatment group. 
Electrocardiogram parameters at study visits will be summarized by 
treatment group. Change from Baseline values will also be 
summarized. Categorical analyses will be conducted on the incidence 
of subjects with prolonged QTc intervals and changes in QTc intervals 
in accordance with ICH guidelines. 
For the C-SSRS, the number and percentage of subjects with suicidal 
ideation or suicidal behavior during the study will be tabulated. 
MDS UPDRS Part III observed value and change from Baseline to 
Week 4 will be summarized by treatment group. The change from 
Baseline to Week 4 in the MDS UPDRS Part III score will be analyzed 
using an analysis of covariance (ANCOVA) model with treatment 
group as a factor and the Baseline value as a covariate.  
Date 
31 January 2020 


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Figure S–1 
Schematic of Study Design for ACP-103-056 
 
 
R=randomization 
* Pre-drug actigraphy data and handheld device assessments are conducted prior to randomization (Baseline) 
Note: A schematic for study drug dispensing and dose adjustments is provided in Figure S–2 
 
 
 


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Figure S–2 
Schematic for Study Drug Dispensing and Dose Adjustments 
 
* Week 2 (Visit 4) & Week 3 (Visit 5): Subjects may remain on blinded study drug dose consistent with 50 mg quetiapine or be optionally increased to 100 mg 
quetiapine. 
Abbreviations: EOT=end of treatment; R=randomization 
Note: Dose adjustments and study drug dispensing are only allowed at scheduled visits (i.e., not at unscheduled visits). Subjects should not take study drug on the 
mornings of clinic visit days until instructed to do so by the site staff. At Baseline and at each subsequent clinic visit, subjects will be dosed and will remain 
in the clinic for observation for a minimum of 60 minutes after dosing. At Week 1 (Visit 3), Week 2 (Visit 4), and Week 3 (Visit 5), the Investigator will be 
encouraged to increase the dose of blinded study drug, consistent with 50-100 mg quetiapine, based on the Investigator’s assessment of clinical response. 
Dose adjustments will be implemented through the IRT. In actuality, only the dose of quetiapine would be increased (to 50 mg at Week 1 [Visit 3] and then 
optionally to 100 mg at Week 2 [Visit 4] or Week 3 [Visit 5]); the pimavanserin dose will remain fixed at 34 mg per day throughout the study. Subjects for 
whom the Investigator does not increase the dose of blinded study drug consistent with 50 mg quetiapine at Week 1 (Visit 3) will be withdrawn from the 
study and replaced. The Investigator will be blinded to study drug and thus will not know whether their decision to increase the dose of blinded study drug 
results in an actual increase in study drug dose. The dose of study drug (pimavanserin, quetiapine or placebo) may not be decreased. If a subject cannot 
tolerate their dose, they must be withdrawn from the study. 
 


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Table S–1 
Schedule of Events and Assessments for ACP-103-056 
 
Screening 
Baseline 
Double-blind Treatment Period 
Safety 
Follow-up 
Visit Week 
(Study Day) 
-4 
0 
1 
(Day 7) 
2 
(Day 14) 
3 
(Day 21) 
4/EOT 
(Day 28) 
8 l 
(Day 58) 
Visit Number 
1 
2 
3 
4 
5 
6/ET 
7 
Visit window (days) 
0 
0 
±3 
±3 
±3 
±3 
±4 
Type of Visit 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Telephone 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
Medical history and demographics 
X 
 
 
 
 
 
 
Psychiatric and neurological history 
X 
 
 
 
 
 
 
Physical examination (including neurologic examination)  
X 
X 
 
 
 
X 
 
Training on the use of the handheld device and the 
actigrapha 
X 
X 
 
 
 
 
 
Orthostatic vital signs 
X 
X 
X 
X 
X 
X 
 
Weight and BMIb 
X 
X 
 
 
 
X 
 
Height 
X 
 
 
 
 
 
 
12-lead ECGc 
X 
X 
X 
X 
X 
X 
 
Clinical laboratory tests 
X 
X 
 
X 
 
X 
 
Pregnancy testd 
X 
X 
 
 
 
X 
 
Urine drug screen 
X 
Xk 
 
 
 
X 
 
Capsule swallowing teste 
X 
 
 
 
 
 
 
MMSE 
X 
 
 
 
 
 
 
Dispense study drugg 
 
X 
X 
X 
X 
 
 
CGI-Sf 
X 
X 
 
 
 
 
 
Trail Making Testf 
 
X 
X 
X 
 
X 
 
HVLT-Rf 
 
X 
X 
X 
 
X 
 
Table continued on next page 
 


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Table S-1 
Schedule of Events and Assessments for ACP-103-056 (Continued) 
 
Screening 
Baseline 
Double-blind Treatment Period 
Safety 
Follow-up 
Visit Week 
(Study Day) 
-4 
0 
1 
(Day 7) 
2 
(Day 14) 
3 
(Day 21) 
4/EOT 
(Day 28) 
8 l 
(Day 58) 
Visit Number 
1 
2 
3 
4 
5 
6/ET 
7 
Visit window (days) 
0 
0 
±3 
±3 
±3 
±3 
±4 
Type of Visit 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Telephone 
Handheld device questionnairesh 
 
X-------------------------------------------------------------X 
 
Actigraphy data collection
i 
 
X-------------------------------------------------------------X 
 
PD NMS Questionnairef 
 
X 
 
X 
X 
X 
 
PGI-If 
 
 
X 
X 
X 
X 
 
CGI-If 
 
 
X 
X 
X 
X 
 
MDS UPDRSf 
 
X 
 
 
 
X 
 
Subject and Informant satisfaction question 
 
 
X 
X 
X 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
C-SSRSf,j 
X 
X 
X 
X 
X 
X 
 
Assessment of adverse events 
X 
X 
X 
X 
X 
X 
X 
Study drug accountability 
 
 
X 
X 
X 
X 
 
Abbreviations: CGI-I=Clinical Global Impression-Improvement; CGI-S=Clinical Global Impression-Severity; C-SSRS=Columbia-Suicide Severity Rating Scale; 
ECG=electrocardiogram; EOT=end of treatment; ET=early termination; HVLT-R=Hopkins Verbal Learning Test-Revised; MDS UPDRS=Movement 
Disorders Society Unified Parkinson’s Disease Rating Scale; MMSE=Mini-Mental State Examination; PD NMS=Parkinson’s Disease Non-motor 
Symptoms; PGI-I=Patient Global Impression-Improvement  
a 
Training on the handheld device and actigraph may be done on the first day of Screening but must take place at least 7 days before the Baseline visit. 
b 
Measurement of weight and BMI are required at Screening and Baseline; measurement of weight (not BMI) is required at Week 4/EOT.  
c 
The ECG will be completed in triplicate at Visit 1 (Screening) and collected within an approximately 5-minute period. A single ECG tracing should be 
completed at all other designated visits.  
d 
A pregnancy test is only required for women of childbearing potential. Serum pregnancy should only be performed at Visit 1 (Screening); a urine pregnancy 
test should be performed at Baseline and EOT visits. If urine cannot be obtained in women of childbearing potential, a serum pregnancy test should be done. 
e 
Subjects will be assessed for their ability to swallow a test capsule (i.e., placebo). 


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f 
This clinician-administered assessment should be conducted at least one hour after dosing when conducted at Weeks 1-4. The Baseline clinician-
administered assessments should be conducted prior to dosing. 
g 
The site staff must observe the subject for a minimum of 60 minutes in the clinic after dosing. Subjects should not take study drug on the mornings of clinic 
visit days until instructed to do so by the site staff. 
h 
Baseline handheld device data will be collected during the 7-day period before the Baseline visit. Assessments completed on the handheld device should not 
be done on the days of clinic visits. See Table S–2 and Table S–3 for further details on the assessments for the handheld device.  
i 
Baseline actigraphy data will be collected during the 7-day period before the Baseline visit. The handheld device is to be brought with the subject for the 
clinic visits at Visit 2 (Baseline), Visit 3 (Week 1), Visit 4 (Week 2), Visit 5 (Week 3), and Visit 6 (Week 4). Site staff are to review completion of 
assessments on the handheld device and use of actigraph at Visit 3 (Week 1), Visit 4 (Week 2), Visit 5 (Week 3), and Visit 6 (Week 4). 
j 
The Baseline/Screening version of the C-SSRS will be administered at Screening, and the “Since Last Visit” version of the C-SSRS will be administered at 
all other designated visits. 
k 
Urine drug screen at Visit 2 (Baseline) can be performed at the clinical site for rapid results to qualify the subject for study drug administration or exclude the 
subject without dosing. 
l 
The safety follow-up visit is to occur 30 (±4) days after the last dose of study drug. 
 


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Table S–2 
Schedule of Assessments for Subjects on the Handheld Device (EMAs) in Study ACP-103-056 
Three Times Each Week 
Weekly 
 
Sleep Assessments 
PROMIS Cognitive 
Function 
Satisfaction Question 
Nighttime Sleepb 
Sleep-Related 
Impairment 
Karolinska 
Sleepiness Scale 
(KSS) 
9 am ± 2 hoursa 
X 
X 
X 
X 
X 
2 pm ± 2 hours 
 
X 
X 
X 
 
7 pm ± 2 hours 
 
X 
X 
X 
 
Abbreviations: PROMIS=Patient-Reported Outcomes Measurement Information System 
Note: Assessments completed on the handheld device should not be done on the days of clinic visits. It is recommended that assessments on the handheld 
device be done on the first, third and fifth days following clinic visits (except Visit 6, the last visit); however, flexibility is permitted as long as 
assessments are completed 3 times each week. 
a 
Testing should be completed at least 1 hour after the daily administration of study drug. If subject does not complete morning assessment, then no 
assessments can be completed that day. 
b 
Questions related to nighttime sleep will be asked only at the morning assessment. 
 
 


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Table S–3 
Schedule of Assessments for Informants on the Handheld Device in Study ACP-103-056 
 
 
 
Three Times Each Week 
Weekly 
 
Sleep Assessments 
PROMIS 
Cognitive Function 
Satisfaction Question 
Nighttime Sleepb 
Sleep-Related Impairment 
9 am ± 2 hoursa 
X 
X 
 
X 
7 pm ± 2 hours 
 
X 
X 
 
Abbreviations: PROMIS=Patient-Reported Outcomes Measurement Information System 
Note: Assessments completed on the handheld device should not be done on the days of clinic visits. It is recommended that assessments on the handheld 
device be done on the first, third and fifth days following clinic visits (except Visit 6, the last visit); however, flexibility is permitted as long as 
assessments are completed 3 times each week. 
a  
Testing should be completed at least 1 hour after the subject’s daily administration of study drug. 
b  
Questions related to nighttime sleep will be asked only at the morning assessment. 


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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ............................................................................................... 2 
DECLARATION OF INVESTIGATOR ................................................................................... 4 
PROTOCOL SYNOPSIS ........................................................................................................... 5 
TABLE OF CONTENTS ......................................................................................................... 22 
LIST OF TABLES ................................................................................................................... 26 
LIST OF FIGURES ................................................................................................................. 26 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................. 27 
1 
INTRODUCTION ...................................................................................................... 28 
1.1 
Background Information ............................................................................................ 28 
1.2 
Investigational Product ............................................................................................... 29 
1.2.1 
Pimavanserin .............................................................................................................. 29 
1.2.2 
Quetiapine .................................................................................................................. 29 
1.3 
Previous Clinical Experience with Pimavanserin ...................................................... 30 
1.3.1 
Parkinson’s Disease Psychosis Program .................................................................... 30 
1.4 
Study Rationale .......................................................................................................... 31 
2 
STUDY OBJECTIVES AND ENDPOINTS .............................................................. 33 
2.1 
Primary Objectives ..................................................................................................... 33 
2.1.1 
Primary Endpoint ....................................................................................................... 33 
2.2 
Exploratory Objectives ............................................................................................... 33 
2.2.1 
Exploratory Endpoints ................................................................................................ 33 
3 
STUDY DESCRIPTION ............................................................................................ 34 
3.1 
Overview of Study Design ......................................................................................... 34 
3.1.1 
Screening Period (7-28 Days) .................................................................................... 35 
3.1.2 
Double-blind Treatment Period (4 Weeks) ................................................................. 35 
3.1.3 
Safety Follow-up Period (30 Days) ............................................................................ 36 
4 
SUBJECT ELIGIBILITY AND WITHDRAWAL CRITERIA .................................. 36 
4.1 
Inclusion Criteria ........................................................................................................ 36 
4.2 
Exclusion Criteria ....................................................................................................... 38 
4.3 
Subject Withdrawal of Consent .................................................................................. 40 
4.4 
Subject or Study Discontinuation ............................................................................... 40 
4.4.1 
Handling of Subject Discontinuation During the Treatment Period .......................... 41 


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4.5 
Subject Lost to Follow-up .......................................................................................... 42 
4.6 
Prior and Concomitant Therapy ................................................................................. 42 
4.6.1 
Permitted, Restricted, and Prohibited Medications .................................................... 42 
4.6.2 
Rescue Medications, Treatments, and Procedures ..................................................... 43 
5 
INVESTIGATIONAL PRODUCT ............................................................................. 43 
5.1 
Investigational Product Description ........................................................................... 43 
5.1.1 
Formulation, Appearance, Packaging, and Labeling .................................................. 43 
5.1.2 
Product Storage and Stability ..................................................................................... 44 
5.1.3 
Dosing and Administration ......................................................................................... 44 
5.1.4 
Method of Assigning Subjects to Treatment Groups.................................................. 44 
5.1.5 
Blinding ...................................................................................................................... 44 
5.1.6 
Study Drug Compliance ............................................................................................. 45 
5.1.7 
Overdose ..................................................................................................................... 45 
5.2 
Investigational Product Accountability Procedures ................................................... 45 
6 
STUDY PROCEDURES ............................................................................................ 46 
6.1 
Screening Assessments ............................................................................................... 46 
6.1.1 
Mini-Mental State Examination ................................................................................. 46 
6.1.2 
Clinical Global Impression - Severity ........................................................................ 46 
6.1.3 
Capsule Swallowing Test ........................................................................................... 46 
6.1.4 
Medical History and Demographics ........................................................................... 46 
6.1.5 
Psychiatric and Neurological History ......................................................................... 47 
6.2 
Exploratory Efficacy Assessments ............................................................................. 47 
6.2.1 
Patient-Reported Outcomes Measurement Information System ................................ 47 
6.2.1.1 Nighttime Sleep Scale ................................................................................................ 47 
6.2.1.2 Sleep-Related Impairment Scale ................................................................................ 48 
6.2.1.3 Cognitive Function ..................................................................................................... 48 
6.2.2 
Karolinska Sleepiness Scale ....................................................................................... 48 
6.2.3 
Trail Making Tests ...................................................................................................... 48 
6.2.4 
Hopkins Verbal Learning Test - Revised .................................................................... 49 
6.2.5 
Parkinson’s Disease Non-motor Symptoms Questionnaire ....................................... 49 
6.2.6 
Patient Global Impression - Improvement ................................................................. 49 
6.2.7 
Clinical Global Impression - Improvement ................................................................ 50 
6.2.8 
Subject and Informant Satisfaction Question ............................................................. 50 
6.2.9 
Actigraphy .................................................................................................................. 50 
6.3 
Safety Assessments..................................................................................................... 50 
6.3.1 
Physical Examinations ............................................................................................... 50 


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6.3.2 
Vital Signs .................................................................................................................. 50 
6.3.3 
Height, Weight, and Body Mass Index ....................................................................... 51 
6.3.4 
Electrocardiograms ..................................................................................................... 51 
6.3.5 
Movement Disorders Society-Unified Parkinson’s Disease Rating Scale ................. 52 
6.3.6 
Columbia-Suicide Severity Rating Scale ................................................................... 52 
6.3.7 
Laboratory Evaluations .............................................................................................. 52 
6.4 
Safety Follow-up ........................................................................................................ 55 
6.5 
Unscheduled Visits ..................................................................................................... 55 
7 
ADVERSE EVENTS ................................................................................................. 55 
7.1 
Specification of Safety Parameters............................................................................. 55 
7.1.1 
Definition of Adverse Event ....................................................................................... 55 
7.1.2 
Definition of Serious Adverse Event .......................................................................... 56 
7.2 
Classification of an Adverse Event ............................................................................ 58 
7.2.1 
Severity of Event ........................................................................................................ 58 
7.2.2 
Relationship to Study Drug ........................................................................................ 58 
7.2.2.1 Duration ...................................................................................................................... 58 
7.2.2.2 Frequency ................................................................................................................... 58 
7.2.2.3 Action Taken with Study Drug ................................................................................... 59 
7.2.2.4 Therapy ....................................................................................................................... 59 
7.2.2.5 Outcome ..................................................................................................................... 59 
7.2.2.6 Seriousness ................................................................................................................. 59 
7.2.3 
Definition of Unexpectedness .................................................................................... 59 
7.3 
Time Period and Frequency for Event Assessment and Follow-up ........................... 59 
7.4 
Reporting Procedures ................................................................................................. 60 
7.4.1 
Adverse Event Reporting ........................................................................................... 60 
7.4.2 
Serious Adverse Event Reporting............................................................................... 60 
7.4.3 
Reporting of Pregnancy .............................................................................................. 61 
7.4.3.1 Reporting Paternal Drug Exposure............................................................................. 61 
7.4.4 
Reporting of Overdose ............................................................................................... 61 
8 
CLINICAL MONITORING ....................................................................................... 62 
9 
STATISTICAL METHODS AND DATA ANALYSIS .............................................. 62 
9.1 
Statistical and Analytical Plans .................................................................................. 62 
9.2 
Statistical Hypotheses................................................................................................. 62 
9.3 
Sample Size Determination ........................................................................................ 62 
9.4 
Subject Populations for Analysis ................................................................................ 62 


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9.5 
Statistical Analyses ..................................................................................................... 62 
9.5.1 
Primary Analyses ........................................................................................................ 62 
9.5.2 
Exploratory Analyses ................................................................................................. 63 
9.5.2.1 Analysis of Endpoints Measured at Study Visits ....................................................... 63 
9.5.2.2 Analysis of Ecological Momentary Assessment and Actigraphy Data ...................... 63 
9.5.3 
Other Safety Analyses ................................................................................................ 64 
9.6 
Measures to Minimize Bias ........................................................................................ 64 
9.7 
Breaking the Study Blind/Subject Code ..................................................................... 65 
10 
STUDY MANAGEMENT AND DATA COLLECTION .......................................... 65 
10.1 
Data Collection and Management Responsibilities.................................................... 65 
10.2 
Source Documents ...................................................................................................... 65 
10.3 
Case Report Forms ..................................................................................................... 66 
10.4 
Confidentiality ............................................................................................................ 66 
10.5 
Study Records Retention ............................................................................................ 66 
10.6 
Protocol Exceptions and Deviations........................................................................... 66 
10.7 
Protocol Amendments ................................................................................................ 67 
11 
STUDY MONITORING, AUDITING, AND INSPECTING .................................... 67 
11.1 
Quality Control and Quality Assurance...................................................................... 67 
11.2 
Risk Management ....................................................................................................... 68 
12 
ETHICAL CONSIDERATIONS ................................................................................ 68 
12.1 
Ethical Standard ......................................................................................................... 68 
12.2 
Institutional Review Board/Ethics Committee ........................................................... 69 
12.3 
Informed Consent Process .......................................................................................... 69 
12.3.1 Consent and Other Informational Documents Provided to Subjects .......................... 70 
12.3.2 Consent Procedures and Documentation .................................................................... 70 
13 
PUBLICATION PLAN .............................................................................................. 70 
14 
CONFLICT OF INTEREST POLICY ....................................................................... 70 
14.1 
Finance, Insurance, and Indemnity............................................................................. 70 
15 
LITERATURE REFERENCES .................................................................................. 70 
16 
APPENDICES ............................................................................................................ 73 
Appendix A Prohibited and Restricted Medications ............................................................. 73 
Appendix B Prohibited and Restricted Concomitant Medications: Inhibitors and 
Inducers of Cytochrome P450 Enzyme 3A4 .................................................... 77 


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LIST OF TABLES 
Table S–1 
Schedule of Events and Assessments for ACP-103-056 .................................. 17 
Table S–2 
Schedule of Assessments for Subjects on the Handheld Device (EMAs) in 
Study ACP-103-056 ......................................................................................... 20 
Table S–3 
Schedule of Assessments for Informants on the Handheld Device in Study 
ACP-103-056 ................................................................................................... 21 
Table 6–1 
Safety Laboratory Evaluations......................................................................... 55 
 
LIST OF FIGURES 
Figure S–1 
Schematic of Study Design for ACP-103-056 ................................................. 15 
Figure S–2 
Schematic for Study Drug Dispensing and Dose Adjustments........................ 16 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Term 
Definition 
AE(s) 
adverse event(s) 
ANCOVA 
analysis of covariance 
CGI-I 
Clinical Global Impression-Improvement 
CGI-S 
Clinical Global Impression-Severity 
CRF 
case report form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EMA 
Ecological Momentary Assessment 
EOT 
end of treatment 
ET 
early termination 
GCP 
Good Clinical Practice 
HVLT-R 
Hopkins Verbal Learning Test-Revised 
ICF 
informed consent form 
ICH 
International Council for Harmonisation  
IRB 
institutional review board 
KSS 
Karolinska Sleep Scale 
MDS-UPDRS 
Movement Disorders Society-Unified Parkinson’s Disease Rating Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model repeated measures 
MMSE 
Mini-Mental State Examination 
PD 
Parkinson’s disease 
PD NMS 
Parkinson’s disease non-motor symptoms 
PDP 
Parkinson’s disease psychosis 
PGI-I 
Patient Global Impression-Improvement 
PROMIS® 
Patient-Reported Outcomes Measurement Information System 
SAE(s) 
serious adverse event(s) 
TEAE(s) 
treatment emergent adverse event(s) 
US 
United States 


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1 INTRODUCTION 
This document is a research protocol and the described study will be conducted in 
compliance with the protocol and the International Council for Harmonisation (ICH) Good 
Clinical Practice (GCP) Guideline.  
1.1 
Background Information 
Parkinson disease (PD) is one of the most common neurologic disorders, affecting 
approximately 1% of individuals older than 60 years and causing progressive disability that 
can be slowed, but not halted, by treatment. Parkinson’s disease is typically associated with 
motor impairments that include bradykinesia, rest tremor, cogwheel rigidity, and postural 
instability (Postuma et al. 2015). However, it is increasingly recognized that non-motor 
symptoms can precede prodromal and early-stage PD, and as the disease progresses patients 
can develop numerous non-motor symptoms that reduce quality of life, are associated with 
poor outcomes, implicate several non-dopaminergic systems, and can benefit from improved 
therapeutics (Goldman and Postuma 2014). Non-motor symptoms include neurobehavioral 
changes, depression, cognitive deficits, sleep disorders, hyposmia, and autonomic 
abnormalities. Furthermore, drugs often used to treat motor and non-motor symptoms can 
have behavioral side effects or exacerbate existing neurobehavioral symptoms.  
Neuropsychiatric, autonomic, and sensory features can be observed early in PD and can 
increase after chronic exposure to L-dopa. Although symptoms fluctuate with dopaminergic 
treatment, serotonin and norepinephrine denervation, as well as interactions between 
neurotransmitter systems, probably contribute to their diversity 
(Martínez-Fernández et al. 2016). Symptom management, largely resulting from expert 
opinion, includes psychiatric follow-up, non-dopaminergic drugs, and advanced 
dopaminergic treatment, including drug delivery pumps and deep brain stimulation (DBS). 
Of particular interest in the management of neuropsychiatric symptoms is the use of atypical 
antipsychotics. Visual hallucinations are common and are exacerbated by dopaminergic and 
anticholinergic medications. Currently, pimavanserin is the only antipsychotic approved for 
use in patients with Parkinson’s disease, and is indicated for the treatment of delusions and 
hallucinations that occur in a large percentage of patients (Cummings et al. 2014). Although 
pimavanserin is the only approved antipsychotic for any PD behavioral symptoms, quetiapine 
and clozapine are also often used off-label. Quetiapine is used off label for the treatment of 
several neurobehavioral symptoms in PD including psychosis, agitation, and sleep 
disturbances; however, there is a dearth of clinical data to support these indications 
(Kurlan et al. 2007; Mueller et al. 2018; Juri et al. 2005). Additional work is needed to 
evaluate the use of antipsychotics for the treatment of behavioral disturbances in PD, 
particularly in the early stages. 


