Clinical trial NCT03037203
Conditions: Excessive Sleepiness Parkinson Disease
Sponsor: Jazz Pharmaceuticals
Start date: 2017-01-01; Completion date: 2018-08-01
Enrollment: 66 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study is a 4-week, multicenter, randomized, double-blind, placebo-controlled, ascending dose, 4-period crossover study designed to evaluate the safety, tolerability, efficacy, and PK of JZP-110 (75, 150, and 300 mg) in the treatment of excessive sleepiness in adult subjects with idiopathic PD.

Detailed description:

Arms: arm 1: JZP-110 and Placebo arm 2: JZP-110 and Placebo arm 3: Placebo
Interventions: intervention 1: JZP-110 intervention 2: Placebo
Intervention descriptions: intervention 1: 75 mg, 150 mg, 300 mg intervention 2: None

Protocol documents:
Prot_000.pdf: 
Signature Date: 20180129
JP: JZP166-201 Protocol Amendment 2.pdf
Signature Date:
JP: JZP166-201 Protocol Amendment 2.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: JZP166-201 Amendment 2 
 
 
 
 
 
 
 
 
 Clinical Trial Protocol: JZP166-201 
Study Title: 
A 4-Week, Double-blind, Placebo-controlled, Randomized, 
Multicenter, Crossover Study of the Safety, Efficacy, and 
Pharmacokinetics of JZP-110 [(R)-2-amino-3-phenylpropylcarbamate 
hydrochloride] in Subjects with Parkinson’s Disease and Excessive 
Sleepiness 
Study Phase: 
2 
Product Name: 
JZP-110 
IND Number: 
132,121 
Indication: 
Excessive sleepiness in adult patients with Parkinson’s disease 
Investigators: 
Multicenter 
Sponsor: 
Jazz Pharmaceuticals 
3170 Porter Drive 
Palo Alto, CA 94304 
Tel: (650) 496-3777 
 
Original Protocol: 
28 September 2016  
Amendment 1: 
29 March 2017 
Amendment 2: 
26 January 2018  
 
Confidentiality Statement 
The information in this document is Jazz Pharmaceuticals confidential information. This 
material may be used only for evaluating or conducting clinical investigations; any other 
proposed use requires written consent from Jazz Pharmaceuticals. Acceptance of this 
document constitutes an agreement by the recipient(s) that no unpublished information 
contained herein will be published or disclosed without first obtaining written approval from 
Jazz Pharmaceuticals. This document may be disclosed to appropriate Investigational Review 
Boards/Ethics Committees under the condition of confidentiality. 
 
 
This study will be conducted under Good Clinical Practice guidelines. 
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Jazz Pharmaceuticals 
Clinical Trial Protocol: JZP166-201 Amendment 2 
 
 
 
 
 
 
 
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SYNOPSIS 
SPONSOR 
Jazz Pharmaceuticals 
PRODUCT 
JZP-110 [(R)-2-amino-3-phenylpropylcarbamate 
hydrochloride] 
TITLE 
A 4-Week, Double-blind, Placebo-controlled, Randomized, 
Multicenter, Crossover Study of the Safety, Efficacy, and 
Pharmacokinetics of JZP-110 [(R)-2-amino-3-
phenylpropylcarbamate hydrochloride] in Subjects with 
Parkinson’s Disease and Excessive Sleepiness 
STUDY NUMBER 
JZP166-201 
STUDY PHASE 
Phase 2 
LOCATION 
This trial will be conducted at approximately 25 sites in the 
United States. 
PRIMARY 
OBJECTIVE 
The primary objective of the study is to evaluate the safety and 
tolerability of JZP-110 in the treatment of excessive sleepiness 
in adult subjects with Parkinson’s disease (PD). 
SECONDARY 
OBJECTIVES 
The secondary objectives of the study are as follows: 
• To evaluate the efficacy of JZP-110 in the treatment of 
excessive sleepiness, as measured by the ESS, in adult 
subjects with PD  
• To characterize the pharmacokinetics (PK) of JZP-110 in 
subjects with PD  
EXPLORATORY 
OBJECTIVES 
Exploratory objectives of the study are to evaluate the effect of 
JZP-110 on mean sleep latency, as measured by the MWT (in a 
subpopulation); and the effect of JZP-110 on motor function 
and nonmotor symptoms (i.e., fatigue, apathy, and cognition) 
(in all subjects). 
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Clinical Trial Protocol: JZP166-201 Amendment 2 
 
 
 
 
 
 
 
CONFIDENTIAL 
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DESIGN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This study is a 4-week, multicenter, randomized, double-blind, 
placebo-controlled, ascending dose, 4-period crossover study 
designed to evaluate the safety, tolerability, efficacy, and PK 
of JZP-110 (75, 150, and 300 mg) in the treatment of excessive 
sleepiness in adult subjects with idiopathic PD. Depending on 
study center capabilities, subjects will have the option of 
enrolling into 1 of 2 groups: Group 1 and Group 2. Subjects 
enrolled in Group 1 will undergo both objective (Maintenance 
of Wakefulness Test [MWT]) and subjective (Epworth 
Sleepiness Scale [ESS]) assessments of sleepiness. Subjects 
enrolled in Group 2 will undergo only the subjective (ESS) 
assessment of sleepiness. Following completion of the 
Screening and Baseline visits, approximately 49 eligible 
subjects will be randomly assigned (3:3:1) to 1 of 3 treatment 
sequences in order to have approximately 34 subjects complete 
Treatment Sequences A and B, and 6 subjects complete 
Treatment Sequence C. There will be no stratification based on 
group. 
Treatment 
Sequence 
Period  
1 
Period 
2 
Period 
3 
Period 
4 
Week 1 
Week 2 
Week 3 
Week 4 
A 
(n=21) 
Placebo 
JZP-110 
75 mg 
JZP-110 
150 mg 
JZP-110 
300 mg 
B 
(n=21) 
JZP-110 
75 mg 
JZP-110 
150 mg 
JZP-110 
300 mg 
Placebo 
C 
(n=7) 
Placebo 
Placebo 
Placebo 
Placebo 
 
During the first 6 days of each treatment period, subjects will 
take once-daily, oral doses of study drug (placebo, 75, 150, or 
300 mg JZP-110) with water at home, without regard to food, 
and within 1 hour of awakening in the morning (at 
approximately the same time each day). If a subject fails to 
take the study drug within an hour of awakening, the subject 
should be instructed to take the study drug, if he/she is able to 
do so, at least 12 hours before his/her anticipated bedtime. If 
the subject cannot take the study drug at least 12 hours before 
his/her anticipated bedtime, the subject should not take the 
study drug for that day. Subjects should take their PD 
medications and sleep medications allowed by the protocol as 
per their usual schedule each day.  
On the last day of each treatment period (i.e., Days 7, 14, 21, 
and 28), subjects will take their usual PD medications and 
sleep medications allowed by the protocol as per their usual 
schedule, and return to the study center where they will take 
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Clinical Trial Protocol: JZP166-201 Amendment 2 
 
 
 
 
 
 
 
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their dose of study drug for that day and undergo assessments 
for efficacy, safety, and tolerability (Visits 3, 4, 5, and 6).  
Subjects will take their study drug with water in the morning at 
the study clinic after predose assessments are completed. 
Subjects may be served a light meal at 15 minutes after dosing. 
Pending the investigator’s assessment of safety and 
tolerability, subjects will proceed to the next treatment period. 
Subjects who do not tolerate the study drug will be considered 
for early termination (at the discretion of the investigator). 
Subjects will receive their last dose of study drug at Visit 6 
(Day 28) prior to the Week 4 visit assessments. Subjects will 
return for a Safety Follow-up visit (Visit 7) approximately 
7 days after the last dose of study drug for follow-up safety 
assessments. Unless there are outstanding safety issues that 
require additional follow-up, subjects will be discharged from 
the study at the Safety Follow-up Visit (Visit 7). 
Safety and tolerability will be assessed throughout the study 
and will include the following: monitoring of adverse events 
(AEs), discontinuations due to AEs, changes in physical 
examination findings, electrocardiograms (ECGs), clinical 
laboratory tests, vital sign measurements (including measuring 
seated and standing blood pressure), and change in response to 
the Columbia-Suicide Severity Rating Scale (C-SSRS) at each 
visit. 
Efficacy will be assessed by the change from baseline in the 
ESS score, and for subjects who enroll in Group 1 and subjects 
who enrolled prior to Amendment 2, by the change from 
baseline in mean sleep latency time as objectively measured 
using either 3 or 4 trials of the MWT. 
Exploratory efficacy assessments will include changes in 
scores from baseline and/or the percentages of subjects 
improved, as applicable, on the Clinical Global Impression of 
Change (CGIc), Patient Global Impression of Change (PGIc), 
Fatigue Severity Scale (FSS), Apathy Scale, and Scales for 
Outcomes in Parkinson's disease-cognition (SCOPA-cog). 
Parkinson’s disease clinical status (i.e., motor fluctuations, 
dyskinesia, and motor function) will be assessed using the 
Movement Disorders Society-Unified Parkinson’s Disease 
Rating Scale (MDS-UPDRS) Parts III and IV.  
In addition, subjects who enrolled in the study prior to 
Amendment 2 implementation would have participated in the 
PK evaluation. Blood samples for PK analysis were to be 
collected from each subject at predose and at 1, 2, 3, 4, 5, and 6 
hours after dosing at Visits 3, 4, 5, and 6. A sample was also 
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Clinical Trial Protocol: JZP166-201 Amendment 2 
 
 
 
 
 
 
 