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1.2 
Investigational Product 
1.2.1 
Pimavanserin 
Pimavanserin is an atypical antipsychotic that is present in the investigational product (IP) 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 
for the treatment of hallucinations and delusions associated with Parkinson’s disease 
psychosis (PDP). 
Pimavanserin is a novel small molecule designed to specifically block serotoninergic 
neurotransmission mediated by the 5-hydroxytryptamine (5-HT [serotonin]) 2A (5-HT2A) 
receptor. At higher doses, pimavanserin may block 5-HT2C receptors (Vanover et al. 2006). 
Pimavanserin shows no appreciable activity at dopaminergic, adrenergic, histaminergic, or 
muscarinic receptors. Activity at these receptors has been implicated in a range of dose-
limiting side effects associated with existing antipsychotic drugs including cognitive dulling 
(Saeedi et al. 2006; Mehta et al. 2004; Peretti et al. 1997) and an increased risk of mortality 
in elderly patients with dementia (Wang et al. 2005). On the basis of its novel receptor 
binding profile, pimavanserin may have benefits with regard to overall tolerability relative to 
other antipsychotic agents. 
A potential risk for QT prolongation with pimavanserin treatment and a boxed warning in the 
pimavanserin prescribing information are described in Section 1.3.1. 
1.2.2 
Quetiapine 
Quetiapine is a second-generation antipsychotic that has affinity for D2, 5-HT2A, H1, alpha 1 
and 5-HT1A receptors. Its precise mechanism of action is unknown, but according to the 
dopamine theory of schizophrenia, antipsychotic effects might be related to the drug’s ability 
to reduce dopaminergic neurotransmission in the mesolimbic pathway. 
Quetiapine immediate-release is an orally administered antipsychotic approved in the United 
States for the treatment of schizophrenia, acute treatment of manic episodes associated with 
bipolar I disorder, depressive episodes associated with bipolar disorder, and maintenance 
treatment of bipolar I disorder (Northstar Rx LLC. 2019). The extended-release formulation 
is approved in the US for use as adjunctive treatment to antidepressant therapy of major 
depressive disorder. Quetiapine is also commonly used in off-label indications such as 
behavioral and psychological symptoms of dementia, posttraumatic stress disorder, 
depression psychosis in Parkinson’s disease, anxiety disorders and insomnia 
(El-Saifi et al. 2016). In randomized controlled trials that recruited relatively younger and 
healthier populations, as opposed to the patients prescribed the medication in clinical 


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practice, the most frequent quetiapine side effects included somnolence (18%), dizziness 
(11%), dry mouth (9%), constipation (8%), orthostatic hypotension (4%), weight gain (5%), 
and lethargy dyspepsia (5%) (El-Saifi et al. 2016).  
In April 2005, the US Food and Drug Administration (FDA) issued a warning about the 
increased risk of mortality associated with the use of second-generation antipsychotics in 
older adults with dementia-related psychosis, based on the analyses of 17 placebo-controlled 
trials. Most of the deaths were cardiovascular (e.g., heart failure, sudden death) or infectious 
(e.g., pneumonia) in nature. The quetiapine prescribing information also includes a warning 
regarding QT prolongation. 
Additional information is provided in the US package insert for quetiapine 
(Northstar Rx LLC 2019).  
1.3 
Previous Clinical Experience with Pimavanserin 
Pimavanserin is an atypical antipsychotic that is approved for the treatment of hallucinations 
and delusions associated with PDP. Studies have also been conducted in Alzheimer’s disease 
psychosis (ADP) and studies are ongoing in schizophrenia, Alzheimer’s disease agitation, 
major depressive disorder, dementia-related psychosis, and depression in PD. The clinical 
program for PDP is 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 (Cummings et al. 2014). 
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 in patients with PDP. 
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 


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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. 
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. In 
addition to a warning describing QT prolongation in the NUPLAZID® (pimavanserin) 
Prescribing Information (ACADIA Pharmaceuticals Inc. 2019), a boxed warning regarding 
the potential for increased risk of mortality in elderly patients with dementia-related 
psychosis taking atypical antipsychotics is present.  
Additional information is provided in the pimavanserin IB and in the NUPLAZID® 
(pimavanserin) US package insert. 
1.4 
Study Rationale 
This is a pilot, hypothesis-generating study to explore the effects of pimavanserin and low-
dose quetiapine in subjects with PD that will be used to guide the design of future studies. In 
addition, the present study will explore the sensitivity of assessments/instruments (Ecological 
Momentary Assessments [EMAs] on the handheld device and actigraphy) that are novel for 
evaluating the experience of subjects with PD with respect to sedation/sleep, cognition, and 
other non-motor symptoms. 
Pimavanserin is the only medication approved in the US for the treatment of hallucinations 
and delusions associated with PDP. The safety database supporting the approval of 
pimavanserin consisted of >1200 patients and healthy subjects, including >600 PDP patients, 
representing the largest development program in PDP ever conducted. In the PDP 
development program, pimavanserin demonstrated statistically significant improvement on 
measures of hallucinations and delusions, caregiver burden, clinical global impression, 
nighttime sleep and daytime sleepiness. Antipsychotic benefits have also been shown in 
subjects with Alzheimer’s disease psychosis (ADP). Pimavanserin is currently being 
investigated in other neuropsychiatric conditions, including schizophrenia, major depressive 
disorder (MDD), and neurobehavioral symptoms of neurodegenerative disorders.   
Low-dose quetiapine (50-100 mg daily) is commonly used off-label to treat neurobehavioral 
disturbances in the PD population, despite limited efficacy data supporting its use and 
clinically meaningful safety concerns (Chen 2018). Even at low doses, daytime sedation has 


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been reported with quetiapine, and is associated with worsened cognition, dizziness, 
decreased daytime activities and increased risk of falls in this vulnerable population.  
Pimavanserin is a selective serotonergic 5-HT2a antagonist/inverse agonist with no 
appreciable binding at dopaminergic, histaminergic, muscarinic or nicotinic receptors. In PDP 
and ADP studies, pimavanserin has demonstrated a distinct safety profile consistent with this 
unique pharmacology. Adverse event rates of extrapyramidal symptoms, cognitive 
impairment, metabolic abnormalities, orthostatic hypotension, sedation and falls are low and 
comparable to placebo. Altogether, the efficacy and safety profile of pimavanserin offers 
potentially unique and significant advantages over quetiapine in patients with 
neuropsychiatric symptoms associated with neurodegenerative disease.  
The impact of daytime sedation will be assessed with a variety of outcome measures, 
including cognitive performance tasks, subjective patient and informant reports, treatment 
satisfaction, and physical activity. Ecological Momentary Assessments (EMAs) have been 
used effectively in non-PD clinical trials to enhance the precision and quality of outcome 
measures, detect signals, and measure quality of life. Potential advantages of EMAs on the 
handheld device for nighttime sleep (Nighttime Sleep Scale), sleep impairment (Sleep-
Related Impairment Scale), daytime sleepiness (Karolinska Sleepiness Scale [KSS]), 
cognition (Patient-Reported Outcomes Measurement Information System [PROMIS®] 
Cognition Assessment), and satisfaction (Patient and Informant Satisfaction Question) in the 
PD population are to reduce memory bias and for gathering intra-individual data more 
frequently and in real time. Further, the actigraphy instrument being used in the present study 
will provide reports of movement and day/night objective reporting. The use of these 
assessments/instruments is novel in clinical studies of subjects with PD and the present study 
aims to evaluate their usefulness in this population. 
The 34 mg dose of pimavanserin is approved for the treatment of hallucinations and 
delusions associated with Parkinson’s disease psychosis. Low-dose quetiapine (50 mg to 
100 mg) is commonly used off-label in the PD population for the treatment of behavioral 
disorders. The use of placebo in the present study is necessary to establish assay sensitivity 
when using these assessments/instruments and ensure precise mapping of their data to 
outcomes. 
For this hypothesis-generating study, safety and tolerability is the primary objective. In 
addition, there is limited availability of data on the use of these assessments/instruments 
(EMAs on the handheld device and actigraphy) in PD. Therefore, outcomes of the 
exploratory measures in the present study will expand the understanding of these 
assessments/instruments in an optimal placebo-controlled setting. 


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2 STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objectives 
The primary objectives of this study are to assess the safety and tolerability of pimavanserin 
and low-dose quetiapine compared to placebo in subjects with Parkinson’s disease. 
2.1.1 
Primary Endpoint 
The primary endpoint for this study is treatment-emergent adverse events (TEAEs). 
2.2 
Exploratory Objectives 
The exploratory objectives of this study are:  
• to explore the sensitivity of assessments/instruments that are novel for evaluating 
the experience of subjects with Parkinson’s disease with respect to sedation/sleep, 
cognition, and other non-motor symptoms.   
• to explore the effects of pimavanserin and low-dose quetiapine compared to 
placebo in subjects with Parkinson’s disease on: 
o Daytime sleepiness 
o Nighttime sleep 
o Cognition 
o Other non-motor symptoms 
o Treatment satisfaction 
o Safety and tolerability 
2.2.1 
Exploratory Endpoints 
The exploratory endpoints of this study are: 
• Measures related to daytime sedation   
o Karolinska Sleepiness Scale (KSS) 
o Sleep-Related Impairment Scale 
o Nighttime Sleep Scale 
o Sleep/wake cycle and nighttime and daytime activity as measured by 
actigraphy via a wearable instrument 
• Measures of cognition 


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o Patient-Reported Outcomes Measurement Information System (PROMIS®) 
Cognition Assessment 
o Trail Making Test (TMT) Parts A and B  
o Hopkins Verbal Learning Test-Revised (HVLT-R) 
• Measures of other nonmotor symptoms 
o Parkinson’s disease Non-motor Symptoms (PD NMS) Questionnaire 
o Patient Global Impression - Improvement (PGI-I) 
o Clinical Global Impression - Improvement (CGI-I) 
• Patient and Informant Satisfaction Question 
• Other measures of safety and tolerability 
o Movement Disorders Society-Unified Parkinson’s Disease Rating Scale 
(MDS-UPDRS) Part III (motor examination) 
o Columbia-Suicide Severity Rating Scale (C-SSRS) score 
3 STUDY DESCRIPTION 
3.1 
Overview of Study Design 
This study will be conducted as a multicenter, randomized, double-blind, placebo- and 
active-control, parallel-group pilot study in subjects with Parkinson’s disease. Subjects with 
at least moderate neurobehavioral symptoms that could benefit from treatment will be 
included in the study. Up to 60 subjects will be randomized in a 1:1:1 ratio to pimavanserin, 
quetiapine, or placebo. Up to approximately 120 subjects will be screened. A maximum of 
20% of subjects across treatment groups (12 subjects) will be replaced. Subject replacement 
may occur as described in Section 3.1.2. The duration of participation for individual subjects 
will be approximately 12 weeks. Approximately 23 sites within the United States will 
participate in this study. 
The study will have 3 periods: 
• Screening period (7-28 days) 
• Double-blind treatment period (4 weeks) 
• Safety follow-up period (30 [±4] days) 
The study design schema is provided in Figure S–1. 


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The study completion date is defined as the date the final subject, across all sites, completes 
their final protocol-defined assessment (Note: this includes the safety follow-up phone call). 
If the study is terminated for any reason, subjects remaining in the study will return to 
standard of care. Procedures for when a subject is lost to follow-up are provided in 
Section 4.5. 
3.1.1 
Screening Period (7-28 Days) 
During the Screening period, subjects will be assessed for study eligibility, the ability to 
swallow a test capsule (i.e., placebo), and prohibited medications will be discontinued. Only 
those subjects who are able to swallow the test capsule at the Screening visit and who meet 
all inclusion and no exclusion criteria will be eligible for the study.  
A wearable device (i.e., actigraph) will be used to continuously evaluate activity and sleep of 
subjects during the study. Training on the handheld device and actigraph may be done on the 
first day of Screening but must take place at least 7 days before the Baseline visit. Baseline 
data for the handheld device and actigraph will be collected during the 7-day period before 
the Baseline visit.  
Subjects who screen fail will be allowed to rescreen within 3 months with agreement of the 
Sponsor’s Medical Monitor. A subject may be rescreened up to two times. 
Investigators should not withdraw 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 and in consultation with the treating physician. 
3.1.2 
Double-blind Treatment Period (4 Weeks) 
The Baseline visit (Visit 2) may occur after screening procedures are completed, subject 
eligibility has been confirmed, and no earlier than 7 days after the subject has been given the 
wearable device. At the Baseline visit (Visit 2), eligible subjects will be randomized in a 
1:1:1 ratio to pimavanserin 34 mg, quetiapine 25 mg, or matching placebo.  
Subjects who are randomized to the quetiapine treatment group will begin dosing at 25 mg. 
At Week 1 (Visit 3), Week 2 (Visit 4) and Week 3 (Visit 5), the Investigator will be 
encouraged to increase the dose of blinded study drug, consistent with 50-100 mg quetiapine, 
based on the Investigator’s assessment of clinical response (Figure S–2). Dose adjustments 
will be implemented through interactive response technology (IRT) system. In actuality, only 
the dose of quetiapine would be increased (to 50 mg at Week 1 and then optionally to 100 mg 
at Week 2 or Week 3); the pimavanserin dose will remain fixed at 34 mg per day throughout 
the study. The Investigator will be blinded to study drug and thus will not know whether their 
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dose. The dose of study drug (pimavanserin, quetiapine or placebo) may not be decreased. If 
a subject cannot tolerate their dose, they must be withdrawn from the study. 
Subjects for whom the Investigator does not increase the dose of blinded study drug 
consistent with 50 mg quetiapine at Week 1 (Visit 3) will be withdrawn from the study and 
replaced. A maximum of 12 subjects across treatment groups (20%) will be replaced for this 
and only this reason. 
Assessments in the clinic will be conducted at Weeks 0 (Baseline), 1, 2, 3, and 4/end of 
treatment (EOT). Assessments on the handheld device will be collected from Baseline to 
Week 4/EOT on a regular basis (see Table S–2). 
Subjects will be provided standard of care treatment per investigator judgment for 3 months 
following their completion of the double-blind treatment period. 
3.1.3 
Safety Follow-up Period (30 Days) 
A follow-up safety assessment telephone call will be conducted 30 (±4) days after the last 
dose of study drug. 
4 SUBJECT ELIGIBILITY AND WITHDRAWAL CRITERIA 
To be eligible for this study, subjects must meet all of the inclusion criteria and none of the 
exclusion criteria. 
4.1 
Inclusion Criteria 
A subject must meet all of the following inclusion criteria to be eligible for participation in 
the study: 
1. Male or female subjects 50 to 85 years of age, inclusive, at Screening and Baseline 
2. Can understand the nature of the trial and protocol requirements and provide written 
informed consent 
3. Is able to demonstrate the ability to complete subject-reported outcome measures on a 
handheld device, is willing to wear a data capture instrument (e.g., an actigraph), and 
can be reliably rated on assessment scales (in the opinion of the Investigator) 
4. Can designate an “informant” (a relative, housemate, or friend) who the subject agrees 
can provide reliable information on the subject’s well-being and is willing to attend 
clinic visits with the subject 
5. Is able to swallow the test capsule without difficulty during the Screening visit  
6. Has a Mini-Mental State Examination (MMSE) score ≥19 


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7. Has a diagnosis of idiopathic Parkinson’s disease, without any other known or 
suspected cause of parkinsonism, according to the UK Parkinson’s Disease Society 
Brain Bank Clinical Diagnostic Criteria (Hughes et al. 1992). Initial diagnosis of PD 
must have been made more than 1 year prior to Screening. 
8. [Inclusion criterion eliminated] 
9. Has at both Visit 1 (Screening) and Visit 2 (Baseline), a CGI-S score of ≥3 on at least 
one of the following non-motor neuropsychiatric symptoms that warrant treatment 
with an antipsychotic agent based on Investigator judgement. Such symptoms do not 
need to be the same at Screening and Baseline, and all symptoms should be assessed at 
both Screening and Baseline. 
a. Delusions 
b. Hallucinations 
c. Depression/Dysphoria 
d. Apathy/Indifference 
e. Disinhibition 
f. Irritability/Lability 
10. If the subject is on anti-Parkinsonian medication, they must be on a stable regimen for 
1 month prior to Baseline and not planning (at the time of the Baseline visit) to make a 
major change in dose(s)  
11. If the subject has had stereotaxic surgery for subthalamic nucleus deep brain 
stimulation, they must be at least 6 months post-surgery. The stimulator settings must 
have been stable for at least 1 month prior to the Baseline visit and are expected to 
remain stable during the trial.  
12. If the subject is female, she must not be pregnant or breastfeeding. She must also be of 
non-childbearing potential (defined as either surgically sterilized or at least 1 year 
postmenopausal) or must agree to use a clinically acceptable method of contraception 
or be abstinent for at least 1 month prior to the Baseline visit, during the study, and 
41 days following completion of double-blind treatment. 
If intercourse does occur, an acceptable method of birth control is required. 
Acceptable methods of birth control include the following: 
• Condom, diaphragm, or cervical cap with spermicide 
• Hormonal contraception, including oral, injectable, transdermal, or 
implantable methods 
• Intrauterine device (IUD) 


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4.2 
Exclusion Criteria 
A subject must meet none of the following exclusion criteria to be eligible for the study: 
1. Has atypical parkinsonism (Parkinson’s plus, multiple system atrophy [MSA], 
progressive supranuclear palsy [PSP]), or secondary parkinsonism variants such as 
tardive or medication-induced parkinsonism 
2. Has undergone ablative procedures such as a pallidotomy, thalamotomy, or treatment 
with focused ultrasound  
3. Is in hospice, is receiving end-of-life palliative care, or is bedridden or confined to a 
wheelchair (as defined by spending >80% of the day in a wheelchair)  
4. Has neuropsychiatric symptoms that are primarily attributable to current delirium or 
substance abuse 
5. Has current evidence of an unstable neurological, cardiovascular, respiratory, 
gastrointestinal, renal, hepatic, hematologic, or other medical or psychiatric disorder, 
including cancer or malignancies that, in the judgment of the Investigator, would 
jeopardize the safe participation of the subject in the study or significantly interfere 
with the conduct or interpretation of the study 
6. Has a history of epilepsy 
7. Has atrial fibrillation unless adequately anticoagulated 
8. Has a history of myocardial infarction, unstable angina, acute coronary syndrome, or 
cerebrovascular accident within the last 6 months prior to Visit 1 (Screening) 
9. Has any of the following: 
a. greater than New York Heart Association (NYHA) Class 2 congestive heart 
failure  
b. Grade 2 or greater angina pectoris (by Canadian Cardiovascular Society 
Angina Grading Scale)  
c. sustained ventricular tachycardia 
d. ventricular fibrillation 
e. torsades de pointes 
f. syncope due to an arrhythmia 
g. an implantable cardiac defibrillator 
10. Has a known history of a positive hepatitis B virus (HBV) or hepatitis C virus (HCV) 
test 
11. Has a history of human immunodeficiency virus (HIV) 


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12. Has a history of neuroleptic malignant syndrome or serotonin syndrome 
13. Has a known personal or family history of long QT syndrome or family history of 
sudden cardiac death 
14. Has any of the following electrocardiogram (ECG) results at the Screening or Baseline 
visit: 
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 
If the mean QTcF value from the centrally read set of triplicate ECGs done at 
Screening is prolonged due to an identifiable cause, and it is medically appropriate to 
address that cause, a repeat set of triplicate ECGs may be performed during Screening 
at the discretion of the Medical Monitor.  
15. Has a heart rate as measured at Screening by the ECG machine <50 beats per minute 
(mean value from centrally read set of triplicate ECGs). If bradycardia is secondary to 
iatrogenic or treatable causes and these causes are treated, a heart rate assessment can 
be repeated during the screening period.  
16. Has major surgery planned during the screening through the end of the treatment or 
follow-up periods 
17. Requires treatment with a medication or other substance that is prohibited by the 
protocol 
18. Has a body mass index (BMI) <18.5 kg/m2 or >35 kg/m2 at Screening or Baseline or 
known unintentional clinically significant weight loss (i.e., ≥7%) over past 6 months  
19. The urine drug screen result at Visit 1 (Screening) or Visit 2 (Baseline) indicates the 
presence of amphetamine/methamphetamine, barbiturates, cocaine, or phencyclidine 
(PCP). The presence of benzodiazepines, marijuana (THC), or opiates does not 
necessarily exclude the subject from the study. 
20. Is suicidal at Screening or Baseline as defined below: 
a. According to the C-SSRS, he or she must not be 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]) and must not have 
attempted suicide in the 2 years prior to Visit 1 (Screening); OR 


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b. The subject is actively suicidal in the Investigator’s judgment 
21. Has participated in or is participating in a clinical trial of any investigational drug, 
device, or intervention, within 30 days or 5 half-lives, whichever is longer, of Visit 2 
(Baseline) 
22. Has previously been enrolled in any prior clinical study with pimavanserin  
23. Has previously or is currently taking pimavanserin 
24. Has taken an antipsychotic medication in the last 2 weeks or less than 5 half-lives 
(whichever is longer) prior to Baseline or is currently taking an antipsychotic 
medication 
25. Has a significant sensitivity or allergic reaction to pimavanserin, quetiapine or its 
excipients 
26. Is an employee or is a family member of an employee of ACADIA Pharmaceuticals 
Inc. 
27. Is judged by the Investigator or the Medical Monitor to be inappropriate for the study 
for any reason, including if the subject is judged to be a danger to self or others 
28. Has orthostatic hypotension at Screening or Baseline. A drop in systolic BP of ≥20 mm 
Hg, or in diastolic BP of ≥10 mm Hg, within 3 minutes of standing, or experiencing 
significant lightheadedness or dizziness after standing, along with a remarkable drop 
in BP as judged by the Investigator with agreement of the Sponsor’s Medical Monitor, 
is considered orthostatic hypotension. 
4.3 
Subject Withdrawal of Consent 
In accordance with the Declaration of Helsinki and other applicable regulations, a subject has 
the right to withdraw from the study at any time, and for any reason, without prejudice to his 
or her future medical care. 
Should a subject request or decide to withdraw consent, every reasonable effort should be 
made to complete and report observations as thoroughly as possible up to the date of 
withdrawal, including the evaluations specified at the early termination (ET) visit or safety 
follow-up contact (whichever visit is applicable), as outlined in Table S–1. 
4.4 
Subject or Study Discontinuation 
Subjects may be discontinued from the study for a number of reasons, including, but not 
limited to, those listed below: 
• Adverse event 
• Death 


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• Lack of efficacy (in the opinion of the Investigator) 
• Lost to follow-up (Section 4.5) 
• Non-compliance with study drug 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Study terminated by sponsor 
• Use of prohibited medication 
• Lack of a reliable 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). 
The Sponsor reserves the right to discontinue the study at any time for any reason. Such 
reasons may be any of, but not limited to, the following: 
• Occurrence of AEs unknown to date in respect of their nature, severity, and duration 
or the unexpected incidence of known AEs 
• Medical, ethical or business reasons affecting the continued performance of the study 
Regulatory authorities also have the right to terminate the conduct of the study in their region 
for any reason. 
4.4.1 
Handling of Subject Discontinuation During the Treatment Period 
Unless the subject has withdrawn consent to be contacted for this study, every reasonable 
effort should be made to complete Visit 6/ET and the safety follow-up contact (as outlined in 
Table S–1) if a subject discontinues prematurely for any reason. All information will be 
reported on the applicable pages of the electronic case report form (eCRF). 
If a subject is discontinued from the study because of an AE, every reasonable attempt should 
be made to follow the subject until the AE resolves or until the Investigator deems the AE to 
be chronic or stable. For subjects who continue to be followed for safety, SAEs should 
continue to be reported as described in Section 7.4.2. All SAEs will continue to be followed 
until such events have resolved or the Investigator deems them to be chronic or stable. 


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4.5 
Subject Lost to Follow-up 
A subject will be considered lost to follow-up if they fail to attend a scheduled visit 
(excluding the safety follow-up contact) and are unable to be contacted by the study site.  
Every reasonable effort should be made to contact the subject and will include a minimum of 
3 documented phone calls (each performed at different times of the day) and, if necessary, a 
certified letter to the subject’s last known mailing address or local equivalent methods. All 
contact attempts are to be documented in the source documents. 
4.6 
Prior and Concomitant Therapy 
All medications used from study screening through the Safety Follow-up Visit 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). 
The Investigator may prescribe appropriate medication to treat AEs. The Sponsor and 
Investigator or designee will confer to determine whether it is appropriate to continue such a 
subject in the trial if a prohibited medication is prescribed. 
4.6.1 
Permitted, Restricted, and Prohibited Medications 
Prohibitions and restrictions for concomitant medications should be followed between the 
initial screening visit and Week 4/Visit 6/ET as specified in Appendix A and Appendix B. 
These appendices do not constitute an exhaustive list and any questions regarding prohibited 
and restricted medications should be discussed with the Medical Monitor or designee. 
Use of medications that could interfere with study conduct or any questions regarding 
prohibited and restricted concomitant medications should be reviewed and/or discussed with 
the Medical Monitor or designee. 
Medications that can prolong QT interval are prohibited (or restricted if approved by the 
Medical Monitor) as specified in Appendix A. 
Permitted concomitant medications should remain at a stable dose throughout the study.  
If a subject is on a medication restricted by the protocol, the medication should be adjusted if 
it is determined by the Investigator to be clinically appropriate (e.g., if the subjects 
symptoms are not well-controlled or if the subject cannot tolerate the current medication) in 
consultation with the treating physician. 
Subjects who require current treatment with a prohibited medication will be withdrawn from 
the study. 


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Subjects who have previously taken a prohibited medication during the study will be 
withdrawn from the study unless: 
• the prohibited medication has been discontinued AND 
• withdrawal from the study presents an unacceptable medical risk to the subject 
The justification to allow the subject to continue in the trial will be made by the 
Sponsor/Medical Monitor, with medical input from the Investigator, and will be documented. 
If a subject is allowed to remain in the trial, this will be reported as a major protocol 
deviation and not a waiver. 
4.6.2 
Rescue Medications, Treatments, and Procedures 
Rescue medications will not be allowed in the study. 
5 INVESTIGATIONAL PRODUCT 
5.1 
Investigational Product Description 
The investigational product will be pimavanserin 34 mg (provided as 2×17 mg encapsulated 
tablets), immediate release quetiapine 25 mg (provided as 1×25 mg quetiapine encapsulated 
tablet and 1×placebo encapsulated tablet), quetiapine 50 mg (provided as 2×25 mg quetiapine 
encapsulated tablets), quetiapine 100 mg (provided as 2×50 mg encapsulated tablets), or 
matching placebo (2×placebo encapsulated tablets). Capsules will be administered orally as a 
single dose once daily.  
Blinding will be maintained by encapsulation to ensure shape, color, and size match. 
5.1.1 
Formulation, Appearance, Packaging, and Labeling 
The Sponsor will supply pimavanserin 17 mg encapsulated tablets, quetiapine 25 and 50 mg 
encapsulated tablets, and matching placebo encapsulated tablets. 
Pimavanserin tartrate is a white to off-white powder. Pimavanserin 17 mg tablets include the 
active compound (pimavanserin tartrate) and the following excipients: pregelatinized starch, 
magnesium stearate, and microcrystalline cellulose, and the tablet coating is 
 
. The drug product is formulated with standard pharmaceutical excipients 
at 17 mg strength (20 mg of pimavanserin tartrate). 
Placebo tablets contain all of the same excipients as pimavanserin 17 mg tablets but do not 
contain any pimavanserin tartrate. 
Pimavanserin and placebo tablets are manufactured under current Good Manufacturing 
Practices by 
 


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Quetiapine fumarate is a white to off-white crystalline powder. It is supplied for oral 
administration as 25 mg (round, pink) and 50 mg (round, white to off-white) tablets. Inactive 
ingredients are povidone, dibasic dicalcium phosphate dihydrate, microcrystalline cellulose, 
sodium starch glycolate, lactose monohydrate, magnesium stearate, hypromellose, 
polyethylene glycol, and titanium dioxide. The 25 mg tablets contain iron oxide red and 
yellow. 
5.1.2 
Product Storage and Stability 
Investigational product must be stored at room temperature, between 20°C to 25°C (68°F to 
77°F); excursions permitted 15°C to 30°C (59°F to 86°F) [see United States Pharmacopeia 
(USP) controlled room temperature] in a secure area with restricted access and according to 
local and national regulations. 
5.1.3 
Dosing and Administration 
Bottles of study drug will be dispensed to the subject at Baseline and at Weeks 1, 2 and 3. 
Each daily dose consists of two individual capsules that should be taken together. Subjects 
will begin dosing at the Baseline visit after eligibility is confirmed. At Baseline and at each 
subsequent clinic visit, subjects will be dosed and will remain in the clinic for observation for 
a minimum of 60 minutes after dosing. Subjects should not take study drug on the mornings 
of clinic visit days until instructed to do so by the site staff. 
Subjects are to take two whole capsules, orally, once daily in the morning (prior to the 
subject’s daily assessments). Investigators/study staff and subjects should be instructed to not 
open the capsules. The capsules may be taken with or without food. 
Subjects who are randomized to the quetiapine treatment group will begin dosing at 25 mg. 
At Week 1 (Visit 3), Week 2 (Visit 4) and Week 3 (Visit 5), the Investigator will be 
encouraged to increase the dose of blinded study drug, consistent with 50-100 mg quetiapine, 
based on the Investigator’s assessment of clinical response (Figure S–2). Dose adjustments 
will be implemented through the IRT. In actuality, only the dose of quetiapine would be 
increased (to 50 mg at Week 1 and then optionally to 100 mg at Week 2 or Week 3); the 
pimavanserin dose will remain fixed at 34 mg per day throughout the study (Figure S–2).  
5.1.4 
Method of Assigning Subjects to Treatment Groups 
At Baseline (Visit 2), eligible subjects who meet inclusion and do not meet exclusion criteria 
will be randomized in a 1:1:1 ratio to pimavanserin, quetiapine, or matching placebo.  
5.1.5 
Blinding 
Treatment assignments will be blinded to all study subjects, study partners/informants 
(if applicable), Investigators, raters, site personnel, and Sponsor personnel.  


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In the event of a potential serious unexpected suspected adverse reaction (SUSAR), in 
accordance with current health authority guidance, treatment assignments for the affected 
subject may be unblinded to a controlled group of the Sponsor’s Safety and/or Regulatory 
personnel for reporting purposes.  
Details regarding medical emergency unblinding procedures are provided in Section 9.7. 
5.1.6 
Study Drug Compliance 
If a subject misses one dose of study drug, he or she should not take an extra dose the next 
day. 
If a subject shows insufficient compliance (<70%) between any two scheduled visits, the 
Medical Monitor should be notified to determine if the subject remains eligible for the study 
and whether the incident should be considered a protocol deviation. 
In the event that a subject is permanently unable to return study drug to the site (i.e., drug is 
lost, destroyed, or discarded), the subject/informant testimony is to be used in determining 
compliance. 
5.1.7 
Overdose 
An overdose is a deliberate or inadvertent administration of a treatment at a dose higher than 
the maximum recommended dose per protocol. It must be reported, irrespective of outcome, 
even if toxic effects were not observed (Section 7.4.4). All events of overdose are to be 
captured as protocol deviations. 
5.2 
Investigational Product Accountability Procedures 
The Investigator or designee will keep current and accurate records of the study drug product 
dispensed, used, and returned for each subject to assure the regulatory authority and the 
Sponsor that the study drug is being handled appropriately. Subjects should be instructed to 
return all packaging and unused study drug to the Investigator at regularly scheduled clinic 
visits and ET visits. Any study drug supplied is for use in this study only and should not be 
used for any other purpose. 
At appropriate intervals during the study, study drug reconciliation will be performed by the 
Sponsor (or designee) who may return appropriate unused study drug and used and unused 
packaging to the Sponsor’s designee for destruction. 
At the conclusion of the study, final study drug reconciliation will be conducted at the site. 
Final study drug accountability documentation will be maintained at both the site and at the 
Sponsor. Any remaining unused study drug and all used and unused packaging will be sent 
back to the Sponsor’s designee for destruction, as allowed by country specific regulations. 


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Documentation of study drug destruction will be recorded and maintained by both the 
Sponsor and the Sponsor’s designee. 
6 STUDY PROCEDURES 
Study specific procedures are detailed below. All assessments will be completed according to 
the schedule described in Table S–1. Every effort should be made to complete the required 
procedures and evaluations at the designated visits and times. It is recommended that the 
same informant is used throughout the study to complete the assessments. 
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. Only subtraction of serial 7s will be used in this 
study; spelling the word ‘world’ backwards option should not be used. The MMSE, a 
clinician-administered scale, is being used in this study to screen for cognitive impairment. 
6.1.2 
Clinical Global Impression - Severity 
The CGI-S scale is a clinician-rated, 7-point scale that is designed to rate the severity of the 
subject’s non-motor neuropsychiatric symptoms at the time of assessment using the 
Investigator’s judgment and past experience with subjects who have the same disorder 
(Guy 1976). Subjects may be eligible for the study if they have at least one CGI-S score of 
≥3 when assessing delusions, hallucinations, depression/dysphoria, apathy/indifference, 
disinhibition, and irritability/lability at both Screening (Visit 1) and Baseline (Visit 2); these 
symptoms need not be the same at Screening and Baseline. 
6.1.3 
Capsule Swallowing Test 
At the Screening visit, subjects will be assessed for their ability to swallow a test capsule 
(i.e., placebo). Subjects must be able to swallow the test capsule in order to be eligible for 
study entry. 
6.1.4 
Medical History and Demographics 
A complete medical history will be obtained from each potential subject. Demographic 
information, including date of birth, gender, race, and ethnicity will be recorded as well. Any 
new medical condition beginning after the informed consent form (ICF) has been signed will 
be captured as an AE. Subjects may be asked to provide pharmacy or medical records to 
substantiate the medication history. 


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6.1.5 
Psychiatric and Neurological History 
Details of the subject’s psychiatric history and treatment will be collected. Details of the 
subject’s neurological diagnosis and treatment will be collected, including the date that any 
neurological disease was determined. 
6.2 
Exploratory Efficacy Assessments 
This section describes all exploratory efficacy assessments. Those exploratory efficacy 
assessments which are completed on the handheld device (EMAs, see below) should not be 
done on the days of clinic visits. An initial assessment on the handheld device should be 
collected during the 7-day period before the Baseline visit. It is recommended that 
subsequently, assessments be done on the first, third and fifth days following clinic visits 
(except Visit 6, the last visit); however, flexibility is permitted as long as post-baseline 
assessments are completed 3 times each week. The clinician-administered assessments should 
be conducted at least one hour after dosing when conducted at Weeks 1-4. The Baseline 
clinician-administered assessments should be conducted prior to dosing. 
6.2.1 
Patient-Reported Outcomes Measurement Information System 
PROMIS® is a set of person-centered measures that evaluates and monitors physical, mental, 
and social health in adults and children, developed and evaluated with US National Institutes 
of Health (NIH) funding and owned by the US Department of Health and Human Services. 
Patient-reported outcome domains—including pain, fatigue, emotional distress, physical 
functioning and social role participation—are based on common metrics that allow for 
comparisons across domains, across chronic diseases, and with the general population. 
Questions taken from the PROMIS assessments will be administered on the handheld device 
to subjects and informants at the designated timepoints (see Table S–2 for subjects and 
Table S–3 for informants).  
6.2.1.1 
Nighttime Sleep Scale 
A nighttime sleep question taken from the Sleep Disturbance measure form (Short Form 8b) 
will be administered. The Sleep Disturbance Scale assesses perceptions of sleep quality, sleep 
depth, and restoration associated with sleep. The question on nighttime sleep for the subject 
is taken directly from the PROMIS scale. The same questions were modified to be asked to 
the informant for rating the subject’s nighttime sleep. 
The morning assessment on the handheld device should be done at least 1 hour after the dose 
of study drug is taken in the morning. 


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6.2.1.2 
Sleep-Related Impairment Scale 
A sleep-related impairment question taken from the Sleep-Related Impairment measure form 
(Short Form 8a) will be administered. The Sleep-Related Impairment Scale assesses 
perceptions of alertness, sleepiness, and tiredness during usual waking hours, and the 
perceived functional impairments during wakefulness associated with sleep problems or 
impaired alertness. Nighttime sleep-related questions will be asked only in the morning, 
daytime sleepiness questions will be asked morning, afternoon, and evening. The questions 
on sleep-related impairment for the subject are taken directly from the PROMIS scale. The 
same questions were modified to be asked to the informant for rating the subject’s daytime 
sleepiness. 
The morning assessment on the handheld device should be done at least 1 hour after the dose 
of study drug is taken in the morning. 
6.2.1.3 
Cognitive Function 
Assessment of the subject’s perceived cognitive deficits will be completed using the 
Cognitive Function measure form (Short Form 4a) of PROMIS®. Items are taken from the 
PROMIS® Cognitive Function and Cognitive Function Abilities Subset item banks. 
Components include mental acuity, concentration, verbal and nonverbal memory, verbal 
fluency, and perceived changes in these cognitive functions (Lai et al. 2014). 
The morning assessment on the handheld device should be done at least 1 hour after the dose 
of study drug is taken in the morning. 
6.2.2 
Karolinska Sleepiness Scale 
The KSS is a 9-item, self-reported subjective measure of a subject’s level of drowsiness 
(Åkerstedt and Gillberg 1990). Respondents must choose the statement that most accurately 
describes their level of sleepiness over the past few minutes. The KSS will be administered 
on the handheld device. 
The morning assessment on the handheld device should be done at least 1 hour after the dose 
of study drug is taken in the morning. 
6.2.3 
Trail Making Tests  
The TMT is a neuropsychological test of visual attention and task switching (Reitan 1958). 
The TMT has two parts, Parts A and B. Part A measures rote memory and consists of 
25 circles on a piece of paper with the numbers 1-25 written randomly in the circles. The 
subject is to connect the circles in numerical order. Part B measures executive functioning 
and consists of 24 circles on a piece of paper, half of the circles have the numbers 1-12 in 


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them and the other half (12) contain the letters A-L. The subject must alternate connecting 
circles with numbers and circles with letters. 
This clinician-administered assessment is to be completed at the clinic visits indicated in 
Table S–1. 
6.2.4 
Hopkins Verbal Learning Test - Revised 
The HVLT is a brief verbal learning and memory test with six alternate forms (Brandt 1991). 
The HVLT is ideal in situations calling for repeated neuropsychological examinations, but it 
lacks a delayed recall trial which is essential for the assessment of abnormal forgetting and 
therefore the revised version of the HVLT (HVLT-R) was developed. The HVLT-R test 
consists of three trials of free-recall of a 12-item, semantically categorized list, followed by 
yes/no recognition. Approximately 20-25 min later, a delayed recall trial and a recognition 
trial are completed. 
This clinician-administered assessment is to be completed at the clinic visits indicated in 
Table S–1. 
6.2.5 
Parkinson’s Disease Non-motor Symptoms Questionnaire 
The NMS questionnaire is a validated, clinician-rated questionnaire that assesses non-motor 
issues that that may be present in Parkinsons disease (Chaudhuri et al. 2006). The PD NMS 
is comprised of 30 items grouped into nine domains: digestive, urinary tract, 
apathy/attention/memory, hallucinations/delusions, depression/anxiety, sexual function, 
cardiovascular, sleep disorders, and miscellaneous. 
This clinician-administered assessment is to be completed at the clinic visits indicated in 
Table S–1.  
6.2.6 
Patient Global Impression - Improvement 
The PGI-I is a global index used to rate the response of a condition to a therapy. It is a 
simple, direct, easy to use scale that is intuitively understandable to subjects and clinicians. 
The PGI-I asks the patient to rate their symptoms now, as compared with how it was at 
Baseline before beginning treatment, ranging from 1=very much better to 7=very much 
worse.  
Severity ratings should be based on the behavioral symptom(s) of clinical concern used for 
eligibility. 
This assessment is to be completed at the clinic visits indicated in Table S–1. 