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collected any time between 7 to 8 hours after dosing, as 
feasible, at each visit.  
ESTIMATED 
DURATION OF 
STUDY 
The estimated duration of the study is approximately 9 weeks 
including up to 30 days for the screening and baseline 
procedures, 4 weeks (28 days) for the Double-blind Treatment 
Phase, and approximately 7 days for the Follow-up Phase.  
STUDY POPULATION 
Subjects must have a diagnosis of idiopathic PD according to 
the United Kingdom (UK) Parkinson’s Disease Society (PDS) 
Brain Bank Criteria and excessive sleepiness as demonstrated 
by subjective (ESS) criteria. Approximately 49 subjects will be 
enrolled with the goal of 40 subjects completing the study.  
DIAGNOSIS AND 
MAIN CRITERIA FOR 
INCLUSION 
Inclusion Criteria 
Each subject must meet the following criteria to be enrolled in 
the study. 
1. Willing and able to provide written informed consent. 
2. Males and females ≥35 and ≤80 years of age at the time of 
consent. 
3. Diagnosis of idiopathic PD according to the UK PDS Brain 
Bank Criteria. NOTE: Having >1 affected relative is not 
exclusionary for diagnosis of idiopathic PD for purposes of 
this protocol. 
4. Hoehn and Yahr stage 1, 2, or 3 (see Part III in 
Appendix 14). 
5. Must be on a stable treatment regimen for PD including 
dopaminergic therapy, monoamine oxidase B (MAO-B) 
inhibitors, COMT inhibitors, amantadine, and medications 
for treatment of non-motor symptoms including depression, 
for at least 4 weeks prior to screening, with no anticipated 
need to adjust these medications for the study duration. 
Amantadine use is not allowed if used solely for the 
treatment of excessive sleepiness. 
6. ESS score >11 at both Screening and Baseline visits. Any 
subject who is on a wake promoting agent or stimulant at 
screening will only have to meet the ESS score >11 
requirement at the Baseline visit, after they have washed 
out of their wake promoting agent or stimulant (see 
Section 5.7).  
7. This criterion was removed in Amendment 2.  
8. Body mass index ≥17 and ≤40 kg/m2. 
9. Consent to use a medically acceptable method of 
contraception for at least 2 months prior to the first dose of 
study drug, throughout the entire study period, and for 
30 days after the study is completed (see Section 4.3 for 
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medically acceptable methods). 
10. Willing and able to comply with the study design schedule, 
all study procedures, and other requirements. 
11. This criterion was removed in Amendment 2. 
Exclusion Criteria 
Subjects who demonstrate any of the following criteria will be 
excluded from the study. 
1. Diagnosis of other degenerative Parkinsonian syndromes 
(e.g., progressive supranuclear palsy, multiple system 
atrophy [MSA], or dementia with Lewy bodies [DLB]). 
2. Prior use of or planned use during the study of 
neurostimulation methods including deep brain stimulation 
(DBS). 
3. Female subjects who are pregnant, nursing, or lactating. 
4. Usual nightly time in bed of <6 hours, including the night 
before the Baseline visit. 
5. Occupation requiring nighttime or variable shift work. 
6. This criterion was removed during Amendment 1. 
7. Diagnosis of narcolepsy by history or in the judgement of 
the investigator. 
8. Any other clinically relevant medical, behavioral, or 
psychiatric disorder other than PD that is associated with 
excessive sleepiness (e.g., narcolepsy, inadequately 
controlled rapid eye movement sleep behavior disorder 
[RBD], and inadequately controlled restless leg syndrome 
[RLS] or periodic limb movement disorder [PLMD]) by 
history or in the judgment of the investigator. 
9. History or presence of bipolar disorder, bipolar-related 
disorders, schizophrenia, schizophrenia spectrum disorders, 
or other psychotic disorders according to Diagnostic and 
Statistical Manual of Mental Disorders, Fifth Edition 
(DSM-5) criteria or severe depression, or a BDI-2 score of 
>28. 
10. History or presence of any acutely unstable medical 
condition, malignancy other than basal cell carcinoma or 
resected noninvasive cutaneous squamous cell carcinoma, 
behavioral or psychiatric disorder (including active suicidal 
ideation), or surgical history that could affect the safety of 
the subject or interfere with study efficacy or safety 
assessments; or the ability of the subject to complete the 
trial per the judgment of the investigator. 
11. History of bariatric surgery within the past year, history of 
roux-en-Y procedure, or history of any gastric bypass 
procedure. 
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12. Presence of renal impairment or calculated creatinine 
clearance <60 mL/min by Cockcroft-Gault formula. 
13. Clinically significant ECG abnormality or a QTcF interval 
of >450 msec for males and >470 msec for females at 
screening as assessed by the principal investigator.   
14. Presence of significant cardiovascular disease at screening 
including but not limited to the following: myocardial 
infarction within the past year; unstable angina pectoris; 
symptomatic congestive heart failure (American College of 
Cardiology/American Heart Association stage C or D); 
revascularization procedures within the past year; 
ventricular cardiac arrhythmias requiring automatic 
implantable cardioverter defibrillator or medication 
therapy; uncontrolled hypertension, or systolic blood 
pressure ≥155 mmHg or diastolic blood pressure 
≥95 mmHg (at screening, or consistently across baseline 
measures according to protocol specifications); or any 
history of cardiovascular disease or any significant 
cardiovascular condition that in the investigator’s opinion 
may jeopardize subject safety in the study. 
15. History of cerebrovascular accident. 
16. This criterion was removed in Amendment 2. 
17. Laboratory value(s) at screening outside the laboratory 
reference range that is (are) considered to be clinically 
significant by the investigator (clinical chemistry, 
hematology, and urinalysis). NOTE: Screening laboratory 
tests may be repeated 1 time. 
18. Excessive caffeine use 1 week prior to baseline 
assessments or anticipated excessive use during the study 
defined as >600 mg/day of caffeine (refer to the list of 
caffeinated beverages in Appendix 7). 
19. Use of neurostimulants including any over-the-counter 
(OTC) (eg, pseudoephedrine) or prescription medications 
(eg, amphetamines or dextroamphetamines [eg, Adderall], 
modafinil, armodafinil, or methylphenidate) within 14 days 
prior to the Baseline visit or planned use at any time during 
the study.  
20. Use of diphenhydramine or sodium oxybate (ie, Xyrem) 
within 14 days prior to the Baseline visit or at any time 
during the study. 
21. Use of any other medications, that in the opinion of the 
investigator, could affect the evaluation of excessive 
sleepiness within 14 days prior to the Baseline visit or 
planned use at any time during the study. 
22. Use of trazodone, benzodiazepines, nonbenzodiazepines 
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(e.g., zolpidem, zaleplon, or eszopiclone), suvorexant, or 
melatonin receptor agonists for insomnia unless the subject 
has been on a stable daily regimen for 14 days prior to the 
Baseline visit and will continue this regimen during the 
study. 
23. Use of parenteral dopaminergic therapy within 14 days of 
the Baseline visit or planned use at any time during the 
study. 
24. Received an investigational drug 30 days or 5 half-lives 
prior to the Baseline visit (whichever is longer), or plans to 
use an investigational drug (other than the study drug) 
during the study. 
25. Current or past (within the past 2 years) diagnosis of a 
moderate or severe substance use disorder according to 
DSM-5 criteria. 
26. Nicotine dependence that has an effect on sleep (e.g., a 
subject who routinely awakens at night to smoke). In 
addition, subjects who routinely are unable to abstain from 
nicotine products for at least a 24-hour period are excluded. 
27. Current, past (within the past 2 years), or seeking treatment 
for a substance-related disorder. 
28. Urine drug screen positive for drugs of abuse at screening, 
except for a prescribed drug allowed by the protocol (e.g., 
benzodiazepine or opiate) at screening. Cannabinoid use is 
not permitted either recreationally or medically at 
screening or throughout the duration of the study. 
29. History of phenylketonuria (PKU) or history of 
hypersensitivity to phenylalanine-derived products. 
30. Has evidence at screening of severe cognitive impairment 
as defined by a SCOPA-cog score ≤24, or has cognitive 
impairment that in the opinion of the investigator would 
prevent completion of study procedures or the ability to 
provide informed consent. 
31. Evidence at screening of impulse control disorder (ICD) as 
measured by the Questionnaire for Impulsive-Compulsive 
Disorders in Parkinson’s Disease–Rating Scale (QUIP-RS) 
assessment tool (total QUIP-RS score >30 or an individual 
score >10 in any of the individual components of 
gambling, buying, sex, or eating). 
32. Has travelled across at least 3 time zones within a week 
prior to screening or planned travel that would require 
crossing >2 time zones during the study. 
33. This criterion was removed in Amendment 2. 
34. Use of droxidopa within 7 days of the Baseline visit or 
planned use at any time during the study. 
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For subjects with no documented history of moderate or severe 
OSA: 
35. Evidence of moderate or severe OSA as determined by a 
positive score in both Categories 1 and 3 on the Berlin 
Sleep Apnea Questionnaire.  
If the investigator suspects the Berlin result is inaccurate, 
1 of the following may be used to determine eligibility 
instead of the Berlin result: 
a) An in-laboratory nocturnal polysomnography (PSG) 
(Apnea Index >10 events/hour is exclusionary). 
b) Out-of-center sleep test (OCST) (i.e., home sleep test) 
(Apnea Index >10 events/hour is exclusionary). 
c) Overnight pulse oximetry (Oxygen Desaturation Index 
[ODI] >20 events/hour with ≥3% drop in oxygen 
saturation is exclusionary). 
Assessments a through c can be performed either during 
the Screening period or at Visit 2 (Baseline), or can be a 
historical evaluation performed within 12 months of Visit 1 
(Screening) and accompanied by no more than a 
5% increase in the subject’s weight since the evaluation. 
For subjects with a documented history of moderate or severe 
OSA: 
36. Untreated or inadequately treated moderate to severe OSA 
(i.e., Apnea Index >10 events/hour after treatment). 
Subjects who currently use a primary therapy for OSA are 
excluded unless the subject has been stable on their device 
settings for at least 4 weeks prior to Baseline and during 
this time frame demonstrated adequate compliance (use for 
a minimum of 4 hours/night on a minimum of 70% of 
nights). 
TEST PRODUCT, 
DOSE, AND MODE OF 
ADMINISTRATION 
JZP-110 [(R)-2-amino-3-phenylpropylcarbamate 
hydrochloride] will be supplied as 75, 150, and 300 mg tablets 
that will be over-encapsulated in identical opaque gelatin 
capsules. The doses of JZP-110 will be based on the free base 
of the molecule. Subjects will receive 75, 150, or 300 mg 
tablets, each over-encapsulated. On Days 1 to 6 of each 
treatment period, subjects will be instructed to take the 
assigned daily dose of study drug (1 capsule) with water at 
home, without regard to food, and within 1 hour of awakening 
in the morning (at approximately the same time each day). At 
each study visit (Days 7, 14, 21, and 28), subjects will take 
their study drug (1 capsule) with water in the morning at the 
study clinic. Subjects may be served a light meal at 15 minutes 
after dosing.  
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Clinical Trial Protocol: JZP166-201 Amendment 2 
 
 
 
 
 
 
 
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REFERENCE 
THERAPY, DOSE, 
AND MODE OF 
ADMINISTRATION 
Placebo tablets will be over-encapsulated in opaque gelatin 
capsules that will be identical to the active JZP-110 treatments. 
Mode of administration will be the same as for the test product 
above. 
DURATION OF 
TREATMENT 
The treatment duration for each subject will be approximately 
4 weeks. 
EFFICACY 
ENDPOINTS 
The following key efficacy endpoint is defined in terms of 
change from study baseline (prior to first dose in Period 1) to 
the end of each Treatment Period (Days 7, 14, 21, and 28): 
• Change from Baseline in ESS score   
EXPLORATORY 
ENDPOINTS 
Exploratory efficacy endpoints: 
• Change from Baseline in the mean sleep latency time (in 
minutes), as determined from the 40-minute MWT 
• Change from Baseline in MDS-UPDRS Parts III and IV 
scores 
• CGIc score and percentage of subjects reported as 
improved (minimally, much, or very much) 
• PGIc score and percentage of subjects reported as 
improved (minimally, much, or very much)  
• Change from Baseline in FSS score 
• Change from Baseline in Apathy Scale score 
• Change from Baseline in SCOPA-cog score 
PHARMACOKINETIC 
ASSESSMENTS 
For subjects who enroll in the study prior to Amendment 2 
implementation, the PK profile of JZP-110 will be evaluated 
over an 8-hour period based on blood samples (4 mL) collected 
at predose and at 1, 2, 3, 4, 5, and 6 hours after dosing at 
Visits 3, 4, 5, and 6. A sample was also collected 7 to 8 hours 
after dosing, if feasible, at each visit. The PK parameters to be 
calculated for plasma JZP-110 concentrations will include the 
maximum concentration (Cmax), time to Cmax (Tmax), terminal 
half-life (t1/2), and area under the curve (AUC), as appropriate. 
SAFETY 
ASSESSMENTS 
Safety and tolerability evaluations will consist of 
treatment-emergent adverse events (TEAEs), discontinuations 
due to AEs, and changes in clinical laboratory tests (chemistry, 
hematology, and urinalysis), vital signs (including 
measurement of seated and standing blood pressure), 12-lead 
ECGs, physical exams, and C-SSRS assessments.  
STATISTICAL 
ANALYSIS 
Sample Size 
Approximately 49 subjects will be randomized (3:3:1) to the 
3 sequence groups (A, B, and C) with the goal of 40 subjects 
completing the study: 34 subjects each in Sequences A and B, 
and up to 6 subjects in sequence C. Although the primary 
objective of this study is to assess safety, efficacy 
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endpoint-based power calculations were performed for 
reference. A sample size of 34 subjects (assuming 
17 completing in each of the Sequences A and B) will provide 
80% power to detect a difference of 3 points in the change 
from baseline in ESS score between one of the JZP-110 and 
placebo groups not adjusting for multiple comparisons. This 
calculation assumes a common standard deviation (SD) of 
6 points for the change from baseline in ESS score and a 
2-sided significance level of 0.05 using an analysis of variance 
(ANOVA)-based t-test for difference of means in a crossover 
design.  
The rationale for including Sequence C in the study is to 
preserve study blinding. 
Statistical Analysis 
Safety and tolerability of JZP-110 is the primary objective of 
this study and descriptive statistics of all safety endpoints will 
be presented by treatment. No inferential statistics will be 
provided for safety endpoints.  
For the analysis of the key efficacy endpoint of change from 
baseline in ESS, a mixed-effects model will be used as the 
primary method of analysis. This model will include fixed 
effects for treatment (dose), sequence, treatment-by-sequence 
interaction, and baseline value of the efficacy endpoint. The 
model will also include a random effect for subject within 
sequence. Model-adjusted differences between each active 
treatment dose (75, 150, and 300 mg) and placebo, along with 
95% confidence intervals, will be presented.  
For the analysis of the MWT exploratory endpoint, a similar 
mixed-effects model as for ESS will be used. However, 
because the MWT will be optional and consequently result in a 
reduced sample size, there may be convergence issues 
associated with the mixed-effects model. In the event such 
issues do arise, an analysis of covariance (ANCOVA) model 
without accounting for treatment sequence may be used at each 
visit. 
For the analysis of the efficacy endpoints of improvement in 
PGIc and CGIc scores, chi-square tests will be used to test 
hypotheses of differences between placebo and each active 
dose. A mixed-effects model similar to the model described 
above will be used for the analysis of MDS-UPDRS, FSS, 
Apathy Scale, and SCOPA-cog endpoints. No adjustment for 
multiple testing will be performed.  
Summary statistics for all efficacy assessments will be 
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presented by treatment. As a sensitivity analysis, the efficacy 
endpoint summary may be reported separately for Group 1 and 
Group 2 to address any potential bias.  
Individual plasma JZP-110 concentrations and corresponding 
PK parameters will be listed by treatment. Descriptive statistics 
including the number of subjects, mean, SD, minimum, 
median, maximum, coefficient of variation, geometric mean, 
and geometric SD will be used to summarize concentration 
data and PK parameters by treatment, as appropriate. 
PK/pharmacodynamic modeling may be used to explore 
exposure-response relationships in subjects with PD. 
DATE OF ORIGINAL 
PROTOCOL 
28 September 2016 
DATE OF 
AMENDMENT 1 
29 March 2017 
DATE OF 
AMENDMENT 2 
26 January 2018  
 