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6.2.7 
Clinical Global Impression - Improvement 
The CGI-I is a clinician-rated, 7-point scale that is designed to rate the improvement in the 
subject’s non-motor neuropsychiatric symptoms at the time of assessment, relative to the 
symptoms at Baseline (Guy 1976). 
Severity ratings should be based on the neuropsychiatric symptom(s) of clinical concern used 
for eligibility. 
This clinician-administered assessment is to be completed at the clinic visits indicated in 
Table S–1. 
6.2.8 
Subject and Informant Satisfaction Question 
Subject and informant will be assessed as to the satisfaction of the treatment the subject is 
getting during the study. The general question, “How satisfied are you with the treatment 
[you are] / [subject is] getting?” will be asked to the subject and separately to the informant. 
Answers will be rated on a scale of one (lowest, not satisfied) to five (highest, very satisfied). 
This assessment is to be completed on the handheld device. 
6.2.9 
Actigraphy 
An actigraph is a non-invasive instrument to assess cycles of activity and rest, and will be 
used in this study as a method to monitor rest/activity cycles of participants. An actigraphy 
instrument worn on the wrist will record movements and physiological measures to estimate 
activity parameters including daily activity, gait, and sleep parameters. 
6.3 
Safety Assessments  
6.3.1 
Physical Examinations 
A physical examination including neurological exam (cranial nerves, motor, sensory, reflexes, 
gait, and coordination) will be conducted. 
6.3.2 
Vital Signs 
Vital signs will include body temperature, resting respiration rate, systolic and diastolic blood 
pressure, and pulse rate.  
Each time vital signs are measured the following procedures for orthostatic blood pressure 
(BP) and pulse rate (PR) evaluation should be followed: 
• After the subject is supine for approximately 5 minutes, BP and PR will be measured and 
the subject will then be instructed to rise to a standing position if able. Then BP and PR 
will again be measured 1-3 minutes after standing. A drop in systolic BP of ≥20 mm Hg, 
or in diastolic BP of ≥10 mm Hg, within 3 minutes of standing, or experiencing 


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significant lightheadedness or dizziness after standing, along with a remarkable drop in 
BP as judged by the Investigator with agreement of the Sponsor’s Medical Monitor, is 
considered orthostatic hypotension. Patients who have orthostatic hypotension at 
Screening (Visit 1) or Baseline (Visit 2) are not eligible for the study. 
6.3.3 
Height, Weight, and Body Mass Index 
Height will be reported in centimeters or inches. 
Weight will be reported in kilograms or pounds. 
BMI will be calculated using the following formula:  Weight (kg) / [height (m)]2. 
6.3.4 
Electrocardiograms 
All 12-lead ECGs will be complete, standardized recordings. All ECGs will be centrally read; 
the interpretation by the central cardiologist is considered the official interpretation. The ECG 
will be completed in triplicate at Visit 1 (Screening) and will be collected within an 
approximately 5-minute period. A single ECG tracing is to be completed at all other 
designated visits. 
The following conditions apply: 
• If a site performs additional ECGs beyond the set of triplicate ECGs prescribed at 
Screening or the single ECG prescribed at Baseline, the mean QTcF/QRS values of all 
the tracings of adequate quality will be used to determine eligibility. Values from 
tracings of inadequate quality will not be included in calculating the mean.  
• If the mean QTcF value from the set of ECGs done at Screening is prolonged due to 
an identifiable cause, and it is medically appropriate to address that cause, a repeat set 
of triplicate ECGs may be performed during Screening at the discretion of the 
Medical Monitor. In this case, the repeat set of triplicate ECGs will be used in 
determination of subject eligibility. 
• At Baseline, a subject may be enrolled based on the machine read of the locally 
completed ECG. If the interpretation of the ECG by the central cardiologist indicates 
QTcF outside of the allowable range, the subject will be discontinued from the study, 
but enrollment of the subject will not be considered a protocol deviation. 
The subject must rest in a supine position for at least 3 minutes before the ECG is obtained. 
ECG tracings (paper or electronic) will be reviewed and interpreted by a qualified clinician. 
ECG tracings and results (ventricular rate, PR, QRS, QT, QTcF and QTcB intervals) will be 
included and summarized in the subjects study records.  


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6.3.5 
Movement Disorders Society-Unified Parkinson’s Disease Rating Scale 
The MDS-UPDRS is a comprehensive battery of motor and behavioral indices derived from 
the Columbia Scale (Fahn et al. 1987). The MDS-UPDRS Part III will be used to assess 
motor function and is a motor examination consisting of 18 rater-based items. Only Part III 
will be administered during the study.  
The MDS-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. 
This is a clinician-administered assessment and is to be completed at the clinic visits 
indicated in Table S–1. 
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 four 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 
administered at all other designated 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). 
This is a clinician-administered assessment and is to be completed at all clinic visits. 
6.3.7 
Laboratory Evaluations 
Clinical laboratory sample collection (including HbA1c at Screening only) is encouraged, but 
not required, to be completed under fasting conditions. The laboratory evaluations will 
include, but are not limited to, the following: 
• Clinical chemistry serum tests 
o Sodium (Na), potassium (K), chloride (Cl), phosphorus (P), calcium (Ca), 
magnesium (Mg), carbon dioxide (CO2), blood urea nitrogen (BUN), creatinine 
(CR), uric acid 
 Mg should only be performed at Visit 1 (Screening) 


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o Alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), total 
bilirubin (TBIL), lactate dehydrogenase (LDH) 
o Vitamin B12 
 Vitamin B12 should only be performed at Visit 1 (Screening) 
o HbA1c 
 HbA1c should only be performed at Visit 1 (Screening) 
o Glucose 
o Albumin (ALB), total protein 
o Prolactin (Week 4/EOT will be blinded, also performed at Baseline) 
o Thyroid stimulating hormone (TSH) and reflex free T4, if TSH is out of range 
 TSH/free T4 should only be performed at Visit 1 (Screening) 
o Creatine kinase (CK)/creatine phosphokinase (CPK) 
o Insulin (at Baseline and Week 4 only) 
o Lipid panel 
 Total cholesterol, HDL-cholesterol, triglycerides, LDL-cholesterol, 
cholesterol/HDL ratio, non-HDL cholesterol, very low density lipoprotein 
cholesterol 
• Pregnancy test 
o A serum pregnancy test should only be performed at Visit 1 (Table 6–1) for 
women of childbearing potential 
o A urine pregnancy test should be performed at all designated visits after Visit 1 
(Table 6–1) for women of child-bearing potential 
 If urine cannot be obtained in women of childbearing potential, a serum 
pregnancy test should be done 
• Hematology tests 
o Complete blood count (CBC) including: 
 White blood cell (WBC) count 
 Absolute neutrophil count 
 Complete differential (relative and absolute) 


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 Hematocrit (Hct), hemoglobin, red blood cells (RBC), platelets 
 Reticulocyte count 
• Urinalysis 
o Blood, RBCs, WBCs, protein, glucose, ketones, specific gravity, pH 
o Reasonable efforts should be made to collect a urine sample from all subjects. 
Where collection of a urine sample proves impractical or impossible (e.g., because 
the subject is incontinent), failure to collect a urine sample should be recorded in 
the subject’s case report form (CRF), and will not be considered a protocol 
deviation 
• Urine toxicity screen 
o The following controlled substances may be tested with a urine toxicity screen 
according to the schedule presented in Table 6–1: amphetamine, barbiturates, 
benzodiazepines, cocaine, methadone, morphine/opiates, methamphetamine, 
marijuana (THC), phencyclidine (PCP), ecstasy (MDMA). 
o Subjects who test positive for benzodiazepines, THC, or opiates may continue in 
the study and last usage should be noted at the study visit. In addition, restrictions 
listed in Appendix A should be followed. 
o Reasonable efforts should be made to collect a urine sample (as described in 
“Urinalysis” above) at all designated visits 
Laboratory evaluations will be completed according to the schedule presented in Table 6–1 
and procedures detailed in the study Manual of Procedures. Additional safety testing may be 
performed at the discretion of the Investigator or designee. All laboratory results should be 
evaluated for clinical significance and be reported as an AE/SAE, as applicable.  


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Table 6–1 
Safety Laboratory Evaluations 
Visit 
Testsa,b 
Visit 1  
(Screening, Week -4) 
CHEM, CBC, UA, urine toxicity screen, and serum pregnancy test 
Visit 2  
(Baseline, Week 0) 
CHEM, CBC, UA, insulin, prolactin, urine toxicity screen, and 
urine pregnancy test 
Visit 4  
(Week 2) 
CHEM, CBC, and UA  
Visit 6/ET  
(Week 4/EOT) 
CHEM, CBC, UA, insulin, prolactin (blinded), urine toxicity 
screen, and urine pregnancy test  
Abbreviations: CBC=complete blood count; CHEM=clinical chemistry serum tests; EOT=end of treatment; 
ET=early termination; TSH=thyroid stimulating hormone; UA=urinalysis 
a 
A pregnancy test is only required for women of childbearing potential. If urine cannot be obtained in 
women of childbearing potential, a serum pregnancy test should be done. 
b 
A vitamin B12 test, HbA1c, Mg level, and TSH/free T4 test are only required at Visit 1 (Screening). 
6.4 
Safety Follow-up 
A 30-day safety follow-up telephone contact is to be completed for subjects who complete 
the treatment period of the study as well as those who discontinue prematurely from the 
study. Subjects should have the following completed 30 (±4) days after last dose of study 
drug: 
• Assessment of concomitant medications/treatments 
• Assessment of AEs 
6.5 
Unscheduled Visits 
Unscheduled visits may occur as determined by the Investigator and may include any safety 
evaluations deemed by the Investigator to be clinically indicated. The following safety 
assessments will typically be performed; however, these are neither required nor all those that 
may be performed: assessment of AEs, assessment of concomitant medications/treatments, 
measurement of vital signs, study drug accountability, and completion of the C-SSRS.  
7 ADVERSE EVENTS 
7.1 
Specification of Safety Parameters 
7.1.1 
Definition of Adverse Event 
An AE is defined as “any untoward medical occurrence in a patient or clinical study 
participant, temporally associated with the use of study drug, whether or not considered 
related to study drug”. 


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An AE can therefore be any unfavorable and unintended sign (e.g., an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a drug, without any 
judgment about causality or seriousness. An AE can arise from any use of the drug (e.g., 
off-label use, use in combination with another drug) and from any route of administration, 
formulation, or dose, including an overdose. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
drug caused the AE. 
AEs do not include the following: 
• Stable or intermittent chronic conditions (such as myopia requiring eyeglasses) that 
are present prior to Baseline and do not worsen during the study 
• Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, 
transfusion). The condition that leads to the procedure is an AE if not present at 
Baseline. 
• Overdose of concomitant medication without any signs or symptoms unless the 
subject is hospitalized for observation 
• Hospitalization for elective surgery planned prior to study (situation where an 
untoward medical occurrence has not occurred) 
• Pregnancy will not be considered an AE, but if it occurs, it will be reported on a 
pregnancy form 
7.1.2 
Definition of Serious Adverse Event 
In addition to the severity rating, each AE will be classified by the Investigator as “serious” 
or “not serious.” The seriousness of an event will be defined according to the applicable 
regulations and generally refers to the outcome of an event. An SAE is one that meets one or 
more of the following: 
• Is fatal 
• Is immediately life threatening 
• Results in disability or permanent damage 
• Requires hospitalization 
• Prolongs existing hospitalization 
• Is a congenital anomaly or birth defect (in an offspring) 
• Is medically significant 


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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 product under investigation (i.e., there are facts, evidence, or 
arguments to suggest possible causation). 
Consider the following when assessing causality: 
• Temporal associations between the agent and the event 
• Response to cessation (de-challenge) or re-challenge 
• Compatibility with known class effect 
• Known effects of concomitant medications 
• Pre-existing risk factors 
• A plausible mechanism 
• Concurrent illnesses 
7.2.2.1 
Duration 
The start and stop dates for AEs will be recorded using the following criteria: 
• Start: Date of the first episode of the AE or date of significant sustained worsening in 
severity 
• Stop: Date when AE either ceased permanently or changed in severity 
7.2.2.2 
Frequency 
The frequency of the AE should be indicated according to the following definitions: 
• Single: Experienced once, without recurrence 
• Recurrent: More than one discrete episode with the same severity 


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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 
• Not applicable 
• Unknown 
7.2.2.4 
Therapy 
• None: No new treatment instituted 
• Medication: New treatment initiated as a direct result of AE 
• Other: Other action required 
7.2.2.5 
Outcome 
• Recovered/resolved: Recovered or resolved 
• Recovered/resolved with sequelae: Recovered or resolved with sequelae 
• Not recovered/not resolved: Not recovered or not resolved 
• Fatal: Death due to an AE 
• Unknown: Unknown 
7.2.2.6 
Seriousness 
• Not serious 
• Serious 
7.2.3 
Definition of Unexpectedness 
An AE, the nature or severity of which is not consistent with the information provided in the 
Reference Safety Information section of the current pimavanserin Investigator’s brochure. 
7.3 
Time Period and Frequency for Event Assessment and Follow-up 
Adverse events will be recorded from the time informed consent is obtained through the 
safety follow-up period. All AEs must be either resolved or stable at the end of the safety 
follow-up period. If ongoing at the end of the safety follow-up period, the subject should be 
referred for appropriate treatment. 
In the event that a subject discontinues and has an ongoing AE at the time of discontinuation 
(Section 4.4.1) or is withdrawn from the study because of an AE, the subject should be 


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followed and treated by the Investigator until the AE has resolved, stabilized, or a new 
chronic baseline has been established. 
7.4 
Reporting Procedures 
7.4.1 
Adverse Event Reporting 
The Investigator must record all observed AEs and all reported AEs. At each visit, the 
Investigator should ask the subject a nonspecific question (e.g., “Have you noticed anything 
different since your last visit?”) to assess whether any AEs have been experienced since the 
last report or visit. 
Note that any use of medication (and specifically any newly prescribed medication) during 
the course of a study may indicate the occurrence of an AE that may need to be recorded on 
both the AE and the concomitant medication page. 
All AEs, serious and not serious, will be recorded on the AE eCRF page using appropriate 
medical terminology. Severity and relationship to study drug will be assessed by the 
Investigator. 
When possible, clinical AEs should be described by diagnosis and not by symptoms (e.g., 
“cold” or “seasonal allergies” instead of “runny nose”). 
All AEs, whether or not related to the study drug, must be fully and completely documented 
on the AE eCRF and in the subject’s notes. 
7.4.2 
Serious Adverse Event Reporting 
The reporting of SAEs by the Sponsor or designee to the regulatory authorities is a regulatory 
requirement. Each regulatory authority has established a timetable for reporting SAEs based 
upon established criteria. 
Serious AEs must be reported within 24 hours of discovery to the Sponsor or its designee; use 
the appropriate form for initial and/or follow-up reporting.  
At a minimum, events identified by the Sponsor to require expedited reporting as serious, 
unexpected, and related to study drug must be brought to the attention of the responsible 
institutional review board/ethics committee (IRB/EC), as per applicable regulations. These 
will be provided by the Sponsor after their assessment. For European Union member states, 
the Sponsor or its designee will provide reports of SUSARs directly to the ECs, as required 
by local legislation. In all other countries, it is the Investigator’s responsibility to provide 
these expedited reports to the responsible IRB/EC. It is also the Investigator’s responsibility 
to notify the responsible IRB/EC regarding any new and significant safety information. 


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When an SAE occurs, Investigators will review all documentation related to the event and 
will complete the paper SAE form (for initial and/or follow-up information) and fax or email 
(within 24 hours of discovery) to the contact information provided on the SAE form. 
Subjects will be followed through the safety follow-up period for 30 days after the last dose 
of study drug for any SAEs and/or other reportable information until such events have 
resolved or the Investigator, in conjunction with the Sponsor, deems them to be chronic or 
stable. 
In the event of any SAE (other than death), the study subject will be instructed to contact the 
Investigator (or designee) using the telephone number provided in the ICF. All subjects 
experiencing an SAE will be seen by the Investigator or designee as soon as is feasible 
following the report of the SAE. 
Serious AEs occurring after the safety follow-up period of 30 days after the last dose of study 
drug should be reported if in the judgment of the Investigator there is “a reasonable 
possibility” that the event may have been caused by the product. 
SAEs should also be reported to the IRB/EC according to local regulations. 
7.4.3 
Reporting of Pregnancy 
Any female subject who becomes pregnant during the study (with or without AEs) must be 
withdrawn from the study and the pregnancy must be reported on the Pregnancy form within 
24 hours of discovery to the Sponsor or its designee. Any female subject who becomes 
pregnant during the study will be followed through the pregnancy outcome. 
Any AEs that are the consequence of pregnancy and which meet the criteria for serious 
should also be reported via the SAE form. 
7.4.3.1 
Reporting Paternal Drug Exposure 
Paternal drug exposure is defined as a father’s exposure to a medicinal product before or 
during his partner’s pregnancy. Any paternal drug exposure cases must be reported to the 
Sponsor within 24 hours of discovery via the Pregnancy form. Any AEs that are the 
consequence of paternal drug exposure and which meet the criteria for serious must also be 
reported to the Sponsor within 24 hours of discovery via the SAE form. 
7.4.4 
Reporting of Overdose 
An overdose is a deliberate or inadvertent administration of a treatment at a dose higher than 
the maximum recommended dose per protocol. It must be reported to the Sponsor or 
designee on the Overdose form within 24 hours of discovery. In addition, all events of 
overdose are to be captured as protocol deviations. 


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8 CLINICAL MONITORING  
Routine monitoring of study sites is described in Section 11. 
Clinical site monitoring is conducted to ensure that the rights and well-being of human 
subjects are protected, that the reported study data are accurate, complete, and verifiable, and 
that the conduct of the study is in compliance with the currently approved protocol and 
amendment(s) as applicable, with GCP, and with applicable regulatory requirements. Details 
of the study site monitoring process are described in a separate clinical monitoring plan 
document. 
9 STATISTICAL METHODS AND DATA ANALYSIS 
9.1 
Statistical and Analytical Plans 
Statistical methods will be documented in detail in a statistical analysis plan (SAP) to be 
approved by the Sponsor prior to database lock. 
9.2 
Statistical Hypotheses 
This is a pilot study and is not designed to make definitive comparisons between the 
treatment groups. Hypothesis tests comparing pimavanserin versus placebo and low-dose 
quetiapine versus placebo will be performed for exploratory endpoints, but this testing is 
considered to be exploratory. 
9.3 
Sample Size Determination 
This is a pilot study and is not powered for statistical significance. 
9.4 
Subject Populations for Analysis 
The Safety Analysis Set will consist of all subjects who have taken at least 1 dose of study 
drug. Safety analyses will be based on the Safety Analysis Set. 
The Exploratory Analysis Set will consist of randomized subjects in the Safety Analysis Set 
excluding subjects who were replaced due to no increase of the dose of blinded study drug 
consistent with 50 mg quetiapine at Week 1 (Visit 3). Exploratory analyses will be based on 
the Exploratory Analysis Set. 
9.5 
Statistical Analyses 
9.5.1 
Primary Analyses 
Adverse events will be classified into standard terminology using the Medical Dictionary for 
Regulatory Activities. All AEs will be listed and TEAEs will be summarized by system organ 
class and preferred term. 


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A TEAE is defined as an AE that occurs after the first dose of study drug and up to 30 days 
after the last dose of study drug. Summaries by maximum severity and by relationship will 
also be provided. Serious TEAEs, fatal AEs, and TEAEs leading to discontinuation will also 
be summarized. 
9.5.2 
Exploratory Analyses 
9.5.2.1 
Analysis of Endpoints Measured at Study Visits 
The change from Baseline in the exploratory endpoints measured at scheduled visits 
including Trail Making Test Parts A and B, HVLT-R, and PD NMS Questionnaire will be 
summarized using a mixed model repeated measures (MMRM) model. The model will 
include effects for treatment group, visit, treatment-by-visit interaction, Baseline score, and 
Baseline score-by-visit interaction. CGI-I score will be analyzed using a similar MMRM 
model with the effects for treatment group, visit, treatment-by-visit interaction, Baseline 
CGI-S score, and Baseline CGI-S score-by-visit interaction. PGI-I score will be summarized 
using a MMRM model that will include effects for treatment group, visit, and treatment-by-
visit interaction. The treatment comparisons will be based on the difference in least squares 
means at Week 4. 
9.5.2.2 
Analysis of Ecological Momentary Assessment and Actigraphy Data 
EMA Analyses 
EMA includes scales for nighttime sleep (Nighttime Sleep Scale), sleep impairment (Sleep-
Related Impairment Scale), daytime sleepiness (Karolinska Sleepiness Scale [KSS]), 
cognition (Patient-Reported Outcomes Measurement Information System [PROMIS®] 
Cognition Assessment), and satisfaction (Patient and Informant Satisfaction Question) 
collected on a handheld device multiple times per week with an initial baseline assessment 
collected during the 7-day period before the Baseline visit. The outcome and change from 
Baseline in EMA scales will be evaluated using an MMRM model. This model will include 
fixed effects of treatment, time of day, and day of visit, as well as the continuous fixed 
covariate of Baseline scores. All of these factors have naturally occurring interaction terms, 
which will also be included in analysis models.  
Actigraphy Analyses 
Actigraphy data on physical activity will be collected continuously using a wearable device 
from at least one week before the Baseline visit through Week 4. Exploratory analyses will be 
used to see how the data should be collapsed into average values for each time of day, day, 
and week. The outcome and change from Baseline in actigraphy data will be evaluated using 
an MMRM model. This model will include fixed effects of treatment, time of day, and day of 


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visit, as well as the continuous fixed covariate of Baseline scores. All of these factors have 
naturally occurring interaction terms, which will also be included in analysis models. 
Exploratory analyses will be used to see if data can be collapsed into average values for each 
week. 
9.5.3 
Other Safety Analyses 
The serum clinical chemistry, hematology, and urinalysis results at each time point will be 
summarized by treatment group. Change from Baseline values will also be summarized. 
The number and percentage of subjects with potentially clinically important (PCI) 
post-Baseline laboratory values will be summarized by treatment group at each post-Baseline 
visit and overall post Baseline for selected parameters. The PCI criteria will be specified in 
the statistical analysis plan. 
Vital signs and body weight at Baseline and each post-Baseline visit will be summarized by 
treatment group. Change from Baseline values will also be summarized. 
The results of the physical examinations at each visit will be tabulated by treatment group. 
Electrocardiogram parameters at study visits will be summarized by treatment group. Change 
from Baseline values will also be summarized. Categorical analyses will be conducted on the 
incidence of subjects with prolonged QTc intervals and changes in QTc intervals in 
accordance with ICH guidelines. 
For the C-SSRS, the number and percentage of subjects with suicidal ideation or suicidal 
behavior during the study will be tabulated. 
MDS UPDRS Part III observed value and change from Baseline to Week 4 will be 
summarized by treatment group. The change from Baseline to Week 4 in the MDS UPDRS 
Part III score will be analyzed using an analysis of covariance (ANCOVA) model with 
treatment group as a factor and the Baseline value as a covariate.  
9.6 
Measures to Minimize Bias 
Eligible subjects will be randomized into one of three treatment groups (pimavanserin 34 mg, 
quetiapine 25 mg, or matching placebo) in a 1:1:1 ratio using an IRT system. The 
assignments will be based on a pre-generated permuted-block randomization schedule. 
Blinding will be assured by restricting access of Investigators and Sponsor personnel and/or 
designee to the treatment codes, and providing identical encapsulated tablets and packaging 
for the pimavanserin, quetiapine, and placebo treatments. 


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9.7 
Breaking the Study Blind/Subject Code 
For the final analysis, the treatment codes for all subjects will be released to the Sponsor after 
all subjects have completed the study and the clinical database is locked. 
Unblinding of individual treatment assignment during the study is discouraged. The 
Investigator may break the blind in the event of a medical emergency if it is considered 
necessary for the care of the subject. The Investigator should attempt whenever possible to 
contact the Medical Monitor before unblinding a subject’s treatment to discuss the event. 
Lack of Medical Monitor contact does not preclude the Investigator from unblinding the 
subject. In an emergency situation, the subject’s treatment assignment may be obtained by the 
Investigator from the IRT system. Details of the process to be followed are provided in a 
separate IRT manual. In the event that the IRT system is used to perform a code break, the 
Sponsor or designee will be notified immediately via an automated notification from the 
IRT system that an unblinding has occurred. The notification only alerts the Sponsor or 
designee that the unblinding occurred, and does not include any information about the 
unblinded subject’s treatment assignment. 
10 STUDY MANAGEMENT AND DATA COLLECTION 
10.1 Data Collection and Management Responsibilities 
All documents required for the conduct of the study as specified in the ICH GCP guidelines 
will be maintained by the Investigator in an orderly manner and made available for 
monitoring and/or auditing by the Sponsor and regulatory authorities. 
The Investigator and institution must permit authorized representatives of the Sponsor or 
designees (including monitors and auditors), regulatory authorities (including inspectors), 
and the IRB/EC direct access to source documents (such as original medical records). Direct 
access includes permission to examine, analyze, verify, and reproduce any records and 
reports that are needed for the evaluation of the study. The Investigator must ensure the 
reliability and availability of source documents from which the information on the eCRF was 
derived. 
10.2 Source Documents 
All study specific information obtained at each study visit must be recorded in the subject’s 
record (source documentation), and then entered into a validated electronic data capture 
(EDC) database by trained site personnel. The source documentation may consist of source 
notes captured by site personnel as well as laboratory reports, ECG reports, and electronic 
source data. Data collected via the actigraph instrument and the handheld device will not 
transfer into EDC. 


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10.3 Case Report Forms 
Subject data required by this protocol, excluding data recorded on the actigraph instrument 
and the handheld device, are to be recorded in an EDC system on eCRFs. The Investigator 
and his or her site personnel will be responsible for completing the eCRFs. The Investigator 
is responsible for the accuracy and reliability of all the information recorded on the eCRFs. 
All information requested on the eCRFs needs to be supplied, including subject identification 
data, visit date(s), assessment values, etc., and any omission or discrepancy will require 
explanation. All information on eCRFs must be traceable to source documentation at the site. 
10.4 Confidentiality 
The Investigator must ensure that each subject’s anonymity is maintained as described below. 
On the eCRFs or other documents submitted to the Sponsor or designees, subjects must be 
identified by a subject identification number only. Subject identifiers uniquely identify 
subjects within the study and do not identify any person specifically. Documents that are not 
for submission to the Sponsor or designees (e.g., signed ICFs) should be kept in strict 
confidence by the Investigator in compliance with Federal regulations or other applicable 
laws or ICH guidance on GCP. Data collection and handling should comply with the 
European Union General Data Protection Regulation (EU GDPR), where applicable. The 
Sponsor has assigned a Data Protection Officer (DPO) as per the EU GDPR. 
10.5 Study Records Retention 
Investigators are required to maintain all essential study documentation as per ICH GCP 
guidelines. This includes, but is not limited to, copies of signed, dated and completed eCRFs, 
documentation of eCRF corrections, signed ICFs, audio recordings, subject-related source 
documentation, and adequate records for the receipt and disposition of all study drug. 
Investigators should maintain all essential study documentation, for a period of at least 
2 years following the last approval of marketing application in an ICH region (US, Europe, 
and Japan), or until at least 2 years after the drug investigational program is discontinued, 
unless a longer period is required by applicable law or regulation. Only the Sponsor can 
notify an Investigator or vendor when any records may be discarded. Investigators should 
contact the Sponsor before destroying any files. 
10.6 Protocol Exceptions and Deviations 
No prospective entry criteria protocol deviations are allowed; all subjects must meet all 
eligibility criteria in order to participate in the study. 
Protocol waivers for eligibility will not be granted by the Sponsor under any circumstances. 
If, during the course of a subject’s post-enrollment participation in the trial it is discovered 


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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 6.4). The Investigator must report any 
protocol deviation to the Sponsor and, if required, to the IRB/EC in accordance with local 
regulations, within reasonable time. 
10.7 Protocol Amendments 
Changes to the protocol may be made only by the Sponsor (with or without consultation with 
the Investigator). All protocol modifications must be submitted to the site IRB/EC in 
accordance with local requirements and, if required, to regulatory authorities, as either an 
amendment or a notification. Approval for amendments must be awaited before any changes 
can be implemented, except for changes necessary to eliminate an immediate hazard to trial 
subjects, or when the changes involve only logistical or administrative aspects of the trial. 
No approval is required for notifications. 
11 STUDY MONITORING, AUDITING, AND INSPECTING 
11.1 Quality Control and Quality Assurance 
The Sponsor or designees and regulatory authority inspectors are responsible for contacting 
and visiting the Investigator for the purpose of inspecting the facilities and, upon request, 
inspecting the various records of the trial (e.g., eCRFs and other pertinent data) provided that 
subject confidentiality is respected. 
The Sponsor’s or designee’s monitor is responsible for inspecting the eCRFs at regular 
intervals throughout the study to verify adherence to the protocol; completeness, accuracy, 
and consistency of the data; and adherence to local regulations on the conduct of clinical 
research. The monitor should have access to subject medical records and other study-related 
records needed to verify the entries on the eCRFs. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in 
the course of these monitoring visits are resolved. 
In accordance with ICH Guidance on GCP and the Sponsor’s audit plans, a certain 
percentage of sites participating in this study will be audited. These audits may include a 
review of site facilities (e.g., pharmacy, drug storage areas, and laboratories) and review of 
study-related records may occur in order to evaluate the trial conduct and compliance with 
the protocol, ICH Guidance on GCP, and applicable regulatory requirements. 


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The Sponsor’s or designee’s representatives, regulatory authority inspectors and IRB/EC 
representatives who obtain direct access to source documents should also respect subject 
confidentiality, taking all reasonable precautions in accordance with applicable regulatory 
requirements to maintain the confidentiality of subjects’ identities. 
11.2 Risk Management 
The Sponsor utilizes the ICH E6 (GCP) Revision 2 risk management approach that includes 
methods to assure and control the quality of the trial proportionate to the risks inherent in the 
trial and the importance of the information collected. The intent is that all aspects of this trial 
are operationally feasible and that any unnecessary complexity, procedures, and data 
collection are avoided. The Sponsor’s risk management approach includes the following 
documented activities with a focus on data and processes critical to ensure human subject 
protection and the reliability of trial results:  
• Risk Identification: identification of risks to critical study processes, governing 
systems, investigational product, study design, data collection, and recording. 
• Risk Evaluation: identified risks are evaluated by considering the following factors: 
(a) likelihood of error occurrence, (b) impact on human subject protection and data 
integrity, and (c) detectability of errors. 
• Risk Control: risks that can be avoided, reduced (i.e., mitigated), or accepted are 
differentiated. Risk mitigation activities are incorporated in protocol design and 
implementation, study plans, training, processes, and other documents governing the 
oversight and execution of study activities. Where possible, predefined quality 
tolerance limits are defined to identify systematic issues that can impact subject safety 
or data integrity and deviations from the predefined quality tolerance limits will trigger 
an evaluation and possibly an action. Contingency plans are developed for issues with 
a high risk factor that cannot be avoided. 
Periodic risk review, communication and escalation of risk management activities will occur 
during study execution and important deviations from the predefined quality tolerance limits 
are to be reported in the clinical study report (CSR). 
12 ETHICAL CONSIDERATIONS 
12.1 Ethical Standard 
The study will be conducted in compliance with the protocol, the Declaration of Helsinki, 
ICH GCP, and other applicable regulatory requirements (e.g., Serious Breach reporting, 
urgent safety measures, and EU GDPR). 


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The study will be performed in accordance with the US Health Insurance Portability and 
Accountability Act (HIPAA) regulations, US FDA GCP Regulations (US CFR 21 parts 50, 
54, 56, and 312), and ICH Guidance on GCP (E6) and clinical safety data management 
(E2A). 
In accordance with Directive 75/318/EEC, as amended by Directive 91/507/EEC, the final 
clinical study report will be signed by an Investigator and/or Coordinating Investigator who 
will be designated prior to the writing of the clinical study report. 
12.2 Institutional Review Board/Ethics Committee 
The Investigator or designee will provide the IRB/EC with all requisite material, including a 
copy of the protocol, informed consent, and any subject information or advertising materials. 
The study will not be initiated until the IRB/EC provides written approval of the protocol and 
the informed consent and until approved documents have been obtained by the Investigator 
and copies received by the Sponsor. All amendments will be sent to the IRB/EC for 
information (minor amendment) or for submission (major amendment) before 
implementation. The Investigator will supply the IRB/EC and the Sponsor with appropriate 
reports on the progress of this study, including any necessary safety updates, in accordance 
with the applicable government regulations and in agreement with policy established by the 
Sponsor. 
12.3 Informed Consent Process 
Properly executed, written informed consent must be obtained from each subject prior to any 
screening procedures. 
The informed consent must, at a minimum, include the elements of consent described in the 
ICH Guidance on GCP and the US CFR 21 Part 50.25. A copy of the ICF planned for use 
will be reviewed by the Sponsor or designee for acceptability and must be submitted by the 
Investigator or designee together with the protocol, to the appropriate IRB/EC for review and 
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. 


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12.3.1 
Consent and Other Informational Documents Provided to Subjects 
The subject and informant, if applicable, must be given a copy of the signed informed 
consent and the original maintained in the designated location at the site. 
12.3.2 
Consent Procedures and Documentation 
It is the Investigator or designee’s responsibility to obtain written informed consent from the 
subject after adequate explanation of the aims, methods, anticipated benefits, and potential 
hazards of the study. The subject must be given ample time to decide about study participation 
and opportunity to inquire about details of the study. The IRB/EC-approved consent form must 
be personally signed and dated by the subject and by the person who conducted the 
informed-consent discussion. The Investigator or appropriate site personnel must document the 
details of obtaining informed consent in the subject’s study documents. 
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. 
15 LITERATURE REFERENCES 
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Chen JJ. Treatment of psychotic symptoms in patients with Parkinson disease. Ment Health 
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Cummings J, Isaacson S, Mills R, et al. Pimavanserin for patients with Parkinsons disease 
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El-Saifi N, Moyle W, Jones C, Tuffaha H. Quetiapine safety in older adults: a systematic 
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Folstein MF, Folstein SE, McHugh PR. “Mini-Mental state”: A practical method for grading 
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Goldman JG, Postuma R. Premotor and nonmotor features of Parkinsons disease. Curr Opin 
Neurol. 2014;27(4):434-441. 
Guy, W. Clinical Global Impression. In: ECDEU Assessment Manual for 
Psychopharmacology, Revised (DHEW Publ No. ADM 76-338). National Institute of Mental 
Health: Rockville, MD. 1976:218-222. 
Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic 
Parkinson’s disease: a clinicopathological study of 100 cases. J Neurol Neurosurg Psychiatry. 
1992;55:181-184. 
Juri C, Chaná P, Tapia J, Kunstmann C, Parrao T. Quetiapine for insomnia in Parkinson 
disease: results from an open-label trial. Clin Neuropharmacol. 2005;28(4):185-187. 
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Quetiapine for agitation or psychosis in patients with dementia and parkinsonism. Neurology. 
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Lai JS, Wagner LI, Jacobsen PB, Cella D. Self-reported cognitive concerns and abilities: two 
sides of one coin? Psychooncology. 2014;23(10):1133-1141. 
Martínez-Fernández R, Schmitt E, Martinez-Martin P, Krack P. The hidden sister of motor 
fluctuations in Parkinsons disease: A review on nonmotor fluctuations. Mov Disord. 
2016;31(8):1080-1094. 
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. 
Mueller C, Rajkumar AP, Wan YM, Velayudhan L, Ffytche D, Chaudhuri KR, Aarsland D. 
Assessment and Management of Neuropsychiatric Symptoms in Parkinsons Disease. CNS 
Drugs. 2018;32(7):621-635. 


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Northstar Rx LLC. Quetiapine fumarate [package insert]. Memphis, TN; May 2019. 
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f9d265a9-7491-48e1-a39e-
0aaa67294cff 
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. 
Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W, et al. MDS Clinical 
Diagnostic Criteria for Parkinsons Disease. Mov Disord. 2015; 30:1591–1601. 
Reitan RM. Validity of the Trail Making Test as an indicator of organic brain damage. 
Percept Mot Skills. 1958;8:271-276. 
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. 
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. 


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16 APPENDICES 
Appendix A Prohibited and Restricted Medications 
The table below lists prohibitions and restrictions by medication class, including 
representative medications within class. A prohibited medication is not allowed. A restricted 
medication is allowed only under certain conditions. Details regarding procedures for 
subjects who take a prohibited or restricted medication during the study are provided in 
Section 4.6.1. 
Medication Class 
Medicationa 
Prohibition/restrictions 
Antipsychotics other 
than pimavanserin 
and quetiapine as 
study drug 
PROHIBITED 
All in class 
• Must be washed out 2 weeks or 5 half-lives 
(whichever is longer) prior to Baseline 
• Prohibited throughout the study until completion of 
the EOT visit 
Anticholinergics 
PROHIBITED 
• Centrally acting 
anticholinergics 
o benztropine 
o biperiden 
o trihexiphenidyl 
o oral diphenhydramine 
Anticholinergic medications whose primary mechanism 
of action is centrally acting are prohibited and must 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 
Oxybutynin and other anticholinergics may be used if 
dose unchanged for at least 4 weeks prior to Baseline 
and dose is expected to remain unchanged throughout 
the study until completion of the EOT visit. 
Anticonvulsant and 
mood stabilizers 
PROHIBITED 
• carbamazepine 
• lamotrigine 
• lithium 
• phenytoin 
• Must be washed out 5 half-lives prior to Baseline 
• Prohibited throughout the study until completion of 
the EOT visit 
RESTRICTED 
• valproate 
Valproate may be used if dose unchanged for at least 
4 weeks prior to Baseline and dose is expected to 
remain unchanged until completion of the EOT visit. 
Antidepressants 
PROHIBITED 
• mirtazapine 
• nefazadone 
• fluvoxamine 
• mianserin 
• trazodone 
• amitriptyline 
• Prohibited throughout the study until completion of 
the EOT visit 
• 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 
• nortriptyline 
• imipramine 
• trimipramine 
• desipramine 
• clomipramine 
• esketamine 
• ketamine 
RESTRICTED 
• citalopram 
• escitalopram 
• venlafaxine 
• If subject is remaining on these medications, the 
dose of the permitted antidepressants on the left 
must be unchanged for at least 4 weeks prior to 
Baseline and is expected to remain unchanged until 
completion of the EOT visit. If the medication is 
being discontinued, it must be discontinued at least 2 
weeks or 5 half-lives (whichever is longer) prior to 
the Baseline visit. 
o Citalopram is restricted to a maximum dose of 
20 mg/day.  
o Escitalopram is restricted to a maximum dose of 
10 mg/day.  
o Venlafaxine is restricted to a maximum dose of 
225 mg/day 
Anxiolytics 
PROHIBITED 
• chlordiazepoxide 
• diazepam 
• flurazepam 
Prohibited at Baseline and throughout the study until 
completion of the EOT visit 
RESTRICTED 
• alprazolam 
• clonazepam 
• lorazepam 
• oxazepam 
• temazepam 
• midazolam 
• triazolam 
• Short- or medium-acting benzodiazepine may be 
used for acute anxiety. 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 
Hypnotics and 
sleeping agents 
PROHIBITED 
• zolpidem 
• zopiclone 
• eszopiclone 
Prohibited at Baseline and throughout the study until 
completion of the EOT visit 
RESTRICTED 
• zaleplon 
• ramelteon 
May not be used within approximately 12 hours prior to 
an assessment (including assessments on handheld 
device and in clinic), and efforts should be made to 
limit agents to lowest dose for the shortest time needed. 


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Medication Class 
Medicationa 
Prohibition/restrictions 
Stimulants and 
wake-promoting 
agents 
PROHIBITED 
• methylphenidate 
• modafinil 
• armodafinil 
Prohibited at Baseline and throughout the study until 
completion of the EOT visit (see Section 6.3.7 for 
procedures related to a positive amphetamine test at 
study entry) 
Non-stimulant 
ADHD medications 
PROHIBITED 
• atomoxetine 
Prohibited at Baseline and throughout the study until 
completion of the EOT visit 
Serotonin 
antagonists  
PROHIBITED 
• cyproheptadine 
• Prohibited throughout the study until completion of 
the EOT visit 
• Must be discontinued at least 3 weeks 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 until 
completion of the EOT visit 
Opioids 
PROHIBITED 
• methadone 
Prohibited at Baseline and throughout the study until 
completion of the EOT visit 
Antimicrobials, 
antifungals, and 
antimalarials 
PROHIBITED 
• clarithromycin 
• erythromycin 
• levofloxacin 
• moxifloxacin 
• pentamidine 
• roxithromycin 
Prohibited at Baseline and throughout the study until 
completion of the EOT visit 
RESTRICTED 
• artenimol/piperaquine 
• azithromycin 
• 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. 


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Medication Class 
Medicationa 
Prohibition/restrictions 
• bedaquiline 
• ciprofloxacin 
• gemifloxacin 
• norfloxacin 
• ofloxacin 
• fluconazole 
• telavancin 
• telithromycin 
• The medications on the left are only allowed under 
the following conditions: 
o The subject has a Baseline ECG with a QTcF 
<425 ms IF QRS duration is <120 ms OR 
o The subject has a QTcF <450 ms at Baseline IF 
QRS duration ≥120 ms 
a 
Medications within each class include but are not limited to the examples listed in this table. 