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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................2 
TABLE OF CONTENTS .........................................................................................................13 
LIST OF IN-TEXT TABLES ..................................................................................................17 
LIST OF IN-TEXT FIGURES.................................................................................................17 
LIST OF APPENDIXES..........................................................................................................17 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................19 
1 
INTRODUCTION ...........................................................................................................22 
1.1 
Study Rationale ......................................................................................................24 
1.2 
Nonclinical Experience ..........................................................................................25 
1.2.1 
Mechanism of Action ...................................................................................25 
1.2.2 
Nonclinical Pharmacokinetics .....................................................................25 
1.2.3 
Toxicology ...................................................................................................26 
1.3 
Clinical Experience ................................................................................................26 
1.3.1 
Clinical Pharmacokinetics and Product Metabolism ...................................26 
1.3.2 
Clinical Efficacy in Subjects with Excessive Sleepiness in Narcolepsy .....27 
1.3.3 
Safety of JZP-110 in Subjects with Excessive Sleepiness in Narcolepsy ...28 
1.3.4 
Safety of JZP-110 in Clinical Studies of Major Depression and in Healthy 
Subjects ........................................................................................................28 
1.3.5 
Human Abuse Liability Assessment ............................................................29 
1.3.6 
Safety Summary ...........................................................................................29 
1.4 
Summary of Potential Benefits and Risks .............................................................29 
2 
STUDY OBJECTIVES ....................................................................................................31 
2.1 
Primary Objective ..................................................................................................31 
2.2 
Secondary Objectives.............................................................................................31 
2.3 
Exploratory Objectives ..........................................................................................31 
3 
STUDY DESIGN.............................................................................................................32 
3.1 
Overall Study Design and Plan ..............................................................................32 
3.2 
Rationale for Study Design and Control Group .....................................................34 
3.3 
Study Duration and Timing ...................................................................................35 
3.4 
End of Study ..........................................................................................................35 
4 
STUDY POPULATION SELECTION ...........................................................................36 
4.1 
Selection of Study Population ................................................................................36 
4.2 
Inclusion Criteria ...................................................................................................36 
4.3 
Exclusion Criteria ..................................................................................................36 
4.4 
Screening and Randomization Eligibility ..............................................................39 
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5 
STUDY TREATMENTS .................................................................................................40 
5.1 
Description of Treatments......................................................................................40 
5.1.1 
JZP-110 ........................................................................................................40 
5.1.2 
Placebo .........................................................................................................40 
5.2 
Treatments Administered .......................................................................................40 
5.3 
Selection and Timing of Dose for Each Subject ....................................................41 
5.4 
Method of Assigning Subjects to Treatment Groups .............................................41 
5.5 
Randomization .......................................................................................................42 
5.6 
Blinding..................................................................................................................42 
5.7 
Prior and Concomitant Therapy .............................................................................42 
5.8 
Restrictions ............................................................................................................43 
5.8.1 
Prior Therapy ...............................................................................................43 
5.8.2 
Fluid and Food Intake ..................................................................................43 
5.8.3 
Other Restrictions ........................................................................................44 
5.9 
Treatment Compliance ...........................................................................................44 
5.10 
Packaging and Labeling .........................................................................................44 
5.11 
Storage and Accountability ....................................................................................44 
6 
STUDY PROCEDURES .................................................................................................46 
6.1 
Informed Consent...................................................................................................46 
6.2 
Demographics ........................................................................................................46 
6.3 
Medical History .....................................................................................................46 
6.4 
Physical Examination.............................................................................................46 
6.5 
Vital Signs ..............................................................................................................46 
6.6 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease – 
Rating Scale ...........................................................................................................47 
6.7 
Beck Depression Inventory-2 ................................................................................47 
6.8 
Columbia-Suicide Severity Rating Scale ...............................................................48 
6.9 
Electrocardiography ...............................................................................................48 
6.10 
Clinical Laboratory Tests .......................................................................................48 
6.10.1 
Laboratory Parameters .................................................................................48 
6.10.2 
Sample Collection, Storage, and Shipping ..................................................51 
6.10.2.1 
Clinical Laboratory Test Samples ......................................................51 
6.10.2.2 
Blood Samples for Pharmacokinetic Analysis ...................................52 
6.11 
Dispensing Study Drug ..........................................................................................52 
6.12 
Efficacy Assessments.............................................................................................52 
6.12.1 
Epworth Sleepiness Scale ............................................................................52 
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6.12.2 
Movement Disorder Society-Unified Parkinson’s Disease Rating Scale – 
Parts III and IV.............................................................................................52 
6.12.3 
Maintenance of Wakefulness Test ...............................................................53 
6.12.4 
Clinician Global Impression of Severity ......................................................53 
6.12.5 
Clinician Global Impression of Change .......................................................53 
6.12.6 
Patient Global Impression of Change ..........................................................54 
6.12.7 
Apathy Scale ................................................................................................54 
6.12.8 
Fatigue Severity Scale..................................................................................54 
6.12.9 
Scales for Outcomes of Parkinson’s Disease-Cognition .............................54 
6.13 
Pharmacokinetic Assessments ...............................................................................54 
6.13.1 
Blood Samples .............................................................................................54 
6.13.2 
Pharmacokinetic Parameters ........................................................................55 
6.14 
Adverse Event Reporting .......................................................................................55 
6.14.1 
Adverse Events ............................................................................................55 
6.14.1.1 
Severity Assessment ..........................................................................56 
6.14.1.2 
Serious Adverse Events .....................................................................56 
6.14.1.3 
Causal Relationship to Study Drug or Procedure ..............................58 
6.14.1.4 
Other Immediately Reportable Experiences ......................................59 
6.14.1.5 
Adverse Event and Serious Adverse Event Recording and Reporting 
Timeframe ..........................................................................................59 
6.14.1.6 
Follow-up of Adverse Events and Serious Adverse Events ..............59 
6.14.2 
Regulatory Reporting ...................................................................................60 
6.14.3 
Pregnancy .....................................................................................................61 
6.14.4 
Emergency Unblinding ................................................................................61 
6.14.5 
Removal of Subjects from the Trial or Study Drug .....................................61 
6.14.6 
Handling of Early Terminations ..................................................................62 
6.14.7 
Jazz Pharmaceuticals’ Termination of Study ...............................................62 
6.15 
Appropriateness of Measurements .........................................................................63 
7 
STUDY ACTIVITIES .....................................................................................................64 
7.1 
Screening/Visit 1 (Days –31 to -3) (For subjects in Both Groups 1 and 2) ...........64 
7.2 
Group 1: Baseline and Treatment Phase Study Activities (Subjects Participating in 
the MWT Component of the Study) ......................................................................65 
7.2.1 
Group 1: Baseline/Randomization/Visit 2 (Day -2 to -1) ............................65 
7.2.2 
Group 1: Treatment Phase (Day 7 [±1 day], Day 14 [±1 day], 
Day 21 [±1 day], and Day 28 [±1 day]) .......................................................67 
7.3 
Group 2: Baseline and Treatment Phase Study Activities (Subjects Opting Out of 
the MWT Component of the Study) ......................................................................69 
7.3.1 
Group 2: Baseline/Randomization/Visit 2 (Day -1) ....................................69 
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7.3.2 
Group 2: Treatment Phase (Day 7 [±1 day], Day 14 [±1 day], 
Day 21 [±1 day], and Day 28 [±1 day]) .......................................................70 
7.4 
Follow-up (Day 35 [±1 day]) (For Subjects in Both Groups 1 and 2) ...................72 
7.5 
Early Termination Visit (For Subjects in Both Groups 1 and 2) ...........................72 
7.6 
Discontinuations ....................................................................................................73 
8 
QUALITY CONTROL AND ASSURANCE .................................................................74 
9 
PLANNED STATISTICAL METHODS ........................................................................75 
9.1 
General Considerations ..........................................................................................75 
9.2 
Tests of Hypotheses and Significance Levels ........................................................75 
9.3 
Determination of Sample Size ...............................................................................75 
9.4 
Analysis Populations ..............................................................................................75 
9.5 
Demographics and Baseline Characteristics ..........................................................76 
9.6 
Handling of Dropouts and Missing Data ...............................................................76 
9.7 
Pooling of Investigation Centers ............................................................................76 
9.8 
Primary Objective ..................................................................................................76 
9.9 
Key Efficacy Endpoint ...........................................................................................76 
9.10 
Exploratory Endpoints ...........................................................................................77 
9.11 
Pharmacokinetic Analysis ......................................................................................77 
9.12 
Efficacy Analysis ...................................................................................................77 
9.13 
Safety Analysis ......................................................................................................78 
9.13.1 
Adverse Events ............................................................................................78 
9.13.2 
Vital Signs ....................................................................................................78 
9.13.3 
Laboratory Evaluation .................................................................................79 
9.13.4 
12-Lead Electrocardiograms ........................................................................79 
9.13.5 
Physical Examinations .................................................................................80 
9.13.6 
Columbia-Suicide Severity Rating Scale .....................................................80 
9.14 
Analysis of Pharmacokinetic and Pharmacodynamic Variables ...........................80 
9.15 
Subgroup Analyses ................................................................................................80 
9.16 
Interim Analysis and Data Monitoring ..................................................................81 
10 DATA QUALITY ASSURANCE ...................................................................................82 
10.1 
Clinical Data Management ....................................................................................82 
10.2 
Electronic Case Report Forms ...............................................................................82 
10.3 
Retention of Data ...................................................................................................82 
10.4 
Data Safety Monitoring Board ...............................................................................82 
11 ADMINISTRATIVE CONSIDERATIONS ....................................................................83 
11.1 
Investigators and Study Administrative Structure .................................................83 
11.1.1 
Contract Research Organization ..................................................................83 
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11.1.2 
Contract Research Organization’s Medical Monitor ...................................83 
11.1.3 
Jazz Pharmaceuticals’ Medical Monitor ......................................................83 
11.1.4 
Bioanalytical Laboratory .............................................................................83 
11.2 
Ethics Committee Approval ...................................................................................83 
11.3 
Ethical Conduct of the Study .................................................................................84 
11.4 
Subject Information and Consent...........................................................................84 
11.5 
Subject Confidentiality ..........................................................................................85 
11.6 
Protocol Adherence – Amendments ......................................................................85 
11.7 
Required Documents ..............................................................................................85 
11.8 
Study Monitoring ...................................................................................................85 
11.9 
Protocol Violations/Deviations ..............................................................................86 
11.10 Access to Source Documentation ..........................................................................86 
11.11 Publication and Disclosure Policy .........................................................................86 
12 REFERENCE LIST .........................................................................................................87 
 
LIST OF IN-TEXT TABLES 
Table 1  
  List of Laboratory Tests .............................................................................50 
Table 2 
Schedule of Clinical Laboratory Samples and Estimated Blood Volume ...51 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
 JZP166-201: Study Schema ........................................................................34 
 
 LIST OF APPENDIXES 
Appendix 1 
Group 1: Schedule of Events .............................................................92 
Appendix 2 
Group 1: Example Time Schedule for Procedures During the 
                        Baseline Visit....................................................................................94 
Appendix 3 
Group 1: Example Time Schedule for Procedures at Visits 3, 4, 5, or 
                        6..........................................................................................................95 
Appendix 4 
Group 2: Schedule of Events .............................................................97 
Appendix 5 
Group 2: Example Time Schedule for Procedures During the 
                        Baseline Visit ....................................................................................99 
Appendix 6 
Group 2: Example Time Schedule for Procedures at Visits 3, 4, 5, or 
                        6........................................................................................................100 
Appendix 7 
Caffeine Content of Beverages ........................................................101 
Appendix 8 
Berlin Sleep Apnea Questionnaire ...................................................102 
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Appendix 9 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s   
 
Disease Rating Scale ........................................................................104 
Appendix 10 
Beck Depression Inventory-2 Questionnaire ...................................106 
Appendix 11 
Columbia-Suicide Severity Rating Scale Baseline/Screening  
 
Version .............................................................................................109 
Appendix 12 
Columbia-Suicide Severity Rating Scale Since Last Visit Version .113 
Appendix 13 
Epworth Sleepiness Scale ................................................................117 
Appendix 14 
Movement Disorders Society-Unified Parkinson’s Disease Rating  
 
Scale Parts III and IV .......................................................................119 
Appendix 15 
Clinical Global Impression of Severity............................................134 
Appendix 16 
Clinical Global Impression of Change .............................................136 
Appendix 17 
Patient Global Impression of Change ..............................................138 
Appendix 18 
Apathy Scale ....................................................................................140 
Appendix 19 
Fatigue Severity Scale......................................................................143 
Appendix 20 
Scales for Outcomes in Parkinson's Disease-Cognition ..................145 
Signatures of Agreement for Protocol .............................................................................152 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADL 
Activities of daily living  
AE 
Adverse event 
ALT 
Alanine aminotransferase (SGPT) 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
AST 
Aspartate aminotransferase (SGOT) 
AUC 
Area under the concentration-time curve 
BDI-2 
Beck Depression Inventory-2 
βHCG 
Βeta human chorionic gonadotropin 
CFR 
Code of Federal Regulations 
CGIc 
Clinical Global Impression of change 
CGIs 
Clinical Global Impression of severity 
cGMP 
Good Manufacturing Practices 
CL/F 
Apparent oral clearance 
Cmax 
Maximum concentration 
CNS  
Central nervous system 
C-SSRS 
Columbia-Suicide Severity Rating Scale  
CYP 
Cytochrome P450 
DBS 
Deep brain stimulation  
DLB 
Dementia with Lewy bodies 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ESS 
Epworth Sleepiness Scale 
FDA 
Food and Drug Administration 
FSH 
Follicle stimulating hormone 
FSS 
Fatigue Severity Scale 
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GCP 
Good Clinical Practice 
ICD 
Impulse control disorder  
ICF 
Informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IRB 
Institutional Review Board 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
MAO-B 
Monoamine oxidase B 
MCC 
Microcrystalline cellulose 
MDD 
Major depressive disorder 
MDS-UPDRS 
Movement Disorders Society-Unified Parkinson’s Disease Rating Scale  
MI 
Myocardial infarction 
mITT 
Modified Intent-to-treat 
MSA 
Multiple system atrophy 
MWT 
Maintenance of Wakefulness Test 
OCST 
Out-of-center sleep test 
ODI 
Oxygen Desaturation Index 
OSA 
Obstructive Sleep Apnea 
OTC 
Over the counter 
RBD 
Rapid eye movement behavioral disorder 
RLS 
Restless leg syndrome 
PD 
Parkinson’s disease 
PGIc 
Patient Global Impression of change 
PK 
Pharmacokinetic(s) 
PKU 
Phenylketonuria 
PLMD 
Periodic limb movement disorder  
PSG 
Polysomnography 
QTcF 
Q-T interval corrected for heart rate using Fridericia’s formula 
QUIP-RS 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s 
Disease–Rating Scale 
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SAE 
Serious adverse event 
SCOPA-cog 
Scales for Outcomes in Parkinson's disease-cognition 
SD 
Standard deviation 
t1/2 
Half-life 
TEAE 
Treatment-emergent adverse event 
Tmax 
Time to maximum concentration 
UGT 
Uridine diphosphate glucuronosyltransferase 
UK 
United Kingdom 
UK-PDS 
United Kingdom-Parkinson’s Disease Society 
ULN 
Upper limit of normal 
US 
United States 
Vd/F 
Apparent oral volume of distribution  
 