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Appendix 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. Details regarding 
procedures for subjects who take a prohibited or restricted medication during the study are 
provided in Section 4.6.1. 
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 of CYP3A4 are to be stopped at least 7 days or 5 half-lives prior to 
investigational product administration, whichever is longer. Strong inducers of CYP3A4 are 
to be stopped 30 days or 5 half-lives prior to investigational product administration, 
whichever is longer. Moderate inhibitors and inducers of CYP3A4 are allowed but should be 
used with caution. 
STRONG 
INHIBITORS 
grapefruit juicea 
boceprevir (Victrelis®) 
clarithromycin (Biaxin®) 
cobicistat (part of Stribild®) 
conivaptan (Vaprisol®) 
fluvoxamine (Luvox®) 
indinavir (Crixivan®) 
itraconazole (Sporanox®) 
ketoconazole (Nizoral®) 
lopinavir and ritonavir (Kaletra®) 
mibefradil (Posicor®) 
nefazodone (Serzone®) 
nelfinavir (Viracept®) 
posaconazole (Noxafil®) 
quinupristin (Synercid®) 
ritonavir (Norvir®, part of Viekira 
Pak™) 
saquinavir (Invirase®) 
telaprevir (Incivek®) 
telithromycin (Ketek®) 
voriconazole (Vfend®) 
MODERATE 
INHIBITORS 
grapefruit juicea 
amprenavir (Agenerase®) 
aprepitant (Emend®) 
atazanavir (Reyataz®) 
ciprofloxacin (Cipro®) 
darunavir/ritonavir 
(Prezista®/Ritonavir) 
diltiazem 
erythromycin (Erythrocin® 
Lactobionate) 
fluconazole (Diflucan®) 
fosamprenavir (Lexiva®) 
imatinib (Gleevec®) 
verapamil (Calan®) 


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

SAP_001.pdf: 
Official Title: A Pilot Randomized, Double-blind, Placebo-controlled Study to 
Evaluate Safety and Daytime Sedation in Subjects With Parkinson’s Disease With 
Neuropsychiatric Symptoms Treated With Pimavanserin or Low-Dose Quetiapine 
NCT Numbers: NCT04164758 
Document Date: 19 Oct 2020 
 


 
 
STATISTICAL ANALYSIS PLAN 
Protocol No.: 
ACP-103-056 
Protocol Title: 
A Pilot Randomized, Double-blind, Placebo-controlled 
Study to Evaluate Safety and Daytime Sedation in 
Subjects With Parkinson’s Disease With 
Neuropsychiatric Symptoms Treated With 
Pimavanserin or Low-Dose Quetiapine 
Drug: 
Pimavanserin 
Sponsor:  
ACADIA Pharmaceuticals Inc. 
Version No. and Date 
Version 1.0, 19 October 2020 
 
 
 
 
 
 
 
 


 
 
 
Protocol ACP-103-056 
Version 1.0
Statistical Analysis Plan 
   
19 October 2020 
 
SIGNATURE/APPROVAL PAGE 
AUTHORS 
___                                    ___________   
                                                                                              Date 
Associate Director, Biostatistics 
ACADIA Pharmaceuticals Inc. 
 
 
APPROVERS 
____                                   ____________   
                                                                                             Date 
Temporary Senior Medical Director, Medical Affairs  
ACADIA Pharmaceuticals Inc. 
_____                                   ____________   
                                                                                                  Date 
Executive Director, Biostatistics 
ACADIA Pharmaceuticals Inc. 
 
 
  


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TABLE OF CONTENTS 
TABLE OF CONTENTS ........................................................................................................... 3 
LIST OF TABLES ..................................................................................................................... 6 
ABBREVIATIONS ................................................................................................................... 7 
1. 
INTRODUCTION ............................................................................................................ 8 
2. 
OBJECTIVES ................................................................................................................... 9 
2.1 
Primary Objective ............................................................................................................ 9 
2.2 
Exploratory Objective ..................................................................................................... 9 
3. 
STUDY DESIGN ........................................................................................................... 10 
3.1 
General Study Design .................................................................................................... 10 
3.2 
Schedule of Assessments ............................................................................................... 12 
3.3 
Randomization ............................................................................................................... 13 
3.4 
Blinding ......................................................................................................................... 13 
3.5 
Determination of Sample Size ....................................................................................... 13 
3.6 
Coronavirus Disease 2019 ............................................................................................. 13 
4. 
ANALYSIS SETS ........................................................................................................... 14 
5. 
DATA HANDLING CONVENTIONS ........................................................................... 15 
5.1 
General Data Reporting Conventions ............................................................................ 15 
5.2 
Derived Efficacy Variables ............................................................................................ 15 
5.2.1 
Mini-Mental State Examination (MMSE) ................................................................. 15 
5.2.2 
Neuropsychiatric Inventory (NPI) ............................................................................. 15 
5.2.3 
Patient-Reported Outcomes Measurement Information System (PROMIS®) .......... 16 
5.2.4 
Sleep-Related Impairment Scale ............................................................................... 16 
5.2.5 
Nighttime Sleep Scale ............................................................................................... 16 
5.2.6 
Trail Making Test (TMT) Parts A and B.................................................................... 16 
5.2.7 
Hopkins Verbal Learning Test-Revised (HVLT-R) ................................................... 16 
5.2.8 
Parkinson’s Disease Non-motor Symptoms (PD NMS) Questionnaire .................... 17 
5.2.9 
Patient Global Impression – Improvement (PGI-I) ................................................... 17 
5.2.10 Clinical Global Impression – Severity (CGI-S) ........................................................ 18 
5.2.11 
Clinical Global Impression – Improvement (CGI-I) ................................................. 18 
5.2.12 Patient and Informant Satisfaction Question ............................................................. 19 
5.3 
Analysis Visit Windows................................................................................................. 19 


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5.3.1 
Unscheduled Assessments ......................................................................................... 19 
5.3.2 
Multiple Measurements within Visit Windows ......................................................... 20 
5.4 
Missing or Incomplete Date for Last Dose of Study Drug ............................................ 20 
5.5 
Missing or Incomplete Dates for Prior or Concomitant Medications ........................... 20 
5.6 
Missing or Incomplete Date for Adverse Events ........................................................... 20 
5.7 
Missing Severity Assessment for Adverse Events ......................................................... 21 
5.8 
Missing Relationship to Study Drug for Adverse Events .............................................. 21 
5.9 
Character Values of Clinical Laboratory Variables ....................................................... 21 
6. 
SUBJECT DISPOSITION .............................................................................................. 22 
7. 
PROTOCOL DEVIATIONS ........................................................................................... 23 
8. 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ....................... 24 
9. 
MEDICAL HISTORY .................................................................................................... 25 
10. EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE ................................ 26 
10.1 Exposure to Study drug ................................................................................................. 26 
10.2 Measurement of Treatment Compliance ....................................................................... 26 
11. PRIOR, CONCOMITANT, AND POST-TREATMENT MEDICATION ...................... 27 
12. EFFICACY ANALYSES ................................................................................................ 28 
12.1 Efficacy Variables .......................................................................................................... 28 
12.2 Adjustment for Covariates ............................................................................................. 28 
12.3 Handling of Missing Data ............................................................................................. 28 
12.4 Multiple Comparisons / Multiplicity ............................................................................. 28 
12.5 Examination of Subgroups ............................................................................................ 28 
13. METHODS OF EFFICACY ANALYSES ..................................................................... 29 
14. SAFETY ANALYSES .................................................................................................... 30 
14.1 Adverse Events .............................................................................................................. 30 
14.2 Clinical Laboratory Variables ........................................................................................ 31 
14.3 Vital Signs and Weight .................................................................................................. 34 
14.4 Electrocardiogram (ECG) .............................................................................................. 35 
14.5 Physical Examination .................................................................................................... 36 
14.6 Other Safety Endpoints.................................................................................................. 36 


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15. CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES ..... 39 
16. INTERIM ANALYSIS ................................................................................................... 40 
17. DATA MONITORING/REVIEW COMMITTEE .......................................................... 41 
18. COMPUTER METHODS .............................................................................................. 42 
19. CHANGES TO ANALYSES SPECIFIED IN PROTOCOL .......................................... 43 
20. APPENDICES ................................................................................................................ 44 
20.1 Summary of Version Changes ....................................................................................... 44 
20.2 Supplementary Tables ................................................................................................... 45 


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LIST OF TABLES 
Table 1 
Analysis Visit Windows ......................................................................................... 19 
Table 2 
Criteria for Potentially Clinically Important Laboratory Values – Hematology 
and Chemistry ........................................................................................................ 33 
Table 3  
Criteria for Potentially Clinically Important Laboratory Values – Urinalysis ....... 34 
Table 4    Criteria for Potentially Clinically Important (PCI) Vital Signs and Weight .......... 35 
Table 5  
Criteria for Potentially Clinically Important ECG Values ..................................... 36 
Table 6 
Schedule of Events and Assessments .................................................................... 45 
Table 7 
Schedule of Assessments for Subjects on the Handheld Device (EMAs) ............. 47 
Table 8 
Schedule of Assessments for Informants on the Handheld Device (EMAs) ......... 47 


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ABBREVIATIONS 
AE 
Adverse event 
ANCOVA 
analysis of covariance 
CGI-I 
Clinical Global Impressions – Improvement 
CGI-S 
Clinical Global Impressions – Severity  
COVID-19 
Coronavirus disease 2019 
CRO 
Contract Research Organization 
C-SSRS 
Columbia Suicide Severity Rating Scale 
ECG  
electrocardiogram 
eCRF 
electronic case report form  
EDC 
electronic data capture 
EMA 
Ecological Momentary Assessment 
GSD 
Guidance for Site Documentation and Data Management Querying of 
Data Impacted by COVID-19 
IRT 
Interactive Response Technology 
KSS 
Karolinska Sleep Scale 
MDS-UPDRS 
Movement Disorders Society-Unified Parkinson’s Disease Rating Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMSE 
Mini-Mental State Examination 
OC 
observed cases 
PCI 
potentially clinically important 
PD 
Pharmacodynamic(s) 
PD NMS 
Parkinson’s disease non-motor symptoms 
PDP 
Parkinson’s disease psychosis 
PGI-I 
Patient Global Impression - Improvement 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
Standard Deviation 
SE 
Standard Error 
SOC 
system organ class 
TEAE   
treatment-emergent adverse event 


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1. 
INTRODUCTION 
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the 
statistical analyses of efficacy and safety data as described in Protocol Amendment 3, dated 
31 January 2020. Specifications for tables, figures, and listings are contained in a separate 
document. Actigraphy and Ecological Momentary Analysis (EMA) data collected on the 
Handheld Device will be analyzed as described in a separate, stand-alone SAP. 


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2. 
OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to assess the safety and tolerability of pimavanserin and 
low-dose quetiapine compared to placebo in subjects with Parkinson’s disease. 
2.2 
Exploratory Objective 
The exploratory objectives of this study are:  
• to explore the sensitivity of assessments/instruments that are novel for evaluating 
the experience of subjects with Parkinson’s disease with respect to sedation/sleep, 
cognition, and other non-motor symptoms.   
• to explore the effects of pimavanserin and low-dose quetiapine compared to 
placebo in subjects with Parkinson’s disease on: 
o Daytime sleepiness 
o Nighttime sleep 
o Cognition 
o Other non-motor symptoms 
o Treatment satisfaction 
o Safety and tolerability 


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3. 
STUDY DESIGN  
3.1 
General Study Design 
This study is a multicenter, randomized, double-blind, placebo and active-control, 
parallel-group pilot study in subjects with Parkinson’s disease. The study will have 3 periods: 
• Screening period (7-28 days) 
• Double-blind treatment period (4 weeks) 
• Safety follow-up period (30 [±4] days) 
The study completion date is defined as the date the final subject, across all sites, completes 
their final protocol-defined assessment (this includes the safety follow-up phone call). If the 
study is terminated for any reason, subjects remaining in the study will return to standard of 
care. 
Up to 60 subjects will be randomized in a 1:1:1 ratio to pimavanserin, quetiapine, or placebo. 
Subjects for whom the Investigator does not increase the dose of blinded study drug 
consistent with 50 mg quetiapine at Week 1 (Visit 3) will be withdrawn from the study and 
replaced. A maximum of 12 subjects across treatment groups (20%) will be replaced for this 
and only this reason. 
The study design is summarized in Figure 1. 
 
 


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Figure 1 
Schematic of Study Design 
 
 
R= randomization 
* Pre-drug actigraphy data and handheld device assessments are conducted prior to randomization (Baseline) 
Note: A schematic for study drug dispensing and dose adjustments is provided in Figure 2. 
 
 


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Figure 2 
Schematic for Study Drug Dispensing and Dose Adjustments 
 
 
* Week 2 (Visit 4) & Week 3 (Visit 5): Subjects may remain on blinded study drug dose consistent with 50 mg 
quetiapine or be optionally increased to 100 mg quetiapine. 
Abbreviations: EOT=end of treatment; R=randomization 
Note: Dose adjustments and study drug dispensing are only allowed at scheduled visits (i.e., not at unscheduled 
visits). Subjects should not take study drug on the mornings of clinic visit days until instructed to do so by 
the site staff. At Baseline and at each subsequent clinic visit, subjects will be dosed and will remain in the 
clinic for observation for a minimum of 60 minutes after dosing. At Week 1 (Visit 3), Week 2 (Visit 4), and 
Week 3 (Visit 5), the Investigator will be encouraged to increase the dose of blinded study drug, consistent 
with 50-100 mg quetiapine, based on the Investigator’s assessment of clinical response. Dose adjustments 
will be implemented through the IRT. In actuality, only the dose of quetiapine would be increased (to 50 mg 
at Week 1 [Visit 3] and then optionally to 100 mg at Week 2 [Visit 4] or Week 3 [Visit 5]); the pimavanserin 
dose will remain fixed at 34 mg per day throughout the study. Subjects for whom the Investigator does not 
increase the dose of blinded study drug consistent with 50 mg quetiapine at Week 1 (Visit 3) will be 
withdrawn from the study and replaced. The Investigator will be blinded to study drug and thus will not 
know whether their decision to increase the dose of blinded study drug results in an actual increase in study 
drug dose. The dose of study drug (pimavanserin, quetiapine or placebo) may not be decreased. If a subject 
cannot tolerate their dose, they must be withdrawn from the study. 
3.2 
Schedule of Assessments  
The schedule of events and assessments, the schedule of assessments for subjects on the 
handheld device, and the schedule of assessments for informants on the handheld device are 
presented in Tables 6, 7 and 8 in the appendix.


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3.3 
Randomization 
Eligible subjects will be randomized into one of three treatment groups (pimavanserin, 
quetiapine, or matching placebo) in a 1:1:1 ratio using an Interactive Response Technology (IRT) 
system. The assignments will be based on a pre-generated permuted-block randomization 
schedule. 
3.4 
Blinding  
This is a double-blind study. Blinding is assured by restricting access of Investigators and 
Sponsor personnel and/or designee to the treatment codes, and providing identical encapsulated 
tablets and packaging for the pimavanserin, quetiapine, and placebo treatments. 
Unblinding of individual treatment assignment during the study is discouraged. The Investigator 
may break the blind in the event of a medical emergency if it is considered necessary for the care 
of the subject. The Investigator should attempt whenever possible to contact the Medical Monitor 
before unblinding a subject’s treatment to discuss the event. 
For the final analysis, the treatment codes for all subjects will be released to ACADIA after all 
subjects have completed the study and the clinical database (Medidata RAVE) is locked. 
3.5 
Determination of Sample Size 
This is a pilot study and is not powered for statistical significance. Up to 60 subjects will be 
randomized into the study. 
3.6 
Coronavirus Disease 2019  
In March, 2020, the emerging coronavirus disease 2019 (COVID-19) pandemic resulted in 
implementation of urgent safety measures designed to ensure subject safety. Mechanisms to 
record information on the potential impact of the COVID-19 pandemic on data itself, as well as 
data collection and integrity, were implemented (as detailed in the “Guidance for Site 
Documentation and Data Management Querying of Data Impacted by COVID-19” [GSD] in the 
Data Management Plan, Appendix B). 
Due to COVID-19, Screening and enrollment into this study were temporarily halted in 
March 2020, and the decision was made to permanently stop the study as of 24 September 2020. 
The impact of COVID-19 on the statistical analysis is discussed in each of the relevant sections 
of this SAP. 


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4. 
ANALYSIS SETS 
The Randomized Analysis Set will consist of all subjects who were randomized. Subjects will be 
classified according to the randomized treatment assignment. 
The Safety Analysis Set will consist of all subjects who have taken at least 1 dose of study drug. 
Subjects will be classified according to the actual treatment received. Safety analyses will be 
based on the Safety Analysis Set. 
The Exploratory Analysis Set will consist of randomized subjects in the Safety Analysis Set 
excluding subjects who were replaced due to no increase of the dose of blinded study drug 
consistent with 50 mg quetiapine at Week 1 (Visit 3). Subjects will be classified according to the 
randomized treatment assignment. Exploratory efficacy analyses will be based on the 
Exploratory Analysis Set. 


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5. 
DATA HANDLING CONVENTIONS 
All data collected in the study will be listed, excluding actigraphy data or data collected on the 
Handheld Device. 
5.1 
General Data Reporting Conventions 
Continuous variables will be summarized using the following descriptive statistics:  number of 
subjects, mean, median, standard deviation, standard error, minimum, and maximum.  Unless 
specified otherwise, means, medians, and confidence intervals will be presented to one more 
decimal place than the raw data, and the standard deviations and standard errors will be 
presented to two more decimal places than the raw data.  
Categorical and count variables will be summarized by the number of subjects and the percent of 
subjects in each category. Categories with zero counts will not have zero percentages displayed. 
Percentages will be presented with one decimal place. 
Duration in months will be calculated as ([the number of days / 365.25] *12). 
Unless specified otherwise, all statistical tests will be 2-sided hypothesis tests performed at the 
significance level of 5% for main effects and all confidence intervals will be 2-sided 95% 
confidence intervals. P-values will generally be presented to 4 decimal places; values less than 
0.0001 will be presented as <0.0001. 
5.2 
Derived Efficacy Variables  
In general, assessment total scores and subscores will be derived within the analysis datasets. In 
the event that total scores and/or subscores are also collected on the electronic case report from 
(eCRF), the derived values will be used for all analyses. Both the raw and derived scores will be 
presented in listings. 
5.2.1 
Mini-Mental State Examination (MMSE) 
MMSE is assessed at Screening. The MMSE is an 11-area, 30 items questionnaire that is used to 
measure cognitive impairment, with lower scores indicating more severe cognitive impairment. 
The total score (0-30) is calculated as the sum of the 30 item scores. The total score will be 
missing if there are at least one missing items. The MMSE is being used in this study to screen 
for cognitive impairment. 
5.2.2 
Neuropsychiatric Inventory (NPI) 
For subjects enrolled under the Original Protocol or Protocol Amendments 1 or 2, the NPI is 
assessed at Screening. At least one of the following domains must have a Frequency×Severity 
greater than or equal to 3: Domain A Delusions, Domain B Hallucinations, Domain D  


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Depression/Dysphoria, Domain G Apathy/Indifference, Domain H Disinhibition, or Domain I 
Irritability/Lability. The NPI was removed from the list of assessments in Protocol Amendment 3. 
Domain scores will not be derived. Scores, as reported in RAVE, will be listed. 
5.2.3 
Patient-Reported Outcomes Measurement Information System (PROMIS®)  
Data will be collected by the Handheld Device and the analysis method will not be covered by 
this SAP. 
5.2.4 
Sleep-Related Impairment Scale 
Data will be collected by the Handheld Device and the analysis method will not be covered by 
this SAP. 
5.2.5 
Nighttime Sleep Scale  
Data will be collected by the Handheld Device and the analysis method will not be covered by 
this SAP. 
5.2.6 
Trail Making Test (TMT) Parts A and B 
The TMT is a neuropsychological test of visual attention and task switching. The TMT has two 
parts, Parts A and B. Part A measures rote memory and consists of 25 circles on a piece of paper 
with the numbers 1-25 written randomly in the circles. The subject is to connect the circles in 
numerical order. Part B measures executive functioning and consists of 24 circles on a piece of 
paper, half of the circles have the numbers 1-12 in them and the other half (12) contain the letters 
A-L. The subject must alternate connecting circles with numbers and circles with letters. Time to 
completion or maximum time (seconds) for Parts A and B are recorded. The maximum 
completion time for Part A is 150 seconds, and 300 seconds for Part B. Higher completion or 
maximum time denote slower visual attention and task switching. Missing values will not be 
imputed. 
5.2.7 
Hopkins Verbal Learning Test-Revised (HVLT-R) 
The HVLT is a brief verbal learning and memory test with six alternate forms. The HVLT is ideal 
in situations calling for repeated neuropsychological examinations, but it lacks a delayed recall 
trial which is essential for the assessment of abnormal forgetting and therefore the revised 
version of the HVLT (HVLT-R) was developed. The HVLT-R test consists of three trials of free-
recall of a 12-item, semantically categorized list, followed by yes/no recognition. Approximately 
20-25 min later, a delayed recall trial (trial 4) and a delayed recognition trial are completed.  
Total recall will be derived as the sum of total correct responses for Trials 1, 2, and 3. Total recall 
will be set to missing if all 3 trials are not completed. 


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Retention (%) will be derived as (Trial 4 score ÷ Higher score of Trials 2 and 3) × 100. 
The Delayed Recognition Trial will be used to derive the recognition discrimination index, which 
will be calculated as the total number of true-positive responses minus the total number of 
false-positive errors (ranging from -12 to 12). Higher indexes denote better verbal learning and 
memory test results. Missing total numbers of true-positive responses and/or false-positive errors 
will not be imputed. The index will be missing if total number of true-positive responses and/or 
total number of false-positive errors are missing. 
5.2.8 
Parkinson’s Disease Non-motor Symptoms (PD NMS) Questionnaire 
The Non-motor Symptoms questionnaire is a validated, clinician rated questionnaire that 
assesses non-motor issues that may be present in Parkinson's disease. The PD NMS is comprised 
of 30 items grouped into nine domains: cardiovascular including falls, sleep/fatigue, 
mood/cognition, perceptual problems/hallucinations, attention/memory, gastrointestinal tract, 
urinary, sexual function, and miscellaneous. 
Each item is scored with respect to frequency (1=rarely, 2=often, 3=frequent, 4=very frequent) 
and severity (0=none, 1=mild, 2=moderate, 3=severe). Individual item scores are calculated as 
frequency × severity scores. The total score, ranging from 0 to 360, is calculated as the sum of 
the 30 item scores. Higher total scores denote worse non-motor symptoms. If 6 or fewer item 
scores are missing, then the total score will be imputed as the mean of the non-missing item 
scores multiplied by 30 and rounded to the nearest integer. The total score will be missing if 
there are at least 7 missing item scores.  Missing item scores will not be imputed. 
5.2.9 
Patient Global Impression – Improvement (PGI-I) 
The PGI-I is a global index used to rate the response of a condition to a therapy. The PGI-I asks 
the patient to rate their symptoms now, as compared with how it was at Baseline before 
beginning treatment. Severity ratings ranging from 1 to 7 are based on the behavioral domain(s) 
of clinical concern: 
1 = Very much better   
 
4 = No change 
2 = Much better  
 
 
5 = A little worse 
3 = A little better 
 
 
6 = Much worse 
  
 
 
 
 
 
7 = Very much worse 
Higher PGI-I scores denote worse symptoms compared with Baseline before beginning 
treatment. Missing PGI-I scores will not be imputed. 
Beginning with Protocol Amendment 3, rather than being assessed on a single global scale as 
described above, subjects were assessed on the following symptom-specific PGI-I scales: 


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delusions, hallucinations, depression/dysphoria, apathy/indifference, disinhibition, 
irritability/lability. For those subjects assessed with symptom-specific PGI-I scales, a single, 
global score will be derived by taking the arithmetic mean of the non-missing symptom-specific 
scores at the given visit, rounded to the nearest integer. 
5.2.10 Clinical Global Impression – Severity (CGI-S) 
The CGI-S scale is a clinician-rated, 7-point scale that is designed to rate the severity of the 
subject’s neuropsychiatric symptoms at the time of assessment using the Investigator’s judgment 
and past experience with subjects who have the same disorder. The CGI-S will be assessed at 
Screening and at Baseline. Severity ratings ranging from 0 to 7 are based on the behavioral 
domain(s) of clinical concern used for eligibility: 
0 = Not assessed  
 
 
4 = Moderately ill 
1 = Normal, not at all ill  
 
5 = Markedly ill 
2 = Borderline ill 
 
 
6 = Severely ill 
3 = Mildly ill   
 
 
7 = Among the most extremely ill patients 
Higher CGI-S scores denote more severe illness. Missing CGI-S scores will not be imputed. 
Beginning with Protocol Amendment 3, rather than being assessed on a single global scale as 
described above, subjects were assessed on the following symptom-specific CGI-S scales: 
delusions, hallucinations, depression/dysphoria, apathy/indifference, disinhibition, 
irritability/lability. For those subjects assessed with symptom-specific CGI-S scales, a single, 
global score will be derived by taking the arithmetic mean of the non-missing symptom-specific 
scores at the given visit, rounded to the nearest integer. 
5.2.11 Clinical Global Impression – Improvement (CGI-I) 
The CGI-I is a clinician-rated, 7-point scale that is designed to rate the improvement in the 
subject’s symptoms at the time of assessment, relative to the symptoms at Baseline. Severity 
ratings ranging from 0 to 7 are based on the behavioral domain(s) of clinical concern used for 
eligibility: 
0 = Not assessed  
 
 
4 = No change 
1 = Very much improved  
 
5 = Minimally worse 
2 = Much improved  
 
6 = Much Worse 
3 = Minimally improved  
 
7 = Very much worse 
Higher CGI-I scores denote less improvement in illness. Missing CGI-I scores will not be 
imputed. 


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Beginning with Protocol Amendment 3, rather than being assessed on a single global scale as 
described above, subjects were assessed on the following symptom-specific CGI-I scales: 
delusions, hallucinations, depression/dysphoria, apathy/indifference, disinhibition, 
irritability/lability. For those subjects assessed with symptom-specific CGI-I scales, a single, 
global score will be derived by taking the arithmetic mean of the non-missing symptom-specific 
scores at the given visit, rounded to the nearest integer. 
5.2.12 Patient and Informant Satisfaction Question 
Data will be collected by the Handheld Device and the analysis method will not be covered by 
this SAP. 
5.3 
Analysis Visit Windows  
Baseline of the study is defined as the last non-missing result, including results from repeated 
and unscheduled measurements, prior to first dosing. 
Efficacy and safety assessments will be summarized by analysis visit as presented in Table 1 
below. 
Table 1 
Analysis Visit Windows 
Analysis Visit  
Study Visit 
Target Study Day 
@ 
Study Day Interval 
Baseline (Day 1) 
2 (Week 0) 
1 
< 1 
Week 1 
3 (Week 1) 
8 
2 – 11 
Week 2 
4 (Week 2) 
15 
12 – 18 
Week 3 
5 (Week 3) 
22 
19 – 25 
Week 4 
6 (Week 4) 
29 
26 – 32 
Safety Follow-up 
7 (Week 8) 
59 
≥ 33 
@ Derivation of study day: study day = assessment date - first dose date + 1 if the assessment date ≥ first dose date, 
otherwise study day = assessment date – first dose date. Study day 1 is the day of first administration of study drug 
(pimavanserin, quetiapine, or placebo). 
5.3.1 
Unscheduled Assessments 
Both Scheduled and Unscheduled assessments, including the assessments at early termination 
visits, will be used for planned timepoint analyses. All assessments will be presented in data 
listings. 


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5.3.2 
Multiple Measurements within Visit Windows 
In the event that more than one assessment falls within a given window the assessment closest to 
the target study day will be selected for the by-visit analysis. If two assessments are equidistant 
from the target study day then the chronologically last assessment will be used. Exceptions may 
be made for incomplete assessments, in which case, more complete assessments may be given 
priority.  Details are provided in a separate programming conventions document. 
For safety analyses where the extreme values should be selected (e.g., overall post-Baseline 
minimum, overall post-Baseline maximum, and potentially clinically important values), all non-
missing post-Baseline values should be considered, regardless of whether the value is selected 
for the by-visit summaries. All assessments will be presented in data listings. 
5.4 
Missing or Incomplete Date for Last Dose of Study Drug 
In the Safety Analysis Set, if the last dose date of study drug is missing for a subject who 
completed or early terminated from the study, then it will be imputed using the last expected 
dosing date (LED), defined as the earlier of the following three dates: the date of the end-of-
treatment (EOT)/early termination (ET) visit, the last expected dosing date per protocol, and the 
kit return date of the last dispensed drug kit. For the incomplete last dose date of study drug, the 
imputation algorithms will be detailed in the analysis dataset specification document. The 
missing or incomplete dates will be displayed in the data listings as reported on the eCRF rather 
than the imputed dates. 
5.5 
Missing or Incomplete Dates for Prior or Concomitant Medications 
Missing or incomplete medication start or stop dates will be imputed for the purpose of 
determining whether the medication is taken concomitantly or not (see Section 11 for definition). 
When the chronological order of medication use relative to the study drug treatment period is 
unclear due to missing or incomplete date(s), the medication will be considered as concomitant. 
The imputation algorithms will be detailed in the analysis dataset specification document. The 
missing or incomplete dates as captured on the eCRF will be displayed in the data listings. 
5.6 
Missing or Incomplete Date for Adverse Events 
Missing or incomplete adverse event (AE) start dates will be imputed for the purpose of 
determining whether the AEs are treatment-emergent or not (see Section 14.1 for definition). 
When the chronological order of an AE onset relative to the study drug treatment period is 
unclear due to missing or incomplete date(s), the AE will be considered as treatment-emergent. 
The imputation algorithms will be detailed in the analysis dataset specification document. The 
missing or incomplete dates captured on the eCRF will be displayed in the data listings. 


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5.7 
Missing Severity Assessment for Adverse Events 
If the severity is missing for an AE starting on or after the date of the first dose of study drug, 
then a severity of “Severe” will be assigned.  The imputed values for severity assessment will be 
used for incidence summaries, while the actual values will be used in data listings. 
5.8 
Missing Relationship to Study Drug for Adverse Events 
If the relationship to study drug is missing for an AE starting on or after the date of the first dose 
of study drug, a causality of “Related” will be assigned.  The imputed values for relationship to 
study drug will be used for incidence summaries, while the actual values will be presented in 
data listings. 
5.9 
Character Values of Clinical Laboratory Variables 
If the reported value of a clinical laboratory variable cannot be used in a statistical analysis due 
to, for example, a character string reported for a numeric variable, an appropriately determined 
coded value may be used in the statistical analysis. The coding algorithms will be detailed in the 
analysis dataset specification document. The actual values as reported in the database will be 
presented in data listings. 


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6. 
SUBJECT DISPOSITION 
For subjects who participate in the screening phase but are not randomized (screen failures), their 
demographics information (including age, sex, and primary race), screen failure reasons (the 
specific inclusion/exclusion criterion, or criteria, not met or other reasons including the reason 
due to COVID-19) and protocol version will be listed. If a subject is re-screened, then the 
re-screening subject ID and the final enrollment status (whether eventually enrolled) will also be 
displayed in this listing. In addition, the frequency that the screen failure reasons are reported 
will also be summarized. Note that one subject may be deemed ineligible for multiple 
inclusion/exclusion criteria and may be allowed to rescreen with the permission of the Medical 
Monitor, provided the screen failure was due to a temporary condition that subsequently 
resolved. 
The number of sites that screened at least 1 subject, number of sites that randomized at least 
1 subject, number of subjects screened, and number of unique subjects screened will be 
tabulated. In addition, the number of subjects enrolled at each site will also be tabulated by 
analysis set and by treatment group and overall. 
For randomized subjects, the number and percentage of subjects in the Safety Analysis Set and 
Exploratory Analysis Set will be summarized by treatment group and overall. A listing will be 
provided displaying all subjects excluded from the Safety or Exploratory 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 reasons including the reason due to 
COVID-19) will also be summarized by treatment group and overall. 
 


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7. 
PROTOCOL DEVIATIONS 
Protocol deviations will be reviewed periodically over the course of the study. The review 
process, definition of the deviation categories, and the classification of a deviation as major or 
minor are detailed in the Protocol Deviation Management Plan. Protocol deviations will also be 
assessed with respect to relationship to COVID-19. 
A summary of the number and percentage of subjects with major protocol deviations for each 
deviation category will be presented by treatment group for the Randomized Analysis Set in 
three ways: all protocol deviations, COVID-19 related protocol deviations, and non COVID-19 
related protocol deviations. 
Two listings of major protocol deviations will be provided: all deviations and non COVID-19 
related protocol deviations. A listing of all COVID-19 related protocol deviations including the 
major and the minor will be provided. 


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8. 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
Demographics and baseline characteristics will be summarized by treatment group and overall 
for the Randomized and Safety analysis sets, using descriptive statistics. Variables include age, 
sex, race, ethnicity, height, weight, and BMI. 
Race will also be categorized by White vs. Non-White. The reported age reflects a subject’s age 
at the informed consent date. 
Parkinson’s disease history will be summarized by treatment and overall for the Randomized and 
Safety analysis sets using descriptive statistics. Variables include Age at Parkinson’s disease 
diagnosis, prior antipsychotic use (yes/no), and presence of insomnia (yes/no). 


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9. 
MEDICAL HISTORY 
Medical history reported terms will be coded with Medical Dictionary for Regulatory Activities 
(MedDRA), version 23.0 or newer. The subject incidence will be summarized for each system 
organ class (SOC) and preferred term by treatment group and overall for the Safety Analysis Set. 
A subject will be counted only once per SOC or per preferred term for the summary. 
A listing of the SOC, preferred term, body system, verbatim for the medical history 
condition/event, start and stop dates (when available), and an indicator for whether or not the 
condition is ongoing will be provided. 
 


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10. EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE 
Extent of exposure and treatment compliance will be summarized as continuous variables by 
treatment group for the Safety Analysis Set. 
10.1 
Exposure to Study drug  
Duration of exposure to study drug will be calculated for each subject as (last dose date – first 
dose date + 1). The number and percentage of subjects within each of the following exposure 
levels in terms of duration of exposure will also be tabulated: <1 week (1 to 6 days), 1 to 
<2 weeks (7 to 13 days), 2 to <3 weeks (14 to 20 days), 3 to <4 weeks (21 to 27 days), and 
>4 weeks (28 days or longer). 
10.2 
Measurement of Treatment Compliance 
Study drug dosing compliance is defined as the total number of tablets actually taken by a 
subject divided by the number of tablets expected to be taken and then multiplied by 100. The 
total number of tablets actually taken is calculated by the total number of tablets dispensed minus 
the number of tablets returned.  The number of tablets expected to be taken is calculated as the 
duration of exposure multiplied by 2 (the planned number of tablets taken per day). 
Treatment compliance will also be summarized as a categorical variable. The number and 
percentage of subjects within each of the following compliance levels will be tabulated: <80%, 
80 to 120%, and >120%. 


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11. PRIOR, CONCOMITANT, AND POST-TREATMENT MEDICATION 
Prior medication is defined as any medication with the start and stop dates prior to the date of the 
first dose of study drug. Concomitant medication is defined as any medication with a start date 
prior to the date of the first dose of study drug and continuing past the first dose of study drug or 
with a start date between the dates of the first and last doses of study drug, inclusive.  Any 
medication with a start date after the date of the last dose of study drug will be considered as 
post-treatment medication. Medications will be coded using WHO Drug Dictionary March 2018 
or newer version.  The number and percentage of subjects taking each drug class (ATC Level 3) 
and medication preferred term will be tabulated by treatment group and overall for the Safety 
Analysis Set. Multiple medication usage by a subject in the same category will be counted only 
once. 
Prior and Concomitant Medications 
Prior and concomitant medications will be summarized for the Safety Analysis Set by ATC 
Level 3, preferred term, and the study drug (placebo, quetiapine, and pimavanserin). 
Post-Treatment Medications 
Post-treatment medications will be summarized for the Safety Analysis Set by ATC Level 3, 
preferred term, and the study drug (placebo, quetiapine, and pimavanserin) of which subjects 
received their last doses. 
COVID-19 Related Medications 
Relationship to COVID-19 will be assessed for selected medications as detailed in the GSD. 
COVID-19 related concomitant medications will be listed separately. 
 


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12. EFFICACY ANALYSES 
All efficacy analyses will be performed using the planned treatment assignments based on the 
randomization schedule for the Exploratory Analysis Set. 
12.1 
Efficacy Variables 
Exploratory Efficacy Endpoints Measured at Study Visits 
• Change from Baseline to Week 4 in 
o Time to completion or maximum time of TMT Parts A and B, 
o HVLT-R recognition discrimination index, and 
o PD NMS total score 
• CGI-I score at Week 4 
• PGI-I score at Week 4 
12.2 
Adjustment for Covariates 
The corresponding baseline value will be included as a covariate for the analysis of time to 
completion or maximum time of TMT Parts A and B, HVLT-R recognition discrimination index, 
and PD NMS total score. Baseline CGI-S score will be used as a covariate for the CGI-I analysis. 
12.3 
Handling of Missing Data 
Missing data will not be imputed in the analysis of exploratory efficacy endpoints. 
12.4 
Multiple Comparisons / Multiplicity 
Multiplicity will not be adjusted in the analysis of exploratory efficacy endpoints due to the 
exploratory nature of this trial. 
12.5 
Examination of Subgroups 
No subgroup analyses are planned. 


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13. METHODS OF EFFICACY ANALYSES 
The change from Baseline in the exploratory efficacy endpoints measured at scheduled visits 
including time to completion or maximum time of TMT Parts A and B, HVLT-R recognition 
discrimination index, and PD NMS total score will be analyzed using an analysis of covariance 
model (ANCOVA) using observed scores.  The model will include treatment group as a factor 
and the corresponding Baseline measure as a covariate. 
Summary statistics (observed and change from Baseline), LS means, the between-group 
differences (Pimavanserin – Placebo and Quetiapine – Placebo) in LS means with the 
corresponding 95% confidence intervals, p-values, and the effect sizes (Cohen’s d) will be 
presented at each post-Baseline visit for the Exploratory Analysis Set. 
CGI-I score will be analyzed using a similar ANCOVA model with treatment group as a factor 
and Baseline CGI-S score as a covariate. 
PGI-I score will be analyzed using an analysis of variance model with treatment group as a 
factor. 
 


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14. SAFETY ANALYSES 
All safety analyses will be performed using the actual treatment for the Safety Analysis Set. 
14.1 
Adverse Events  
The primary endpoint for this study is treatment-emergent adverse events (TEAEs). Adverse 
events will be coded using MedDRA dictionary, Version 23.0. 
An AE (classified by preferred term) will be considered a treatment-emergent AE (TEAE) if 
started after first study dose administration and no later than last study dose date + 30. AEs 
reported on Day 1 based on Baseline (pre-dose) findings (e.g., clinically significantly abnormal 
vital signs, laboratory test results, or electrocardiogram parameters) will not be considered as 
TEAEs. 
The number and percentage of subjects reporting TEAEs in each treatment group will be 
tabulated by system organ class (SOC) and preferred term; by SOC, preferred term, and 
maximum severity; and by SOC, preferred term, and relationship to study drug.  If more than 
1 AE occurs with the same preferred term for the same subject, then the subject will be counted 
only once for that preferred term using the most severe and most related occurrence for the 
summarization by severity and by relationship to study drug. 
The relationship of selected AEs to COVID-19 will be assessed as detailed in the GSD. 
COVID-19 related adverse events will be listed separately. 
TEAEs will also be tabulated by treatment group and without displaying the SOC terms; this 
table will be sorted in descending order of frequency of preferred term within the pimavanserin 
group. 
The incidence of most frequently reported (preferred terms reported by 2 or more subjects) 
TEAEs, treatment emergent SAEs, and TEAEs leading to discontinuation of study drug will be 
summarized by SOC, preferred term, and treatment group. The tables will be sorted 
alphabetically by SOC and then by descending frequency within each SOC. In addition, the 
incidence of fatal treatment-emergent AEs (i.e., events that cause death) will be summarized 
separately by preferred term and treatment group. 
An AE listing by subject will display all events, including those which occur during screening, 
and will include the verbatim term in addition to the MedDRA SOC and preferred term. This 
listing will also include all relevant eCRF data associated with the event: date of onset, date 
resolved, date of last dose, severity, frequency, outcome, relationship to study drug, and action 
taken with study drug. Separate listings will be presented for subjects with treatment-emergent 
SAEs, subjects with TEAEs leading to discontinuation, subject who died (if any), and 
COVID-19 related adverse events. 


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14.2 
Clinical Laboratory Variables 
Due to COVID-19 disruptions it is possible that some test results may be collected from a local 
laboratory. Local laboratory results will not be included in any data analysis. Local laboratory 
results (if collected) will be included in data listings. 
Clinical laboratory assessments are performed at Screening Visit 1, Baseline (Week 0), Visit 4 
(Week 2), and Visit 6 (Week 4/EOT/ET). 
• Clinical chemistry serum tests include the following: 
o Sodium (Na), potassium (K), chloride (Cl), phosphorus (P), calcium (Ca), 
magnesium (Mg), carbon dioxide (CO2), blood urea nitrogen (BUN), creatinine 
(CR), uric acid 
 Mg is only performed at Visit 1 (Screening) 
o Alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-
glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), total bilirubin 
(TBIL), lactate dehydrogenase (LDH) 
o Vitamin B12 (Screening only) 
o HbA1c (Screening only) 
o Glucose 
o Albumin (ALB), total protein 
o Prolactin (Week 4/EOT will be blinded, also performed at Baseline) 
o Thyroid stimulating hormone (TSH) and reflex free T4, if TSH is out of range 
 TSH/free T4 is only performed at Visit 1 (Screening) 
o Creatine kinase (CK)/creatine phosphokinase (CPK) 
o Insulin (at Baseline and Week 4 only) 
o Lipid panel 
 Total cholesterol, HDL-cholesterol, triglycerides, LDL-cholesterol, 
Cholesterol/HDL ratio, Non-HDL cholesterol, very low density lipoprotein 
cholesterol 
• Hematology tests include the following: 
o Complete blood count (CBC) including: 


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 White blood cell (WBC) count 
 Absolute neutrophil count 
 Complete differential (relative and absolute) 
 Hematocrit (Hct), hemoglobin, red blood cells (RBC), platelets 
 Reticulocyte count 
• Urinalysis tests include the following: 
o Blood, RBCs, WBCs, protein, glucose, ketones, specific gravity, pH 
Clinical laboratory values (in Système International [SI] units) and the change from Baseline 
values will be summarized by treatment group at Weeks 2 and 4(EOT/ET) using descriptive 
statistics. The overall minimum, maximum and last post-Baseline observed and change from 
Baseline values will also be summarized. For hemoglobin, hematocrit and uric acid, the above 
summaries will be presented for each gender as well as for both genders combined. For 
urinalysis with categorical results, the number and percentage of subjects will be tabulated by 
category at Baseline, Weeks 2 and 4 (EOT/ET); and the denominator is the number of subjects 
with non-missing values for the given parameter, visit and treatment group. 
Laboratory values will also be summarized in shift tables by treatment group, to determine the 
number and percentage of subjects with values classified as below, within, and above normal 
ranges at Weeks 2 and 4 (EOT/ET) relative to the same classification at the Baseline visit. For 
the by-visit shift summary, the denominator is the number of subjects with non-missing values at 
Baseline and the given visit for the given parameter and treatment group. For the shift to the 
overall post-Baseline minimum or maximum, all post-Baseline values will be considered, 
including unscheduled and out of window values and the denominator is the number of subjects 
with non-missing Baseline value and at least 1 post-Baseline value for the given parameter and 
treatment group. For hemoglobin, hematocrit and uric acid, the shift summaries will be presented 
for each gender as well as for both genders combined. 
Clinical laboratory values are potentially clinically important (PCI) if they meet either the low or 
high PCI criteria listed in Tables 2 and 3. The number and percentage of subjects with post-
Baseline PCI values for each of the categories in Table 7 and 8 will be summarized by treatment 
group for selected parameters. For the overall post-Baseline summaries of PCI values, all post-
Baseline values will be considered, including unscheduled and out of window values. Subjects 
with multiple PCI values for a given parameter will be counted only once for that parameter. For 
the overall post-Baseline summary, the numerator of the percentage is the number of subjects 
with at least 1 post-Baseline PCI laboratory value for the given parameter and treatment group, 