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1 
INTRODUCTION 
JZP-110 [(R)-2-amino-3-phenylpropylcarbamate hydrochloride] is a phenylalanine derivative 
(previously known as ADX-N05, R228060, and YKP10A) that is currently being 
investigated as a potential treatment for excessive sleepiness in narcolepsy and obstructive 
sleep apnea (OSA). Nonclinical data indicate that JZP-110 is a wake-promoting agent that 
lacks the noradrenergic releasing effects of amphetamines (EDMS PSDB-4956838, 
EDMS-PSDB-2735318, EDMS-PSDB-5305783) and does not produce rebound hypersomnia 
in rodent models (Hasan et al. 2009). Pharmacologically, JZP-110 appears to be a 
low-potency reuptake inhibitor at dopamine and norepinephrine transporters. 
JZP-110 was originally synthesized by SK Life Science (South Korea). The molecule has 
been under development for the treatment of depression and for the treatment of excessive 
sleepiness in narcolepsy under various sponsors. Jazz Pharmaceuticals intends to complete 
development of JZP-110 for the treatment of excessive sleepiness in adult patients with 
narcolepsy and in adult patients with OSA by demonstrating increased ability to stay awake 
throughout the day using the validated Maintenance of Wakefulness Test (MWT) and 
decreased subjective sleepiness using the Epworth Sleepiness Scale (ESS).  
Parkinson’s disease (PD) is a chronic neurodegenerative brain disorder for which no cure has 
been identified. According to Decision Resources 2015, there were 926,000 patients with PD 
in the United States (US) in 2014 (or 4.7 cases per 1000) (Christmann et al. 2015). Due, in 
part, to the aging of the population, the prevalence of PD is estimated to increase 
approximately 2.7% per year through 2029, yielding 1.37 million in 2029. Parkinson’s 
disease is characterized by progressive loss of nigrostriatal dopaminergic neurons that 
clinically results in motor symptoms such as bradykinesia, rigidity, resting tremor, and 
postural instability (Halliday & McCann, 2010). Postmortem studies suggest that 30% to 
50% of dopaminergic cell bodies are lost in the substantia nigra at the time motor symptoms 
appear (Cheng et al. 2010; Ishibashi et al. 2014) and imaging studies of patients with PD 
have shown decreased dopamine transporter levels beginning in the posterior putamen 
(Ishibashi et al. 2014). Although the etiology of PD is unclear, it is thought to involve both 
genetic and environmental factors.  
In addition to motor symptoms, most patients with PD experience clinically significant 
nonmotor symptoms such as changes in mood, memory, blood pressure, bowel and bladder 
function, sleep, fatigue, weight, and sensation. Several lines of evidence suggest that sleep 
disturbances are common and can adversely affect quality of life of patients as well as their 
caregivers; however, sleep disturbances are often not diagnosed and consequently are often 
untreated (Shulman et al. 2002; Karlsen et al. 1999; Weerkamp et al. 2013). Sleep 
disturbances in PD include the following: insomnia, rapid eye movement behavioral disorder 
(RBD), sleep apnea, restless legs syndrome/periodic limb movement disorder, and excessive 
sleepiness (for review see Videnovic and Golombek 2013). In a large multicenter survey of 
nonmotor symptoms of 1072 PD patients, 21.2% of patients complained of excessive 
sleepiness, 36.9% referred insomnia, 29.6% suffered from behavioral sleep disturbances, and 
15.2% from restless legs syndrome (Barone et al. 2009). Further, in a Food and Drug 
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Administration (FDA) patient-focused report that gathered perspectives from PD patients, 
caretakers and other patient representatives, over one-third of participants identified sleep 
disturbances as 1 of their most significant symptoms that impacts daily life 
(FDA Parkinson’s Disease Public Meeting 2015). 
In particular, excessive sleepiness can affect 20% to 50% of patients with PD (Knie 2011; 
Arnulf 2005) and is more frequent in these patients than in age-matched healthy subjects 
(Tandberg et al. 1999; Brodsky et al. 2003). Although excessive sleepiness is observed at all 
levels of PD severity, studies have shown that disease pathology is an important contributor 
of excessive sleepiness (Knie 2011). For instance, in a population-based prevalence study, 
the frequency rate of excessive sleepiness increased from 6% at baseline to 41% after 8 years 
(Gjerstad et al. 2006). In addition, the pathophysiology of excessive sleepiness is 
multifactorial and might be due to the degeneration of the nigrostriatal dopaminergic system 
and other nondopamine neurons involved in sleep-wake regulation as well as secondary 
mechanisms such as other disorders (e.g. OSA, depression) and use of anti-parkinsonian 
medication (Videnovic and Golombek 2013). For instance, commonly prescribed dopamine 
agonists may contribute to excessive sleepiness (Paus et al. 2003). However, 1 study 
demonstrated that the frequency of excessive sleepiness was similar between PD patients 
regardless of dopamine agonist treatment (Gjerstad et al. 2006). Other studies suggest that 
excessive sleepiness may potentially predate PD (Gao et al. 2011; Abbott et al. 2005). For 
example, in a large epidemiological aging study, there was more than a 3-fold increase in the 
risk of developing PD in elderly men with excessive sleepiness that could not be accounted 
for by any other factor (Abbott et al. 2005). Taken together, these data indicate that 
sleepiness may exist, albeit to a lesser degree, before the onset of Parkinsonism and before 
the use of dopamine agents, suggesting that other, disease-dependent factors contribute to the 
sleepiness (Arnulf & Leu-Semenescu 2009; Knie 2011; Gjerstad 2002; Gjerstad et al. 2006). 
Evidence-based guidelines by The Quality Standards Subcommittee of the American 
Academy of Neurology state that there is an urgent need to evaluate drugs to treat the 
nonmotor symptoms, including excessive sleepiness, in PD in controlled clinical trials 
(Zesiewicz et al. 2010). Although there are no currently approved medications to improve 
wakefulness and to treat excessive sleepiness in PD, there are a few specific guidelines for 
the pharmacotherapy of excessive sleepiness in PD patients (Rye 2006; Zesiewicz et al. 
2010; Seppi et al. 2011; Ferreira et al. 2013). For instance, the guidelines specifically 
mention that modafinil should be considered for patients to improve their subjective 
perception of excessive daytime sleepiness. However, modafinil does not appear to 
adequately promote wakefulness throughout the day with once daily dosing in patients with 
PD (Högl et al. 2002; Adler et al. 2003, Ondo et al. 2005; Lou et al. 2009). 
As a result of the findings of significant decreases in excessive sleepiness (lower ESS scores) 
and significant increases in the ability to stay awake throughout the day (higher MWT sleep 
latencies) when adult patients with narcolepsy were treated with JZP-110, as well as the 
urgent clinical need reported by patients with PD for therapies that better treat their 
symptoms that significantly impacts their daily lives (FDA Parkinson’s Disease Public 
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Meeting 2015), Jazz Pharmaceuticals is conducting this study with JZP-110 to generate 
safety, efficacy, and pharmacokinetic (PK) information in this population. 
1.1 
Study Rationale 
The MWT is the standard objective measure of an individual’s ability to remain awake 
during in a darkened, quiet environment and is commonly used to assess response to 
treatment (International Classification of Sleep Disorders, Third Edition, American Academy 
of Sleep Medicine [AASM 2014]). For example, results from a previous Phase 2a, 4-week, 
crossover study of 300 mg JZP-110 (150 mg for 1 week followed by 300 mg for 1 week) 
compared with placebo in patients with narcolepsy demonstrated a maximal difference in the 
means between drug and placebo of 11.8 minutes on a 40-minute MWT (Bogan et al. 2015). 
Similarly, data from a Phase 2b, 12-week, parallel-group study of JZP-110 (150 mg for 
4 weeks followed by 300 mg for 8 weeks) compared with placebo resulted in maximal 
differences in the means of 8.1 and 10.7 minutes between 150 or 300 mg JZP-110 and 
placebo, respectively, on a 40-minute MWT (Ruoff et al. 2016). Moreover, data from the 
Phase 2b study of JZP-110 in subjects with narcolepsy indicate that the therapeutic effects 
appear to last throughout the day. For instance, the mean change from baseline in sleep 
latency on the fifth trial of a 5-trial, 40-minute MWT was 8.2 minutes for the 300-mg dose of 
JZP-110 (significantly greater than placebo, p=0.0007). The mean change from baseline 
(5.4 minutes) on the fifth trial of a 5-trial, 40-minute MWT was also significantly greater 
than placebo (p=0.0002) for the 150-mg dose of JZP-110.  
In contrast, previous studies of modafinil in patients with narcolepsy have demonstrated 
statistically significant increases in mean sleep latency using a 20-minute MWT with 
maximal differences in the means between drug and placebo groups ranging from 2.3 to 
4.5 minutes (US Modafinil in Narcolepsy Multicenter Study Group 1998, 
US Modafinil in Narcolepsy Multicenter Study Group 2000, Harsh et al. 2006). However, a 
limitation of modafinil is that the therapeutic effects of this drug do not appear to last 
throughout the day and are markedly reduced by the fifth trial of a 5- or 6-trial, 20-minute 
MWT (Schwartz et al. 2003). For example, the effects of 200 and 400 mg modafinil 
diminished throughout the day, and the mean changes from baseline in sleep latency were 
almost 0 on the fifth and sixth trials of a 6-trial, 20-minute MWT (5:00 to 7:00 PM) when 
modafinil was given once daily in the morning (Schwartz et al. 2003). Only a few studies 
have used objective measures of excessive sleepiness, such as the MWT, in PD patients with 
subjective reports of excessive sleepiness. Perhaps similar to the limited effects of modafinil 
in patients with narcolepsy, a placebo-controlled, double-blind study of modafinil in patients 
with PD demonstrated no significant increase in mean sleep latency, compared to placebo, 
using a 40-min MWT (Högl et al. 2002). Taken together, these data suggest that JZP-110 
might offer an important advance in the treatment of excessive sleepiness in PD by 
increasing patients’ ability to stay awake throughout the day beyond what has been 
demonstrated with current available therapies. 
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1.2 
Nonclinical Experience 
Nonclinical studies have been conducted to characterize primary pharmacology, secondary 
and safety pharmacology, abuse liability, absorption, distribution, metabolism, and excretion, 
and toxicology of JZP-110. 
1.2.1 
Mechanism of Action 
JZP-110 is a selective, low potency dopamine and norepinephrine reuptake inhibitor that has 
lower binding affinity to the dopamine and norepinephrine transporters than stimulants such 
as cocaine. JZP-110 is a nonamphetamine wake-promoting agent that lacks the 
noradrenergic-releasing effects of amphetamines and does not produce rebound hypersomnia. 
In vivo pharmacologic studies suggest JZP-110 imparts indirect effects on noradrenergic and 
dopaminergic systems and demonstrate a robust wake-promoting profile. JZP-110 enhances 
wakefulness in both wild-type and narcoleptic mice and did not have an impact on sleep 
following prolonged wakefulness, suggesting potential effectiveness in treating excessive 
sleepiness in narcolepsy. The wake-promoting action of JZP-110 differs from that of both 
d-amphetamine and modafinil; both of which are used to treat excessive daytime sleepiness 
in narcolepsy. 
In vitro and in vivo safety pharmacology studies indicated no significant safety concerns. 
JZP-110 has minimal effects on cardiovascular function, including increases in blood 
pressure and heart rate. 
1.2.2 
Nonclinical Pharmacokinetics 
JZP-110 was rapidly and extensively absorbed and showed high oral bioavailability (71% to 
100%) in mice, rats, and dogs. Single-dose half-life (t1/2) values following oral 
administration were 1, 2, and 4 hours in mice, rats (longer in chronic studies at high doses), 
and dogs, respectively, with no unexpected accumulation with repeated administration. In 
rats, the disposition profile in plasma was monophasic and elimination was mostly by renal 
excretion. Overall, the maximum concentration (Cmax) and area under the concentration-time 
curve (AUC) tended to increase proportionally with dose and were comparable in male and 
female animals.  
Plasma protein binding was low (8% to 17%) in mouse, rat, rabbit, dog, and human plasma. 
Metabolism is not an important elimination pathway in humans as almost all (>90%) material 
excreted in urine was unchanged drug with a minor metabolite (N-acetyl derivative of 
JZP-110 base) accounting for <1% of the dose excreted in urine. The main metabolite in 
animal species was an acid metabolite, but a parahydroxyphenyl metabolite and its 
glucuronide were also identified.  
In vitro cytochrome P450 (CYP) experiments indicated low potential for JZP-110 drug-drug 
metabolism interactions by either inhibition or induction mechanisms. JZP-110 did not 
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inhibit CYP enzymes including CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, 
CYP2E1, and CYP3A4. JZP-110 showed no induction of CYP1A2, CYP2B6, CYP3A4, or 
uridine diphosphate glucuronosyltransferase (UGT) 1A1 enzymes. Furthermore, JZP-110 
was not a substrate or inhibitor of major uptake or efflux transporters, and did not inhibit 
UGT1A1 or UGT2B7 enzymes. 
1.2.3 
Toxicology 
Single oral doses of JZP-110 at up to 600, 750, and 140 mg/kg were well tolerated by mice, 
rats, and dogs, respectively. Clinical signs were mainly related to central nervous system 
(CNS) stimulation in all species. In addition to these clinical signs, dogs also had salivation, 
mydriasis, restlessness, panting, and/or marked transient elevation of body temperature. 
Repeat-dose toxicity studies of durations up to 3 months in mice, 6 months in rats, and 
12 months in dogs resulted in similar dose-related CNS effects. 
A battery of in vitro and in vivo assays indicated that JZP-110 has no genotoxic potential. 
Two-year rat and mouse carcinogenicity studies are in progress. 
More detailed information about the toxicology findings is provided in the JZP-110 
Investigator’s Brochure. 
1.3 
Clinical Experience  
Clinical studies of JZP-110 (seven Phase 1 and five Phase 2 studies) have been completed in 
1048 subjects, of whom 690 subjects received 1 or more doses of JZP-110. In studies in 
which subjects received acute doses of JZP-110, doses ranged from 50 mg to 1200 mg. In 
studies in which subjects received repeated, daily doses of JZP-110, doses ranged from 
100 to 1000 mg/day (calculated based on the hydrochloride salt). The highest dose that is 
being used in the Phase 3 studies in patients with narcolepsy or OSA is 300 mg, calculated 
based on free base of the molecule. This is equivalent to 356 mg based on the hydrochloride 
salt. Overall, the highest dose that has been studied in human subjects is 1200 mg with the 
dose calculated using the weight of the hydrochloride salt, which is equivalent to a 1010 mg 
dose calculated using the weight of the free base. 
1.3.1 
Clinical Pharmacokinetics and Product Metabolism 
JZP-110 is eliminated primarily via the renal route, with at least 90% of the dose being 
excreted as unchanged drug within 48 hours. Following single dosing and repeated doses 
administered twice daily, JZP-110 exposure was dose-proportional, absorption (time to 
maximum plasma concentration [tmax]: 1.3 to 3.0 hours) and elimination (t1/2: 5 to 7.6 hours) 
were relatively rapid, and steady state was reached in 3 days. JZP-110 displayed linear PK 
during 14 days of dosing over the dose range of 200 to 1000 mg per day. Limited 
accumulation and no enzyme auto-induction were evident.  
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1.3.2 
Clinical Efficacy in Subjects with Excessive Sleepiness in Narcolepsy 
In the 2 Phase 2 studies in patients with narcolepsy and excessive sleepiness 
(Studies ADX-N05 201 and ADX-N05 202), JZP-110 significantly decreased the excessive 
sleepiness associated with narcolepsy, with statistically significant differences from placebo 
on the primary efficacy endpoints. 
Study ADX-N05 201 was a 4-week, randomized, double-blind, placebo-controlled, 
multicenter, crossover study. JZP-110 (after dosing with 150 mg/day for 1 week followed by 
dosing with 300 mg/day for a second week) effectively increased the mean sleep latency as 
measured by the MWT in subjects with narcolepsy. Subjects were able to stay awake for an 
average of about 11 minutes longer following dosing with JZP-110 than placebo, a 
statistically significant difference. When the 5 MWT trials were analyzed separately, 
improvement in sleep latency statistically favored JZP-110 over placebo for all trials and 
improvements were maintained throughout the approximate 7-hour period after dosing. 
Results from analyses of the subjective measures of the ESS and the Clinical Global 
Impression of Change (CGIc) scale were consistent with MWT findings and statistically 
significant in favor of JZP-110 over placebo. 
Study ADX-N05 202 was a randomized, double-blind, placebo-controlled, multicenter, 
parallel-group study in which subjects in the JZP-110 group received 150 mg JZP-110 daily 
through Week 4 and then received 300 mg daily through Week 12. JZP-110 demonstrated 
statistically significant differences in favor of JZP-110 compared with placebo on all efficacy 
endpoints, including the objective endpoint of the mean sleep latency time measured by the 
MWT, and the subjective endpoints of the subject-completed ESS, investigator-completed 
CGIc, and subject-completed Patient Global Impression of Change (PGIc).  
JZP-110 effectively increased sleep latency time across the first 4 MWT trials. When the 
4 MWT trials were averaged, subjects were able to stay awake for about 8 minutes longer 
after 4 weeks (150 mg/day) and 11 minutes longer after 12 weeks (300 mg/day) of 
administration of JZP-110 than with placebo, a statistically significant difference. When the 
four MWT trials were analyzed separately, improvement in sleep latency also statistically 
favored JZP-110 over placebo for all trials at both Weeks 4 and 12 and was maintained 
throughout the approximate 9-hour period after dosing. 
Analyses of the investigator-completed CGIc scale results were consistent with MWT 
findings and evidenced statistical superiority of JZP-110 over placebo. After 12 weeks, 
86% of subjects in the JZP-110 group experienced at least minimal improvement on the 
CGIc versus only 38% of subjects in the placebo group. Statistically significant improvement 
was observed as early as after 1 week. Analyses of the subject-completed ESS and PGIc 
scales were also consistent with a statistically significant superiority of JZP-110 over 
placebo. 
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1.3.3 
Safety of JZP-110 in Subjects with Excessive Sleepiness in Narcolepsy 
Pooled across the 2 Phase 2 studies in subjects with narcolepsy, the most frequent (≥5%) 
treatment-emergent adverse events (TEAEs) were insomnia, headache, nausea, anxiety, 
diarrhea, palpitations, irritability, bruxism, and chest discomfort; all had a higher incidence 
with JZP-110 than with placebo. No deaths occurred in either study. In Study ADX-N05 201, 
there were no treatment-emergent serious adverse events (SAEs) or discontinuations due to 
AEs. Severe treatment-emergent AEs occurred in 2 subjects (1 with intermittent nausea and 
1 with insomnia). In Study ADX-N05 202, treatment-emergent SAEs occurred in 2 subjects 
(both in the JZP-110 group): 1 subject had conversion disorder and 1 subject had acute 
cholecystitis. Treatment-emergent AEs led to study discontinuation of 3 subjects in the 
JZP-110 group (the subject with conversion disorder noted above; 1 subject with severe 
anxiety, moderate insomnia and moderate bruxism; and 1 subject with moderate insomnia 
and mild palpitations) and 2 subjects in the placebo group (headache and fatigue). 
In Study ADX-N05 202, JZP-110 was associated with minimal effects on placebo-corrected 
changes in heart rate (both measured and from electrocardiograms [ECGs]) and blood 
pressure. There was no effect on ECG interval measures. 
1.3.4 
Safety of JZP-110 in Clinical Studies of Major Depression and in Healthy 
Subjects 
Most of the 322 healthy subjects and 600 depressed subjects in studies with completed data 
analysis experienced AEs, the majority of which were mild or moderate. There were no 
deaths. 
Pooled across 5 studies in healthy subjects and subjects with major depressive disorder 
(MDD) (NED-1, USA-10, MDD-201, SAB-101, and P01-101), the most common (≥5%) 
treatment-emergent AEs that also occurred with a higher incidence with JZP-110 than with 
placebo were insomnia, headache, dizziness, anorexia, dry mouth, nervousness, nausea, 
palpitation, agitation, abdominal pain, anxiety, fatigue, concentration impaired, and diarrhea. 
The only common treatment-emergent AEs that occurred more often with placebo than 
JZP-110 were somnolence and dyspepsia. Safety findings in the other clinical studies were 
consistent with those summarized above. 
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1.3.6 
Safety Summary 
Safety data from 690 subjects who received JZP-110 in completed Phase 1 and 2 clinical 
trials support initiation and continuation of clinical trials. Most AEs were mild or moderate 
and did not lead to study discontinuation. Few SAEs or discontinuations due to AEs 
occurred. No clinically significant effects on ECG were observed. Effects on mean heart rate 
and blood pressure were small and transient (with mean heart rate and blood pressure 
remaining within the normal range) at doses comparable to or lower than those being used in 
the Phase 3 clinical studies for narcolepsy or OSA. In safety monitoring of ongoing trials of 
JZP-110, no new safety signals have been identified to date. 
1.4 
Summary of Potential Benefits and Risks 
Parkinson’s disease is a progressive neurodegenerative disease, which manifests with both 
motor and nonmotor symptoms. Until recently, treatment has focused on improving the 
motor symptoms, however the nonmotor symptoms can also be prominent and disabling and 
treatment guidelines now recognize the need to improve these symptoms. Excessive 
sleepiness is a common nonmotor symptom of PD with limited therapeutic options as no 
therapeutic agents have been approved by the FDA for this indication. 
The wake-promoting effects of JZP-110 (150 and 300 mg administered once daily) on 
subjective (ESS, PGI-c, CGI-c) and objective (MWT sleep latency) endpoints of excessive 
sleepiness were evaluated in Phase 2 randomized, placebo-controlled studies in patients with 
narcolepsy. The results of these studies showed statistically significant effects on both 
subjective and objective endpoints. The magnitude of the effects was robust, with increases 
in mean sleep latency (measured by MWT) of up to 12 minutes compared with placebo 
following 12 weeks of JZP-110 administration. 
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The wake-promoting effects of JZP-110 for patients with PD have not been previously 
evaluated. The present Study JZP-166-201 will evaluate the effects of 75, 150, and 300 mg of 
JZP-110 on excessive sleepiness in patients with PD.  
The safety and tolerability of JZP-110 has been well characterized in multiple populations 
including healthy volunteers, patients with MDD, and patients with narcolepsy. Across 
3 Phase 1 studies in healthy subjects (R228060-NED-1, R228060-P01-101, and 
R228060-SAB-101) and 2 Phase 2 studies in patients with MDD (R228060-USA-10 and 
R228060-MDD-201), data were pooled for 421 subjects who received JZP-110 at doses of 
200 to 1200 mg/day (with doses calculated based on the hydrochloride salt of the molecule) 
and 185 subjects who received placebo. The most common (≥5%) treatment-emergent AEs 
that also occurred with a higher incidence with JZP-110 than with placebo were insomnia, 
headache, dizziness, anorexia, dry mouth, nervousness, nausea, palpitation, agitation, 
abdominal pain, anxiety, fatigue, concentration impaired, and diarrhea. Common 
treatment-emergent AEs that occurred more often with placebo than JZP-110 were 
somnolence and dyspepsia. Based on data pooled across 2 Phase 2 studies 
(Studies ADX-N05 201 and ADX-N05 202) of JZP-110 at doses up to 300 mg/day in 
subjects with narcolepsy (N=77, JZP-110; N=82, placebo), the most frequent (≥5%) 
treatment-emergent AEs were insomnia, headache, nausea, decreased appetite, anxiety, 
diarrhea, palpitations, irritability, bruxism, and chest discomfort; all had a higher incidence 
with JZP-110 than with placebo.  
Randomized, placebo-controlled Phase 3 studies in the narcolepsy and OSA populations are 
currently ongoing and remain blinded. 
No PK-based drug-drug interactions are expected between JZP-110 and the commonly used 
background PD therapy medications, as JZP-110 does not undergo hepatic metabolism, and 
does not inhibit or induce major CYP450 enzymes. JZP-110 is eliminated primarily through 
renal excretion, and in vitro studies indicate that JZP-110 does not inhibit major uptake or 
efflux transporters. The pharmacodynamic-based drug-drug interaction potential between 
JZP-110 (a selective norepinephrine and dopamine reuptake inhibitor) and background 
dopamine replacement therapy used in PD is unknown, and the effect of coadministration 
will be evaluated via safety/efficacy assessments in the current study. 
Since there are limited therapeutic options, with no drugs that have been approved for the 
treatment of excessive sleepiness in PD, there remains an unmet clinical need for a 
well-tolerated and effective therapy. The extensive clinical safety database across multiple 
populations for JZP-110 and the positive efficacy results in narcolepsy patients provide an 
appropriate balance between risk and benefit. When all the considerations are taken together, 
they provide the basis to support the evaluation of the safety, tolerability, efficacy, and PK 
profile of JZP-110 in patients with excessive sleepiness and PD. 
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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of the study is to evaluate the safety and tolerability of JZP-110 in the 
treatment of excessive sleepiness in adult subjects with PD. 
2.2 
Secondary Objectives  
The secondary objectives of the study are as follows: 
• To evaluate the efficacy of JZP-110 in the treatment of excessive sleepiness, as measured 
by the ESS, in adult subjects with PD  
• To characterize the PK of JZP-110 in subjects with PD 
 