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and the denominator is the number of subjects with at least 1 post-Baseline laboratory value for 
the given parameter and treatment group. For hemoglobin, hematocrit and uric acid, the count 
and percentage of subjects with PCI values will be presented for each gender as well as for both 
genders combined. Subjects with PCI values will be presented in an additional listing. 
Table 2 
Criteria for Potentially Clinically Important Laboratory Values – Hematology 
and Chemistry 
 
Analyte 
Conventional 
Unit 
Low PCI 
Criteria 
High PCI 
Criteria 
 
SI Unit 
Low PCI 
Criteria 
High PCI 
Criteria 
Hematology (whole 
blood) 
 
 
 
 
 
 
Hemoglobin (male) 
g/dL 
<11 
>18 
g/L 
<110 
>180 
Hemoglobin (female) 
g/dL 
<10 
>17 
g/L 
<100 
>170 
Hematocrit (male) 
% 
<30 
>55  
L/L 
<0.3 
>0.55  
Hematocrit (female) 
% 
<30 
>50  
L/L 
<0.3 
>0.5  
Leukocyte (White 
Blood Cell Count) 
x 103/uL 
≤2.8 
≥15 
x 109/L 
≤2.8 
≥15 
Neutrophils 
x 103/uL 
≤1.5 
No upper 
limit 
x 109/L 
≤1.5 
No upper 
limit 
Platelet Count 
x 103/uL 
≤75 
≥700 
109/L 
≤75 
≥700 
Chemistry (serum 
or plasma) 
 
 
 
 
 
 
ALT (SGPT) 
U/L 
No lower 
limit  
≥3 X ULN 
U/L 
No lower 
limit  
≥3 X ULN 
AST (SGOT) 
U/L 
No lower 
limit  
≥3 X ULN 
U/L 
No lower 
limit  
≥3 X ULN 
Total Bilirubin 
mg/dL 
No lower 
limit 
≥1.5 ULN 
umol/L 
No lower 
limit 
≥1.5 ULN 
BUN 
mg/dL 
No lower 
limit 
≥30.0 
mmol/L 
No lower 
limit 
≥10.71 
Creatine Kinase (CK) 
U/L 
No lower 
limit 
≥3 ULN 
U/L 
No lower 
limit 
≥3 ULN 
Sodium 
mEq/L 
≤125 
≥155 
mmol/L 
≤125 
≥155 
Potassium 
mEq/L 
≤3.0 
≥5.5 
mmol/L 
≤3.0 
≥5.5 
Calcium, total 
mg/dL 
<8.0 
>11.0 
mmol/L 
<2.0 
>2.75 
Lactate 
Dehydrogenase 
(LDH) 
U/L 
No lower 
limit 
≥3 X ULN 
U/L 
No lower 
limit 
≥3 X ULN 
Alkaline Phosphatase 
U/L 
No lower 
limit 
≥3 X ULN 
U/L 
No lower 
limit 
≥3 X ULN 
 
 
 


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Table 2 
Criteria for Potentially Clinically Important Laboratory Values – Hematology 
and Chemistry (Continued) 
 
Analyte 
Conventional 
Unit 
Low PCI 
Criteria 
High PCI 
Criteria 
 
SI Unit 
Low PCI 
Criteria 
High PCI 
Criteria 
Uric acid (male) 
mg/dL 
No lower 
limit 
≥10.5 
umol/L 
No lower 
limit 
≥624.75 
Uric acid (female) 
mg/dL 
No lower 
limit 
≥8.5 
umol/L 
No lower 
limit 
≥505.75 
Albumin 
g/dL 
≤2.6 
≥6.0 
g/L 
≤26 
≥60 
Total Protein 
g/dL 
≤5.0 
≥10.0 
g/L 
≤50 
≥100 
Chloride 
mEq/L 
≤85 
≥120 
mmol/L 
≤85 
≥120 
Glucose (random) 
mg/dL 
≤45.1 
≥200.0 
mmol/L 
≤2.48 
≥11 
Serum Creatinine 
mg/dL 
Not 
Applicable 
>1.5 ULN 
umol/L 
Not 
Applicable 
>1.5 ULN 
Triglycerides 
mg/dL 
Not 
Applicable 
>300 
mmol/L 
Not 
Applicable 
>3.39 
Gamma-Glutamyl 
Transferase (GGT) 
U/L 
Not 
Applicable 
≥3 ULN 
U/L 
Not 
Applicable 
≥3 ULN 
 
Table 3  
Criteria for Potentially Clinically Important Laboratory Values – Urinalysis 
Urinalysis (qualitative dipstick) 
Low PCI Criteria 
High PCI Criteria 
Blood (occult blood) 
Not Applicable 
≥ Moderate 
Protein 
Not Applicable 
≥ 100 mg/dL 
Glucose 
Not Applicable 
≥ 500 mg/dL 
 
Clinical laboratory data will be displayed in data listings with date and study day of collection.  
All units will be displayed according to SI conventions for units.  Out of range values will be 
flagged in the data listings (i.e., ‘L’ or ‘H’).  A separate listing will be provided for a subset of the 
chemistry, hematology, and urinalysis analytes with values classified as PCI. 
The pregnancy results (positive or negative) for female subjects will be presented in a listing. 
14.3 
Vital Signs and Weight 
Vital signs will be collected throughout the study. Weight and BMI will be observed and/or 
derived at Screening Visit 1, Baseline (Week 0) and Visit 6 (Week 4/EOT/ET). Observed values 
and the changes from Baseline at each post-Baseline visit will be summarized by treatment group 
using descriptive statistics. 
Vital sign and weight values will be considered PCI if they meet the criteria listed in Table 4. The 
number and percentage of subjects with post-Baseline vital signs and weight that are PCI will be 


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summarized by treatment group at each post-Baseline visit and for overall post-Baseline. For the 
overall post-Baseline summaries, all post-Baseline values will be considered, including 
unscheduled and out of window values. Subjects with multiple PCI values for a given parameter 
will be counted only once for that parameter. For the by-visit summary, the numerator for the 
percentage is the number of subjects with a post-Baseline PCI value for the given parameter, 
visit and treatment group, and the denominator is the number of subjects with non-missing 
values for the given parameter, visit and treatment group. For the overall post-Baseline summary, 
the numerator for the percentage is the number of subjects with at least 1 post-Baseline PCI 
value for the given parameter and treatment group, and the denominator is the number of 
subjects with at least 1 post-Baseline value for the given parameter and treatment group. A listing 
of subjects with any PCI value will be provided. 
Table 4 
Criteria for Potentially Clinically Important (PCI) Vital Signs and Weight 
Vital Sign Parameter 
 
Unit 
Criteria 
Observed Value 
And/Or 
Change Relative to Baseline 
Systolic blood pressure 
(supine or sitting) 
mmHg 
≥180 
And 
Increase of ≥20 
≤90 
And 
Decrease of ≥20 
Diastolic blood 
pressure (supine or 
sitting) 
mmHg 
≥105 
And 
Increase of ≥15 
≤50 
And 
Decrease of ≥15 
Pulse (supine or 
sitting) 
bpm 
≥120 
And 
Increase of ≥15 
≤50 
And 
Decrease of ≥15 
Weight  
kg 
Not Applicable 
Increase of ≥7% 
Decrease of ≥7% 
14.4 
Electrocardiogram (ECG) 
12-lead ECGs are collected throughout the study. Observed values of ECG variables (e.g., heart 
rate, PR interval, QRS interval, QT interval, and QTc interval) and the changes from Baseline at 
each assessment time point will be summarized by treatment group. 
QTcF will also be categorized into the following categories (msec) and the number and 
percentage of subjects in each category will be summarized by treatment group at each visit and 
for the overall post-Baseline maximum: 
• Observed: ≤450, 451 - ≤480, 481 - ≤500, and >500; >450; >480. 
• Change from Baseline: ≤10, 11 – 30, 31 – 60, and >60; >30. 


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Electrocardiogram variable values will be considered PCI if they meet the criteria listed in 
Table 5. The number and percentage of subjects with post-baseline PCI values will be 
summarized by treatment group at each post-Baseline visit and for overall post-Baseline. For the 
by-visit summary, the numerator for the percentage is the number of subjects with a 
post-Baseline PCI ECG for the given parameter, visit and treatment group, and the denominator 
is the number of subjects with non-missing values for the given parameter, visit and treatment 
group. For the overall post-Baseline summary, the numerator for the percentage is the number of 
subjects with at least 1 post-Baseline PCI ECG for the given parameter and treatment group, and 
the denominator is the number of subjects with at least 1 post-Baseline ECG value for the given 
parameter and treatment group. A listing of all subjects with any PCI value will be provided. 
Table 5  
Criteria for Potentially Clinically Important ECG Values 
ECG Parameter 
Unit 
High PCI Criteria 
QRS Interval 
msec 
≥120 
PR Interval 
msec 
≥220 
QTcB or QTcF 
msec 
>500 
QTcB or QTcF: change from baseline  
>60 msec  
 
Cardiologist interpretations (normal and abnormal) will be summarized in a frequency table by 
treatment group and visit and for overall post-Baseline. 
14.5 
Physical Examination 
Physical examinations are performed at Screening Visit 1, Baseline (Week 0), and Week 4 
(EOT/ET). Physical examination results (normal, abnormal, and not done) will be summarized in 
a frequency table by treatment group, body system and visit. 
14.6 
Other Safety Endpoints 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS Baseline/Screening version will be completed at the Screening visit and the version 
assessing information since the last visit will be completed at all following visits (including the 
Baseline visit). 
There are 5 questions about suicidal ideation, representing 5 types of suicidal ideation: wish to be 
dead; non-specific active suicidal thoughts; active suicidal ideation with any methods (not plan) 
without intent to act; active suicidal ideation with some intent to act, without specific plan; active 
suicidal ideation with specific plan and intent.  If a subject answers “yes” to any of these 


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5 questions at any post-Baseline visit including unscheduled and out of window visits, this 
subject will be counted as having suicidal ideation in this study. 
There are 5 questions about suicidal behavior, representing 5 types of suicidal behavior: actual 
attempt; interrupted attempt; aborted attempt; preparatory acts or behavior; suicide.  If a subject 
answers “yes” to any of these 5 questions at any post-Baseline visit including unscheduled and 
out of window visits, this subject will be counted as having suicidal behavior in this study. 
Suicidality is defined as a subject who reported at least 1 occurrence of suicidal ideation or at 
least 1 occurrence of suicidal behavior at any post-Baseline visit including unscheduled and out 
of window visits.   
All data will be listed. The event counts and the number and percentage of subjects reporting any 
post-Baseline suicidal ideation, suicidal behavior, or suicidality will be summarized by treatment 
group. 
Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III 
(motor examination) 
The MDS-UPDRS is a comprehensive battery of motor and behavioral indices derived from the 
Columbia Scale. The MDS-UPDRS Part III will be used to assess motor function and is a motor 
examination consisting of 18 rater based items plus Hoehn and Yahr scale (describing how the 
symptoms of Parkinson’s disease progress). Each item rating ranges from 0 to 4: 
 
0: Normal;  
1: Slight;  
2: Mild; 
3: Moderate;     4: Severe 
Some of the 18 items have subitems. In these cases, the item scores are defined as the sum of the 
subitem scores. If any of the subitem scores are missing then the corresponding item score will 
be missing. 
The following item scores will be derived as the sum of the Right and Left subitem scores: finger 
tapping, hand movements, pronation-supination movement of hands, toe tapping, leg agility, 
postural tremor of the hands, and kinetic tremor of the hands. 
The rigidity item score is derived as the sum of the neck, right upper extremity, left upper 
extremity, right lower extremity, and left lower extremity subitem scores. 
The rest tremor amplitude item score is derived as the sum of the lip/jaw, right upper extremity, 
left upper extremity, right lower extremity, and left lower extremity subitem scores. 
The Hoehn and Yahr scale is a single item question that is used to assess the stage of Parkinson’s 
disease; the score ranges from 0 to 5: 
 
0: Asymptomatic 
 
1: Unilateral involvement only 


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2: Bilateral involvement without impairment of balance 
 
3: Mild to moderate involvement; some postural instability but physically independent; 
needs assistance to recover from pull test 
 
4: Severe disability; still able to walk or stand unassisted 
 
5: Wheelchair bound or bedridden unless aided 
The assessment is to be completed at the clinic visits at Baseline (Week 0) and Week 4 
(EOT/ET). 
The observed and change from Baseline values will be summarized. The change from Baseline 
to Week 4 in the score for each of the 18 items as well as Hoehn and Yahr Stage score will be 
analyzed using an ANCOVA model with treatment group as a factor and the Baseline value as a 
covariate. Missing data will not be imputed. 


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15. CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
No pharmacokinetic samples are collected in this study. 


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


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17. DATA MONITORING/REVIEW COMMITTEE 
There is no data monitoring/review committee in this study. 


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


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19. CHANGES TO ANALYSES SPECIFIED IN PROTOCOL 
Because this trial was stopped early after randomizing only 11 subjects, all of the mixed-model 
repeated measures analyses were changed to ANCOVA in order to minimize possible 
non-convergence issues. 
  


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20. APPENDICES 
20.1 
Summary of Version Changes  
Version No: 
Document History 
Description of Update 
Author(s) 
Version Date 
1.0 
Original version 
 
19 October 2020 
 
 
 


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20.2 
Supplementary Tables 
Table 6 
Schedule of Events and Assessments 
 
Screening Baseline Double-blind Treatment Period 
Safety 
Follow-
up 
Visit Week 
(Study Day) 
-4 
0 
1 
(Day 
7) 
2 
(Day 
14) 
3 
(Day 
21) 
4/EOT 
(Day 
28) 
8 l 
(Day 58) 
Visit Number 
1 
2 
3 
4 
5 
6/ET 
7 
Visit window (days) 
0 
0 
±3 
±3 
±3 
±3 
±4 
Type of Visit 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Telephone 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
Medical history and demographics 
X 
 
 
 
 
 
 
Psychiatric and neurological history 
X 
 
 
 
 
 
 
Physical 
examination 
(including 
neurologic examination)  
X 
X 
 
 
 
X 
 
Training on the use of the handheld 
device and the actigrapha 
X 
X 
 
 
 
 
 
Orthostatic vital signs 
X 
X 
X 
X 
X 
X 
 
Weight and BMIb 
X 
X 
 
 
 
X 
 
Height 
X 
 
 
 
 
 
 
12-lead ECGc 
X 
X 
X 
X 
X 
X 
 
Clinical laboratory tests 
X 
X 
 
X 
 
X 
 
Pregnancy testd 
X 
X 
 
 
 
X 
 
Urine drug screen 
X 
Xk 
 
 
 
X 
 
Capsule swallowing teste 
X 
 
 
 
 
 
 
MMSE 
X 
 
 
 
 
 
 
Dispense study drugg 
 
X 
X 
X 
X 
 
 
CGI-Sf 
X 
X 
 
 
 
 
 
Trail Making Testf 
 
X 
X 
X 
 
X 
 
HVLT-Rf 
 
X 
X 
X 
 
X 
 
Handheld device questionnairesh 
 
X----------------------------------------------------
---------X 
 
Actigraphy data collection
i 
 
X----------------------------------------------------
---------X 
 
PD NMS Questionnairef 
 
X 
 
X 
X 
X 
 
PGI-If 
 
 
X 
X 
X 
X 
 
CGI-If 
 
 
X 
X 
X 
X 
 
MDS UPDRSf 
 
X 
 
 
 
X 
 
Subject and Informant satisfaction 
question 
 
 
X 
X 
X 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
C-SSRSf,j 
X 
X 
X 
X 
X 
X 
 


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Screening Baseline Double-blind Treatment Period 
Safety 
Follow-
up 
Visit Week 
(Study Day) 
-4 
0 
1 
(Day 
7) 
2 
(Day 
14) 
3 
(Day 
21) 
4/EOT 
(Day 
28) 
8 l 
(Day 58) 
Visit Number 
1 
2 
3 
4 
5 
6/ET 
7 
Visit window (days) 
0 
0 
±3 
±3 
±3 
±3 
±4 
Type of Visit 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Clinic 
Telephone 
Assessment of adverse events 
X 
X 
X 
X 
X 
X 
X 
Study drug accountability 
 
 
X 
X 
X 
X 
 
Abbreviations: CGI-I=Clinical Global Impression-Improvement; CGI-S=Clinical Global Impression-Severity; C-
SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; EOT=end of treatment; ET=early 
termination; HVLT-R=Hopkins Verbal Learning Test-Revised; MDS UPDRS=Movement Disorders Society 
Unified Parkinson’s Disease Rating Scale; MMSE=Mini-Mental State Examination; PD NMS=Parkinson’s 
Disease Non-motor Symptoms; PGI-I=Patient Global Impression-Improvement  
a 
Training on the handheld device and actigraph may be done on the first day of Screening but must take place at 
least 7 days before the Baseline visit. 
b 
Measurement of weight and BMI are required at Screening and Baseline; measurement of weight (not BMI) is 
required at Week 4/EOT.  
c 
The ECG will be completed in triplicate at Visit 1 (Screening) and collected within an approximately 5-minute 
period. A single ECG tracing should be completed at all other designated visits.  
d 
A pregnancy test is only required for women of childbearing potential. Serum pregnancy should only be 
performed at Visit 1 (Screening); a urine pregnancy test should be performed at Baseline and EOT visits. If 
urine cannot be obtained in women of childbearing potential, a serum pregnancy test should be done. 
e 
Subjects will be assessed for their ability to swallow a test capsule (i.e., placebo). 
f 
This clinician-administered assessment should be conducted at least one hour after dosing when conducted at 
Weeks 1-4. The Baseline clinician-administered assessments should be conducted prior to dosing. 
g 
The site staff must observe the subject for a minimum of 60 minutes in the clinic after dosing. Subjects should 
not take study drug on the mornings of clinic visit days until instructed to do so by the site staff. 
h 
Baseline handheld device data will be collected during the 7-day period before the Baseline visit. Assessments 
completed on the handheld device should not be done on the days of clinic visits. See Table 2 and Table 3 for 
further details on the assessments for the handheld device.  
i 
Baseline actigraphy data will be collected during the 7-day period before the Baseline visit. The handheld 
device is to be brought with the subject for the clinic visits at Visit 2 (Baseline), Visit 3 (Week 1), Visit 4 (Week 
2), Visit 5 (Week 3), and Visit 6 (Week 4). Site staff are to review completion of assessments on the handheld 
device and use of actigraph at Visit 3 (Week 1), Visit 4 (Week 2), Visit 5 (Week 3), and Visit 6 (Week 4). 
j 
The Baseline/Screening version of the C-SSRS will be administered at Screening, and the “Since Last Visit” 
version of the C-SSRS will be administered at all other designated visits. 
k 
Urine drug screen at Visit 2 (Baseline) can be performed at the clinical site for rapid results to qualify the 
subject for study drug administration or exclude the subject without dosing. 
l 
The safety follow-up visit is to occur 30 (±4) days after the last dose of study drug. 
 


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Table 7 
Schedule of Assessments for Subjects on the Handheld Device (EMAs) 
Three Times Each Week 
Weekly 
Sleep Assessments 
PROMIS 
Cognitive 
Function 
Satisfaction 
Question 
Nighttime 
Sleepb 
Sleep-Related 
Impairment 
Karolinska 
Sleepiness 
Scale (KSS) 
9 am ± 2 hoursa 
X 
X 
X 
X 
X 
2 pm ± 2 hours 
 
X 
X 
X 
 
7 pm ± 2 hours 
 
X 
X 
X 
 
Abbreviations: PROMIS=Patient-Reported Outcomes Measurement Information System 
Note: Assessments completed on the handheld device should not be done on the days of clinic visits. It is 
recommended that assessments on the handheld device be done on the first, third and fifth days 
following clinic visits (except Visit 6, the last visit); however, flexibility is permitted as long as assessments 
are completed 3 times each week. 
a 
Testing should be completed at least 1 hour after the daily administration of study drug. If subject does not 
complete morning assessment, then no assessments can be completed that day. 
b 
Questions related to nighttime sleep will be asked only at the morning assessment. 
 
Table 8 
Schedule of Assessments for Informants on the Handheld Device (EMAs) 
 
Three Times Each Week 
Weekly 
 
Sleep Assessments 
PROMIS 
Cognitive 
Function 
Satisfaction 
Question 
Nighttime Sleepb 
Sleep-Related 
Impairment 
9 am ± 2 hoursa 
X 
X 
 
X 
7 pm ± 2 hours 
 
X 
X 
 
Abbreviations: PROMIS=Patient-Reported Outcomes Measurement Information System 
Note: Assessments completed on the handheld device should not be done on the days of clinic visits. It is 
recommended that assessments on the handheld device be done on the first, third and fifth days 
following clinic visits (except Visit 6, the last visit); however, flexibility is permitted as long as assessments 
are completed 3 times each week. 
a  
Testing should be completed at least 1 hour after the subject’s daily administration of study drug. 
b  
Questions related to nighttime sleep will be asked only at the morning assessment.