2.3 
Exploratory Objectives 
Exploratory objectives of the study are to evaluate the effect of JZP-110 on mean sleep 
latency, as measured by the MWT (in a subpopulation); and the effect of JZP-110 on motor 
function and nonmotor symptoms (i.e., fatigue, apathy, and cognition) (in all subjects). 
 
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3 
STUDY DESIGN 
3.1 
Overall Study Design and Plan 
The schedules of events are presented in Appendix 1 and Appendix 4, and the study schema 
in Figure 1. 
This is a 4-week, multicenter, randomized, double-blind, placebo controlled, ascending dose, 
4-period crossover study designed to evaluate the safety, tolerability, efficacy, and PK of 
JZP-110 (75, 150, and 300 mg) in the treatment of excessive sleepiness in adult subjects with 
idiopathic PD. Depending on study center capabilities, subjects will have the option of 
enrolling into 1 of 2 groups: Group 1 and Group 2. Subjects enrolled in Group 1 will undergo 
both objective (MWT) and subjective (ESS) assessments of sleepiness. Subjects enrolled in 
Group 2 will undergo only the subjective (ESS) assessment of sleepiness. Following 
completion of the Screening and Baseline visits, approximately 49 eligible subjects will be 
randomly assigned (3:3:1) to 1 of 3 treatment sequences in order to have approximately 
34 subjects complete Treatment Sequences A and B, and 6 subjects complete Treatment 
Sequence C. There will be no stratification based on group. Sequence C is added to preserve 
blinding across the 4 treatment periods. 
 
Treatment 
Sequence 
Period  
1 
Period 
2 
Period 
3 
Period 
4 
Week 1 
Week 2 
Week 3 
Week 4 
A 
(n=21) 
Placebo 
JZP-110 
75 mg 
JZP-110 
150 mg 
JZP-110 
300 mg 
B 
(n=21) 
JZP-110 
75 mg 
JZP-110 
150 mg 
JZP-110 
300 mg 
Placebo 
C 
(n=7) 
Placebo 
Placebo 
Placebo 
Placebo 
 
During the first 6 days of each treatment period, subjects will take once-daily, oral doses of 
study drug (placebo, 75, 150, or 300 mg JZP-110) with water at home, without regard to 
food, and within 1 hour of awakening in the morning (at approximately the same time each 
day). If a subject fails to take the study drug within an hour of awakening, the subject should 
be instructed to take the study drug, if he/she is able to do so, at least 12 hours before his/her 
anticipated bedtime. If the subject cannot take the study drug at least 12 hours before his/her 
anticipated bedtime, the subject should not take the study drug for that day. Subjects should 
take their PD medications and sleep medications allowed by the protocol as per their usual 
schedule each day.  
On the last day of each treatment period (i.e., Days 7, 14, 21, and 28), subjects will take their 
usual PD medications and sleep medications allowed by the protocol as per their usual 
schedule, and return to the study center where they will take their dose of study drug for that 
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day and undergo assessments for efficacy, safety, and tolerability (Visits 3, 4, 5, and 6). 
Subjects will take their study drug with water in the morning at the study clinic after predose 
assessments are completed. Subjects may be served a light meal at 15 minutes after dosing. 
Pending the investigator’s assessment of safety and tolerability, subjects will proceed to the 
next treatment period. Subjects will receive their last dose of study drug at Visit 6 (Day 28) 
prior to the Week 4 visit assessments. Subjects will return for a Safety Follow-up visit 
(Visit 7) approximately 7 days after the last dose of study drug for follow-up safety 
assessments. Unless there are outstanding safety issues that require additional follow-up, 
subjects will be discharged from the study at the Safety Follow-up visit (Visit 7). 
Safety and tolerability will be assessed throughout the study and will include the following: 
monitoring of AEs, discontinuations due to AEs, changes in physical examination findings, 
ECGs, clinical laboratory tests, vital sign measurements (including measuring seated and 
standing blood pressure), and change in response to the Columbia-Suicide Severity Rating 
Scale (C-SSRS) at each visit. 
Efficacy will be assessed by the change from baseline in the ESS score, and for subjects who 
enroll in Group 1 and subjects who enrolled prior to Amendment 2, by the change from 
baseline in mean sleep latency time as objectively measured using either 3 or 4 trials of the 
MWT. 
Exploratory efficacy assessments will include changes in scores from baseline and/or the 
percentages of subjects improved, as applicable, on the CGIc, PGIc, Fatigue Severity Scale 
(FSS), Apathy Scale, and the Scales for Outcomes in Parkinson's disease-cognition 
(SCOPA-cog). 
Parkinson’s disease clinical status (e.g., motor fluctuations, dyskinesia) will be assessed 
using the Movement Disorders Society-Unified Parkinson’s Disease Rating Scale 
(MDS-UPDRS) Parts III and IV. 
In addition, subjects who enrolled in the study prior to Amendment 2 implementation would 
have participated in the PK evaluation. Blood samples for PK analysis were to be collected 
from each subject at predose and at 1, 2, 3, 4, 5, and 6 hours after dosing at Visits 3, 4, 5, and 
6. A sample was also collected 7 to 8 hours after dosing, as feasible, at each study center 
visit. 
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Figure 1 
JZP166-201: Study Schema 
 
a 
During the first 6 days of each treatment period, subjects will take once-daily, oral doses of study drug (placebo, 75, 
150, or 300 mg JZP 110) with water at home, without regard to food, and within 1 hour of awakening in the morning 
(at approximately the same time each day). On the last day of each treatment period (i.e., Days 7, 14, 21, and 28), 
subjects will take their usual PD medications and sleep medications allowed by the protocol as per their usual schedule, 
and return to the study center where they will take their dose of study drug for that day and undergo assessments for 
efficacy, safety, and tolerability. Subjects will take their study drug with water in the morning at the study clinic after 
predose assessments are completed. Subjects may be served a light meal at 15 minutes after dosing. Pending the 
investigator’s assessment of safety and tolerability, subjects will proceed to the next Treatment Period. Subjects who do 
not tolerate the study drug will be considered for early termination (at the discretion of the investigator). 
 
3.2 
Rationale for Study Design and Control Group 
This study was designed to be consistent with the US FDA Guidance for Industry on 
Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products, with 
the ICH, Guidance on The Extent of Population Exposure to Assess Clinical Safety for Drugs 
Intended for Long-Term Treatment of Non-Life-Threatening Conditions and with the ethical 
principles given in these guidances, which have their origins in the Declaration of Helsinki. 
The inclusion of a placebo as a control into sequences A and B in the Treatment Phase of this 
study is necessary to determine the efficacy and safety of this new investigational medicinal 
product. Inclusion of the placebo sequence C will preserve blinding. A crossover design has 
been selected in order to evaluate the safety, tolerability, and effects on excessive sleepiness 
across a range of doses. Phase 2 studies in patients with narcolepsy have shown that JZP-110 
(150 and 300 mg doses) improves subjective and objective parameters of sleepiness and is 
well tolerated. While the same sleepiness parameters are included as endpoints in this study 
as in the Phase 2 narcolepsy study, the objective MWT assessment was made optional in 
Amendment 2 for this study as unlike in narcolepsy, it is not a common assessment for 
diagnosing sleepiness in PD and it has not been validated in this patient population. The 
Phase 2a narcolepsy study was a crossover design and a carryover effect was not observed. In 
light of this and the short half-life of JZP-110, a placebo washout between each treatment 
period was not included. The doses of 75, 150 and 300 mg selected for evaluation in this 
study are comparable to those currently being evaluated in ongoing Phase 3 studies in the 
OSA and narcolepsy populations. It is feasible that lower doses may be pharmacologically 
active and therefore, a broad range of doses from 75 to 300 mg given once daily for 7 days 
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was selected for evaluation and will provide useful data to inform dose selection for 
subsequent studies. 
3.3 
Study Duration and Timing 
Each subject will participate for up to 30 days for screening and baseline procedures, 28 days 
for the Double-blind Treatment Phase, and approximately 7 days for the Follow-up Phase. 
3.4 
End of Study 
The end of the study will be the date of the last visit of the last subject enrolled in the trial. 
 
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Clinical Trial Protocol: JZP166-201 Amendment 2 
 
 
 
 
 
 
 
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4 
STUDY POPULATION SELECTION 
4.1 
Selection of Study Population 
Subjects must have a diagnosis of idiopathic PD according to the United Kingdom (UK) PDS 
Brain Bank Criteria and excessive sleepiness as demonstrated by subjective (ESS) criteria. 
4.2 
Inclusion Criteria 
Each subject must meet the following criteria to be enrolled in this study. 
1. Willing and able to provide written informed consent. 
2. Males and females ≥35 and ≤80 years of age at the time of consent. 
3. Diagnosis of idiopathic PD according to the UK PDS Brain Bank Criteria. NOTE: 
Having >1 affected relative is not exclusionary for diagnosis of idiopathic PD for 
purposes of this protocol. 
4. Hoehn and Yahr stage 1, 2, or 3 (see Part III in Appendix 14). 
5. Must be on a stable treatment regimen for PD including dopaminergic therapy, 
monoamine oxidase B (MAO-B) inhibitors, COMT inhibitors, amantadine, and 
medications for treatment of non-motor symptoms including depression, for at least 
4 weeks prior to screening, with no anticipated need to adjust these medications for the 
study duration. Amantadine use is not allowed if used solely for the treatment of 
excessive sleepiness. 
6. ESS score >11 at both Screening and Baseline visits. Any subject who is on a wake 
promoting agent or stimulant at screening will only have to meet the ESS score >11 
requirement at the Baseline visit, after they have washed out of their wake promoting 
agent or stimulant (see Section 5.7).  
7. This criterion was removed in Amendment 2.  
8. Body mass index ≥17 and ≤40 kg/m2. 
9. Consent to use a medically acceptable method of contraception for at least 2 months prior 
to the first dose of study drug, throughout the entire study period, and for 30 days after 
the study is completed (see Section 4.3 for medically acceptable methods).  
10. Willing and able to comply with the study design schedule, all study procedures, and 
other requirements. 
11. This criterion was removed in Amendment 2. 
4.3 
Exclusion Criteria 
Subjects who demonstrate any of the following criteria will be excluded from the study. 
1. Diagnosis of other degenerative Parkinsonian syndromes (e.g., progressive supranuclear 
palsy, multiple system atrophy [MSA], or dementia with Lewy bodies [DLB]). 
2. Prior use of or planned use during the study of neurostimulation methods including deep 
brain stimulation (DBS). 
3. Female subjects who are pregnant, nursing, or lactating. 
4. Usual nightly time in bed of < 6 hours, including the night before the Baseline visit. 
5. Occupation requiring nighttime or variable shift work. 
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6. This criterion was removed during Amendment 1. 
7. Diagnosis of narcolepsy by history or in the judgement of the investigator. 
8. Any other clinically relevant medical, behavioral, or psychiatric disorder other than PD 
that is associated with excessive sleepiness (e.g., narcolepsy, inadequately controlled 
rapid eye movement sleep behavior disorder [RBD], and inadequately controlled restless 
leg syndrome [RLS] or periodic limb movement disorder [PLMD]) by history or in the 
judgment of the investigator. 
9. History or presence of bipolar disorder, bipolar-related disorders, schizophrenia, 
schizophrenia spectrum disorders, or other psychotic disorders according to Diagnostic 
and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria or severe 
depression, or a BDI-2 score of >28. 
10. History or presence of any acutely unstable medical condition, malignancy other than 
basal cell carcinoma or resected noninvasive cutaneous squamous cell carcinoma, 
behavioral or psychiatric disorder (including active suicidal ideation), or surgical history 
that could affect the safety of the subject or interfere with study efficacy or safety 
assessments; or the ability of the subject to complete the trial per the judgment of the 
investigator. 
11. History of bariatric surgery within the past year, history of roux-en-Y procedure, or 
history of any gastric bypass procedure. 
12. Presence of renal impairment or calculated creatinine clearance <60 mL/min by 
Cockcroft-Gault formula. 
13. Clinically significant ECG abnormality or a QTcF interval of >450 msec for males and 
>470 msec for females at screening as assessed by the principal investigator.   
14. Presence of significant cardiovascular disease at screening including but not limited to 
the following: myocardial infarction within the past year; unstable angina pectoris; 
symptomatic congestive heart failure (American College of Cardiology/American Heart 
Association stage C or D); revascularization procedures within the past year; ventricular 
cardiac arrhythmias requiring automatic implantable cardioverter defibrillator or 
medication therapy; uncontrolled hypertension, or systolic blood pressure ≥155 mmHg or 
diastolic blood pressure ≥95 mmHg (at screening, or consistently across baseline 
measures according to protocol specifications); or any history of cardiovascular disease 
or any significant cardiovascular condition that in the investigator’s opinion may 
jeopardize subject safety in the study. 
15. History of cerebrovascular accident. 
16. This criterion was removed in Amendment 2. 
17. Laboratory value(s) at screening outside the laboratory reference range that is (are) 
considered to be clinically significant by the investigator (clinical chemistry, hematology, 
and urinalysis). NOTE: Screening laboratory tests may be repeated 1 time. 
18. Excessive caffeine use 1 week prior to baseline assessments or anticipated excessive use 
during the study defined as >600 mg/day of caffeine (refer to the list of caffeinated 
beverages in Appendix 7). 
19. Use of neurostimulants including any over-the-counter (OTC) (eg, pseudoephedrine) or 
prescription medications (eg, amphetamines or dextroamphetamines [e.g., Adderall], 
modafinil, armodafinil, or methylphenidate) within 14 days prior to the Baseline visit or 
planned use at any time during the study. 
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20. Use of diphenhydramine or sodium oxybate (ie, Xyrem) within 14 days prior to the 
Baseline visit or at any time during the study. 
21. Use of any other medications, that in the opinion of the investigator, could affect the 
evaluation of excessive sleepiness within 14 days prior to the Baseline visit or planned 
use at any time during the study. 
22. Use of trazodone, benzodiazepines, nonbenzodiazepines (e.g., zolpidem, zaleplon, or 
eszopiclone), suvorexant, or melatonin receptor agonists for insomnia unless the subject 
has been on a stable daily regimen for 14 days prior to the Baseline visit and will 
continue this regimen during the study. 
23. Use of parenteral dopaminergic therapy within 14 days of the Baseline visit or planned 
use at any time during the study. 
24. Received an investigational drug 30 days or 5 half-lives prior to the Baseline visit 
(whichever is longer), or plans to use an investigational drug (other than the study drug) 
during the study. 
25. Current or past (within the past 2 years) diagnosis of a moderate or severe substance use 
disorder according to DSM-5 criteria. 
26. Nicotine dependence that has an effect on sleep (e.g., a subject who routinely awakens at 
night to smoke). In addition, subjects who routinely are unable to abstain from nicotine 
products for at least a 24-hour period are excluded. 
27. Current, past (within the past 2 years), or seeking treatment for a substance-related 
disorder. 
28. Urine drug screen positive for drugs of abuse at screening, except for a prescribed drug 
allowed by the protocol (e.g., benzodiazepine or opiate) at screening. Cannabinoid use is 
not permitted either recreationally or medically at screening or throughout the duration of 
the study.  
29. History of phenylketonuria (PKU) or history of hypersensitivity to phenylalanine-derived 
products. 
30. Has evidence at screening of severe cognitive impairment as defined by a SCOPA-cog 
score ≤24, or has cognitive impairment that in the opinion of the investigator would 
prevent completion of study procedures or the ability to provide informed consent. 
31. Evidence at screening of impulse control disorder (ICD) as measured by the 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease–Rating Scale 
(QUIP-RS) assessment tool (total QUIP-RS score >30 or an individual score >10 in any 
of the individual components of gambling, buying, sex, or eating). 
32. Has travelled across at least 3 time zones within a week prior to screening or planned 
travel that would require crossing >2 time zones during the study. 
33. This criterion was removed in Amendment 2. 
34. Use of droxidopa within 7 days of the Baseline visit or planned use at any time during the 
study.  
 
For subjects with no documented history of moderate or severe OSA: 
35. Evidence of moderate or severe OSA as determined by a positive score in both 
Categories 1 and 3 on the Berlin Sleep Apnea Questionnaire.  
If the investigator suspects the Berlin result is inaccurate, 1 of the following may be used 
to determine eligibility instead of the Berlin result: 
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a) An in-laboratory nocturnal polysomnography (PSG) (Apnea Index >10 events/hour is 
exclusionary). 
b) Out-of-center sleep test (OCST) (i.e., home sleep test) (Apnea Index >10 events/hour 
is exclusionary). 
c) Overnight pulse oximetry (Oxygen Desaturation Index [ODI] >20 events/hour with 
≥3% drop in oxygen saturation is exclusionary). 
Assessments a through c can be performed either during the Screening period or at 
Visit 2 (Baseline), or can be a historical evaluation performed within 12 months of Visit 1 
(Screening) and accompanied by no more than a 5% increase in the subject’s weight 
since the evaluation. 
 
For subjects with a documented history of moderate or severe OSA: 
36. Untreated or inadequately treated moderate to severe OSA (i.e., Apnea Index 
>10 events/hour after treatment). Subjects who currently use a primary therapy for OSA 
are excluded unless the subject has been stable on their device settings for at least 
4 weeks prior to Baseline and during this time frame demonstrated adequate compliance 
(use for a minimum of 4 hours/night on a minimum of 70% of nights). 
For the purpose of this study, medically acceptable methods of contraception include 
estrogen-progestin oral contraceptive pills, patches, or vaginal ring (if one of these methods 
is chosen it must have been used consistently for 2 months prior to the first dose of study 
drug); progestin implant or injection; diaphragm with spermicide; male condom plus vaginal 
spermicide; surgical sterilization; intrauterine device; post-menopausal (defined as age >50 
and >1 year of amenorrhea); medically documented ovarian failure (defined as age <50 with 
serum estradiol and follicle-stimulating hormone [FSH] levels within the institutional 
postmenopausal range and a negative serum or urine βHCG); vasectomy (>6 months prior to 
baseline); or abstinence. 
4.4 
Screening and Randomization Eligibility  
Subjects will be considered eligible for randomization if they meet the inclusion criteria and 
do not meet any exclusion criteria. Subjects who have signed informed consent and do not 
meet screening criteria will be considered screen failures. 
 
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5 
STUDY TREATMENTS 
5.1 
Description of Treatments 
5.1.1 
JZP-110 
The investigational medicinal product JZP-110 [(R)-2-amino-3-phenylpropylcarbamate 
hydrochloride] will be supplied as 75, 150, and 300 mg tablets (based on the free base of the 
molecule) that will be overencapsulated in an opaque gelatin capsule. The tablets contain the 
excipients hydroxypropyl cellulose and magnesium stearate, and a polymer film coat 
(Opadry®). The capsule backfill will be microcrystalline cellulose (MCC). 
5.1.2 
Placebo  
Placebo tablets are composed of mannitol, MCC, and magnesium stearate, and a polymer 
film coat (Opadry®). Placebo tablets will be overencapsulated in opaque gelatin capsules that 
will be identical to the active JZP-110 treatments. MCC will be used as the capsule backfill. 
Mode of administration will be the same as for the test product above. 
5.2 
Treatments Administered 
Approximately 49 eligible subjects will be randomly assigned (3:3:1) to 1 of 3 treatment 
sequences in order to have approximately 34 subjects complete Treatment Sequences A and 
B, and 6 subjects complete Treatment Sequence C. There will be no stratification based on 
group. Treatment Sequence C is added to preserve blinding across the 4 treatment periods. 
Treatment 
Sequence 
Period  
1 
Period 
2 
Period 
3 
Period 
4 
Week 1 
Week 2 
Week 3 
Week 4 
A 
(n=21) 
Placebo 
JZP-110 
75 mg 
JZP-110 
150 mg 
JZP-110 
300 mg 
B 
(n=21) 
JZP-110 
75 mg 
JZP-110 
150 mg 
JZP-110 
300 mg 
Placebo 
C 
(n=7) 
Placebo 
Placebo 
Placebo 
Placebo 
 
During the first 6 days of each treatment period, subjects will take once-daily, oral doses of 
study drug (placebo, 75, 150, or 300 mg JZP 110) with water at home, without regard to 
food, and within 1 hour of awakening in the morning (at approximately the same time each 
day). If a subject fails to take the study drug within an hour of awakening, the subject should 
be instructed to take the study drug, if he/she is able to do so, at least 12 hours before his/her 
anticipated bedtime. If the subject cannot take the study drug at least 12 hours before his/her 
anticipated bedtime, the subject should not take the study drug for that day. Subjects should 
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take their PD medications and sleep medications allowed by the protocol as per their usual 
schedule each day.  
On the last day of each treatment period (i.e., Days 7, 14, 21, and 28), subjects will take their 
usual PD medications and sleep medications allowed by the protocol as per their usual 
schedule, and return to the study center where they will take their study drug for that day and 
undergo assessments for efficacy, safety, and tolerability (Visits 3, 4, 5, and 6). Subjects will 
take their study drug with water in the morning at the study clinic after predose assessments 
are completed. Subjects may be served a light meal at 15 minutes after dosing. Pending the 
investigator’s assessment of safety and tolerability, subjects will proceed to the next 
Treatment Period. Subjects who do not tolerate the study drug will be considered for early 
termination (at the discretion of the investigator). 
5.3 
Selection and Timing of Dose for Each Subject 
Data from the ADX-N05 201 and ADX-N05 202 trials that were conducted in patients with 
narcolepsy demonstrated that doses of 150 and 300 mg JZP-110 increased the mean sleep 
latency on the first 4 trials of the MWT by 9.5 and 12.8 minutes from baseline, respectively, 
and increased the sleep latency on the fifth trial of the MWT by 5.4 and 8.2 minutes from 
baseline, respectively. Based on these findings and the safety and tolerability profiles of 150 
and 300 mg JZP-110 in adult patients with narcolepsy in these trials, this study will further 
evaluate of the safety and efficacy of 150 and 300 mg, in addition to the lower dose of 75 mg 
JZP-110 given once a day in the morning. 
During the treatment periods, subjects are to continue taking their usual PD medications and 
sleep medications allowed by the protocol as per their usual schedule. Subjects will be 
instructed to take a single daily dose of study drug in the morning, with water at home, 
without regard to food, and within 1 hour of awakening (at approximately the same time each 
day). If a subject fails to take the study drug within an hour of awakening, the subject should 
be instructed to take the study drug, if he/she is able to do so, at least 12 hours before his/her 
anticipated bedtime. If the subject cannot take the study drug at least 12 hours before his/her 
anticipated bedtime, the subject should not take the study drug for that day. On the last day of 
each treatment period (i.e., Days 7, 14, 21, and 28), subjects will take their usual PD 
medications and sleep medications allowed by the protocol as per their usual schedule, and 
return to the study center where they will take their dose of study drug for that day and 
undergo assessments for efficacy, safety, and tolerability (Visits 3, 4, 5, and 6). Subjects will 
take their study drug with water in the morning at the study clinic after predose assessments 
are completed. Subjects may be served a light meal at 15 minutes after dosing.  
5.4 
Method of Assigning Subjects to Treatment Groups 
Eligible subjects will be randomly assigned (3:3:1) to treatment sequences A, B, and C, as 
described in Section 5.2. There will be no stratification based on group. 
The investigator will access an Interactive Voice Response System (IVRS) or an Interactive 
Web Response System (IWRS) to randomize subjects. 
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5.5 
Randomization 
A statistician selected by Jazz Pharmaceuticals will prepare and retain the master 
randomization code for the entire study. This statistician will not be involved in the analysis 
of this study. A copy of the master randomization code will be provided to the head of the 
Quality Department at Jazz Pharmaceuticals, or a designee in the Quality Department. The 
Head of Quality at Jazz Pharmaceuticals will sequester the master randomization code. 
Unless there is an emergency that requires the release of the subject’s assigned treatment, the 
code will not be broken or released until all study data are collected and accepted for 
analysis.   
5.6 
Blinding 
A double-blind approach will be used during the Treatment Phase. All study drug throughout 
the study will be prepared in identical opaque gelatin capsules to ensure adequate blinding of 
the subject and study personnel. A subject’s treatment assignment may be unblinded for 
safety reasons (see Sections 6.14.2 and 6.14.4). 
5.7 
Prior and Concomitant Therapy 
During the Screening Phase, prior (30 days), during the 4-week Treatment Phase, and during 
the 1-week Safety Follow-up Period, concomitant medication use and any medications 
(including stimulants) or devices used for the treatment of excessive sleepiness since 
diagnosis will be documented. These medications will be recorded on the electronic case 
report form (eCRF) for randomized subjects.  
The following OTC or prescription medications must be discontinued within 14 days prior to 
the Baseline visit (Visit 2). These medications are disallowed throughout the study as well 
(including the 1-week Safety Follow-up Period):  
• OTC or prescription medications containing pseudoephedrine 
• Modafinil or Armodafinil 
• Methylphenidate 
• Amphetamines or Dextroamphetamines (e.g., Adderall) 
• Diphenhydramine  
• Sodium oxybate (i.e., Xyrem) 
• Droxidopa (Note: Must be discontinued within 7 days prior to Baseline visit) 
• Any other OTC or prescription medications that, in the opinion of the investigator, could 
affect the evaluation of excessive sleepiness  
 
Use of the following medications for the treatment of PD motor symptoms is allowed at any 
time during the study provided that the subject has been on a stable treatment regimen for 
4 weeks prior to screening and will continue this regimen during the study. 
• Dopaminergic agents (e.g., levodopa, pramipexole, ropinirole, rotigotine) 
• MAO-B inhibitors (e.g., rasagiline, selegiline, safinamide) 
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• COMT inhibitors (e.g., entacapone, opicapone, tolcapone) 
• Amantadine (e.g., for management of dyskinesias). Amantadine use is not allowed if used 
solely for the treatment of excessive sleepiness. 
 
Use of medications for the treatment of non-motor symptoms of PD including depression are 
allowed at any time during the study provided that the subject has been on a stable treatment 
regimen for 4 weeks prior to screening and will continue this regimen during the study. 
Use of the following medications for insomnia is allowed at any time during the study 
provided that the subject has been on a stable daily regimen for 14 days prior to the Baseline 
visit and will continue this regimen during the study.  
• Trazodone 
• Benzodiazepines  
• Nonbenzodiazepines (e.g., zolpidem, zaleplon, or eszopiclone) 
• Suvorexant 
• Melatonin receptor agonists  
 
Subjects must continue to take their usual medications allowed by the protocol at the same 
dose and regimen during the study. Any dose adjustments for PD medications or sleep 
medications during the study must be approved by the sponsor and clearly documented in the 
subject’s medical record. All drugs other than study drugs that are taken during the course of 
study (approved or unapproved; prescription, OTC [including health and dietary 
supplements], or illicit drugs) will be documented, and for randomized subjects, recorded in 
the concomitant medications section of the eCRF. Jazz Pharmaceuticals must be notified in 
advance (or as soon as possible thereafter) of any instances in which excluded therapies are 
administered. 
5.8 
Restrictions 
5.8.1 
Prior Therapy 
Subjects may continue prescription and OTC medications with the exception of the 
disallowed medications described in Section 5.7. 
5.8.2 
Fluid and Food Intake  
Subjects will be encouraged not to increase caffeine use during the study. Study drug may be 
taken with or without food. 
At Visits 3, 4, 5, and 6 (i.e., on the last day of each treatment period [Days 7, 14, 21, and 28, 
respectively]), study drug will be administered at the study center with approximately 
240 mL water (subjects may receive an additional 240 mL of water if necessary).  
Subjects may also be given a light breakfast and light lunch at times indicated in the schedule 
of events (Appendix 1, Appendix 2, Appendix 3, Appendix 4, Appendix 5, and Appendix 6) 
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and Section 7. At Visits 3, 4, 5, and 6, the light breakfast will be served approximately 
15 minutes after dosing and should be consumed within 15 to 20 minutes. For subjects 
enrolled in Group 1, caffeine consumption will not be allowed on the MWT day during the 
Baseline visit (Day -1) and at Visits 3, 4, 5, and 6. 
5.8.3 
Other Restrictions 
MWT restrictions (for subjects enrolled in Group 1 only): 
Subjects should be seated in bed in a darkened room during the MWT trials (Section 6.12.3). 
In between the MWT trials subjects will be free to move about while staying at the sleep lab.  
Cigarette smokers will be allowed to smoke 1 cigarette in the evening prior to each study 
visit, 1 cigarette in the morning at least 1 hour prior to the first trial of the MWT, and 
1 cigarette during the day immediately following the end of an MWT trial. Subjects who use 
nicotine products should be encouraged to maintain a consistent level of use during the study. 
On MWT days, subjects will not be allowed to nap until all study procedures are completed. 
At other times during the study there are no restrictions on activity. 
5.9 
Treatment Compliance 
Study drug in blister cards will be dispensed and collected at clinic visits and, if applicable, at 
intervals specified by State or local regulations. Subjects will be instructed to return any 
unused drug to the study site. Study drug dispensed and returned will be recorded on the 
investigational medicine record by the designated staff member. Drug accountability will be 
assessed at each clinic visit based on the day of the visit and the amount of study drug that is 
returned to the site. Overall treatment compliance will be calculated at the end of the trial 
when the trial is unblinded. 
5.10 Packaging and Labeling 
Jazz Pharmaceuticals will provide the clinical sites with a supply of study drug as described 
in Section 5.1. Clinical study material will consist of tablets overencapsulated in opaque 
gelatin capsules and packaged in blister cards.  
All packaging and labeling operations will be performed according to current Good 
Manufacturing Practices (cGMP), Good Clinical Practices (GCP), and local requirements. 
5.11 Storage and Accountability 
All study medications will be stored, inventoried, reconciled, and retained or destroyed 
according to applicable country and local regulations for a noncontrolled substance and 
instructions from Jazz Pharmaceuticals. 
The drug product should be stored in the supplied packaging according to the label. 
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The investigator or designated pharmacist will maintain accurate records of receipt of all 
study drugs, including dates of receipt. Study drug supplies must be kept in a secure area and 
dispensed according to the protocol. Unused (or partially used) supplies must be accounted 
for on the drug inventory record. Receipt and dispensing of all study drugs must be 
documented throughout the study and reconciled at study completion.  
Following study completion and notification by Jazz Pharmaceuticals, all labels, blister 
cards, and unused JZP-110 and placebo must be destroyed or returned to Jazz 
Pharmaceuticals according to written instructions from Jazz Pharmaceuticals or its designee 
at the completion of the study for reconciliation and destruction. Used blister cards of study 
drug will be destroyed upon Jazz Pharmaceuticals’ instruction following the review of study 
drug accountability. The investigator must provide a written explanation for any missing 
study drug. After review of study drug accountability records at study completion, one copy 
of the drug inventory record will be retained by the CRO TBD/investigator/site and the other 
will be retained by Jazz Pharmaceuticals.  
 
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6 
STUDY PROCEDURES 
6.1 
Informed Consent 
All subjects will provide their written informed consent before the performance of any 
study-related procedures. Subjects will be given a copy of their signed and dated informed 
consent. 
Each subject’s chart will have his or her signed informed consent form (ICF) for study 
participation attached to it. When the study treatment is completed and the eCRF has been 
monitored, the ICF will be kept in the investigator’s central study file. Regulatory authorities 
may check the existence of the signed ICF in this central study folder. 
6.2 
Demographics 
Demographic information will be collected at the Screening visit as permitted by regional or 
national regulations. Demographics will include the date the subject signed the informed 
consent, and the subject’s age (as indicated by date of birth), sex, ethnicity, and race.  
6.3 
Medical History 
A complete medical history will be collected for each subject during screening. The 
information will include, but is not limited to, concomitant medication use; any medications 
or devices used for the treatment of excessive sleepiness and PD since diagnosis; any prior 
reaction to drugs; history and treatment (if any) of cardiovascular, pulmonary, 
gastrointestinal, hepatic, renal, immunologic, neurologic, or psychiatric disease; reproductive 
status; and confirmation of relevant inclusion criteria. Medical history should include 
documenting the diagnosis of excessive sleepiness and PD, and the frequency of use of any 
therapy for excessive sleepiness. Any updates to the medical history will be assessed at the 
Baseline visit. 
6.4 
Physical Examination 
A review of body systems should be obtained on each subject during the Screening visit and 
at the Baseline visit; at Visits 3, 4, 5, and 6/Early Termination; and at the Safety Follow-up 
visit. Physical examinations will include an examination of body systems (except 
genitourinary), height (at screening only), and body weight measurements. Height and weight 
should be assessed in ordinary indoor clothes without shoes. A qualified investigator or 
designee should perform the examination. 
6.5 
Vital Signs 
Vitals signs (systolic and diastolic blood pressure [both seated and standing], pulse [both 
seated and standing], respiratory rate, and body temperature) will be obtained at every clinic 
visit after the subject has been resting and seated for at least 5 minutes. For blood pressure 
and pulse rate measurement, the subject should be seated comfortably with the back 
supported and the upper arm bared without constrictive clothing. The subject’s legs should 
not be crossed. The arm should be supported at heart level, and the bladder of the cuff should 
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encircle at least 80% of the arm circumference. Neither the subject nor the observer should 
talk during the measurement. Standing blood pressure and pulse rate should be taken at 1 and 
3 minutes after the subject has been standing. 
For the seated assessment of blood pressure and pulse rate, a minimum of 2 blood pressure 
and pulse rate measurements should be taken and the measurements should be separated by 
approximately 5 minutes. If there is >5 mm Hg difference between the first and second blood 
pressure measurement (systolic or diastolic reading), an additional third measurement should 
be taken (Pickering et al. 2005).  
The mean of the 2 or 3 seated blood pressure assessments taken at the Screening visit will be 
used to assess whether entrance criteria to the study are met.  
At the baseline visit, body temperature, respiratory rate, blood pressure (seated and standing), 
and pulse (seated and standing) will be taken as part of the initial assessments after arriving 
at the study clinic. For subjects enrolled in Group 1, additional blood pressure (seated and 
standing) and pulse (seated and standing) measurements will be taken before and after the 
MWT assessments as described in Appendix 2. For subjects enrolled in Group 2, additional 
blood pressure (seated and standing) and pulse (seated and standing) measurements will be 
taken approximately 2 and 3 hours after the first set of vital signs as described in Appendix 5.  
At Visits 3, 4, 5, and 6, body temperature, respiratory rate, blood pressure (seated and 
standing), and pulse (seated and standing) will be taken approximately 1 hour prior to dosing 
at the clinic. For subjects enrolled in Group 1, blood pressure (seated and standing) and pulse 
(seated and standing) will also be taken approximately 1, 2, 4, and 6 hours after dosing as 
described in Appendix 3. For subjects enrolled in Group 2, blood pressure (seated and 
standing) and pulse (seated and standing) will also be taken approximately 1 and 2 hours 
after dosing as described in Appendix 6. 
Body temperature, respiratory rate, and blood pressure (seated and standing) and pulse will 
also be obtained on admission to the site in the morning at the Follow-up visit. 
The schedule of assessment for vital signs for subjects enrolled in Group 1 is described in 
Section 7, Appendix 2, and Appendix 3. The schedule of assessment for vital signs for 
subjects enrolled in Group 2 is described in Section 7, Appendix 5, and Appendix 6. 
6.6 
Questionnaire for Impulsive-Compulsive Disorders in 
Parkinson’s Disease – Rating Scale 
At Screening, the QUIP-RS will be administered to subjects (see Appendix 9). This 
instrument supports a diagnosis of impulse control disorder and related disorders in PD 
(Weintraub et al. 2012). 
6.7 
Beck Depression Inventory-2 
At Screening, the Beck Depression Inventory-2 (BDI-2) will be used to measure the severity 
of depression in patients with PD (Schrag et al. 2007; Kirsch-Darrow et al. 2011) 
(Appendix 10). The BDI-2 uses a 4-point scale ranging from 0 to 3 based on severity of each 
item. The maximum total score is 63.  
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6.8 
Columbia-Suicide Severity Rating Scale 
At the Screening visit, the Baseline/Screening Version of the C-SSRS will be administered to 
subjects to exclude any individuals with active suicidal ideation or behavior (Appendix 11). 
The C-SSRS is a widely used measure of suicidal ideation and behavior. The instrument 
reliably predicts a potential suicide attempt in those who had previously attempted suicide 
and is able to determine clinically meaningful points at which a person may be at risk for an 
impending suicide attempt (Posner et al. 2011). Suicidal ideation will be assessed for lifetime 
and over the past 12 months, and suicidal behavior will be assessed for lifetime and over the 
past 5 years with the Baseline/Screening Version of the C-SSRS. The Since Last Visit 
Version of the C-SSRS will be administered to subjects at the Baseline visit; Visits 3, 4, 5, 
and 6/Early Termination; and at the Safety Follow-up visit (Appendix 12). 
6.9 
Electrocardiography 
Standard 12-lead ECGs will be recorded with the subject resting supine for at least 5 minutes. 
ECGs will be performed at every clinic visit. The schedule of ECG assessment is described 
in Section 7, Appendix 2 (Group 1), Appendix 3 (Group 1), Appendix 5 (Group 2), and 
Appendix 6 (Group 2). In addition to local assessment by the principal investigator, a core 
laboratory will independently assess all Baseline and post-Baseline ECGs for calculation of 
changes from Baseline.  
6.10 Clinical Laboratory Tests 
6.10.1 
Laboratory Parameters 
Subjects will be in a seated or supine position during blood collection. Screening labs may be 
repeated 1 time within the 30-day screening window. Clinical laboratory tests to be 
conducted are listed in Table 1.  
The clinical laboratory tests will be analyzed at a central laboratory. An authorized back-up 
laboratory, as indicated on the Form FDA 1572 or equivalent, may be used if necessary as an 
emergency laboratory. The investigator will supply Jazz Pharmaceuticals or its designee with 
the back-up laboratory’s current licensure and laboratory reference ranges. 
Please note exclusionary clinical laboratory parameters listed in the exclusion criteria 
(Section 4.3). Clinically significant findings that represent a worsening from the Screening 
visit must be documented as AEs (see Section 6.14.1). 
The central laboratory will calculate the estimated creatinine clearance rate at screening using 
the Cockcroft-Gault formula (FDA Guidance for Industry. Pharmacokinetics in Patients with 
Impaired Renal Function – Study Design, Data Analysis, and Impact on Dosing and 
Labeling, May 1998). 
CLcr (mL/min) = [140 – age (years)] x weight (kg) x (0.85 if female)  
                                                                72 x serum creatinine (mg/dL) 
 
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If serum creatinine is reported in µmol/L, the value should be divided by 88.4 for conversion 
to mg/dL. 
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Table 1 List of Laboratory Tests 
Hematology: 
- 
Complete blood count, including platelet 
count and white blood cell count with 
differential 
- 
Hemoglobin 
- 
Hematocrit 
 
Urinalysis:  
- 
Appearance 
- 
Bilirubin 
- 
Color 
- 
Glucose 
- 
Ketones 
- 
Leukocyte esterasea 
- 
Nitrite  
- 
Blooda 
- 
pH 
- 
Proteina 
- 
Specific gravity 
- 
Urobilinogen 
 
Urine Drug Test at Screening:  
- 
Amphetamines 
- 
Barbiturates 
- 
Benzodiazepinesb 
- 
Cannabinoids 
- 
Cocaine metabolites 
- 
Opiates 
- 
Phencyclidine-PCP 
- 
Methadone 
 
Pregnancy Screenc:  
- 
Serum (at Screening visit and following a 
positive urine test) 
- 
Urine (at Baseline; at Visits, 3, 4, 5, and 
6/Early Termination; and at the Safety 
Follow-up visit) 
Serum Chemistry: 
- 
Albumin  
- 
Alkaline phosphatase  
- 
Alanine aminotransferase (ALT) 
- 
Aspartate aminotransferase (AST) 
- 
Blood urea nitrogen  
- 
Calcium  
- 
Carbon dioxide  
- 
Chloride  
- 
Creatinine 
- 
Creatine kinase  
- 
Gamma-glutamyl transferase  
- 
Globulin 
- 
Glucose 
- 
Lactate dehydrogenase  
- 
Phosphorus 
- 
Potassium  
- 
Sodium  
- 
Total bilirubin 
- 
Direct bilirubin 
- 
Total cholesterol 
- 
Total protein 
- 
Triglycerides 
- 
Uric acid 
- 
Thyroid stimulating hormone 
 
 
 
Alcohol Screen (breath) at Screening; Baseline; 
at Visits, 3, 4, 5, and 6/Early Termination; and at 
the Safety Follow-up visit  
 
a 
Urine microscopic will be reflexed when blood, leukocyte esterase, or protein are reported greater than trace. 
b 
Use of benzodiazepines for insomnia is allowed if the subject has been on a stable daily regimen for 14 days prior to 
the Baseline visit and will continue this regimen during the study. 
c 
Pregnancy screening is required for all females of childbearing potential. Female subjects who have undergone surgical 
sterilization, who are post-menopausal (defined as age >50 and >1 year of amenorrhea), who have medically 
documented ovarian failure (defined as age <50 with serum estradiol and FSH levels within the institutional 
postmenopausal range and a negative serum or urine βHCG) do not need to undergo pregnancy screening. 
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Table 2 Schedule of Clinical Laboratory Samples and Estimated Blood 
Volume 
Clinical chemistry (including serum 
pregnancy test at Screening for females of 
childbearing potential): 
Screening; Baselinea; Visits 3, 4, 5, and 
6/Early Termination; and at the Safety 
Follow-up visit 
 
7 × 3.5 mL 
 
 
24.5 mL 
 
Hematology: 
Screening; Baselinea; Visits 3, 4, 5, and 
6/Early Termination; and at the Safety 
Follow-up visit 
 
7 × 2 mL 
 
14 mL 
Approximate total blood volume per 
subject 
 
38.5 mL 
a 
Required if the Baseline visit occurs outside of the screening window (i.e., >29 days after the Screening Visit).  
 
6.10.2 
Sample Collection, Storage, and Shipping 
6.10.2.1 
Clinical Laboratory Test Samples 
The laboratory will supply detailed instructions and all containers for blood and urine 
investigations. Blood and urine sample volumes will meet the laboratory’s specifications. 
The actual time of blood collection for all samples will be recorded. 
Safety laboratory blood samples for hematology and serum chemistry tests will be collected 
at Screening; at Visits 3, 4, 5, and 6 or Early Termination; and at the Safety Follow-up visit. 
If the Baseline visit occurs outside of the screening window (i.e., >29 days after the 
Screening visit), hematology and chemistry tests should also be collected at the Baseline 
visit. Table 2 shows the schedule for collection of blood and the total estimated blood volume 
to be collected during the study. 
A urine sample for urinalysis will be collected at Screening; at Visits 3, 4, 5, and 6 or Early 
Termination; and at the Safety Follow-up visit. A repeat urinalysis should be obtained if the 
Baseline visit occurs outside of the screening window (i.e., >29 days after the Screening 
visit). Samples obtained at other unscheduled visits at the investigator’s discretion may be 
analyzed. 
The urine sample taken at Screening will also be used for urine drug testing. 
Alcohol breath tests will be performed at all study visits. 
A serum pregnancy test for females of childbearing potential will be performed at Screening. 
Urine pregnancy tests will be performed at Baseline; at Visits, 3, 4, 5, and 6 or Early 
Termination; and at the Safety Follow-up visit (Table 1). 
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6.10.2.2 
Blood Samples for Pharmacokinetic Analysis 
Subjects who enrolled in the study prior to Amendment 2 implementation would have 
participated in PK evaluation. Refer to Protocol Amendment 1 for the details regarding blood 
sample collection. 
The bioanalysis will be performed by a central bioanalytical laboratory: 
6.11 Dispensing Study Drug 
Study drug will be dispensed to subjects at the Baseline/Randomization (Visit 2) and at 
Visits 3, 4, and 5 or at alternative intervals if necessary to comply with State and local laws 
and regulations. Subjects will be instructed to begin daily dosing with the new supply of 
study drug the day after the completion of Visits 2, 3, 4, and 5. Subjects will also be provided 
with dosing instructions consistent with the restrictions described in Section 5.8. On 
Treatment Visits 3, 4, 5, and 6, dosing from the subject’s drug supply will be observed and 
documented by site staff at the study center as described in Section 7 and Appendix 1.  
6.12 Efficacy Assessments 
6.12.1 
Epworth Sleepiness Scale  
The ESS is a self-administered questionnaire with 8 questions asking the subject how likely 
they would be to doze off or fall asleep in different situations. Responses range from 
0 = would never doze to 3 = high chance of dozing (Appendix 13). Subjects will be asked to 
complete the ESS with regard to the level of sleepiness they experienced over the past 7 days 
at Screening, Baseline; at Visits 3, 4, 5, and 6; and at the Safety Follow-up visit. The ESS 
provides a measure of a person’s general level of sleepiness, or their average sleep propensity 
in daily life. It is a validated measure with high specificity and sensitivity for assessing 
subjective sleepiness (Johns 1991; Broderick et al. 2013).  
6.12.2 
Movement Disorder Society-Unified Parkinson’s Disease Rating Scale – 
Parts III and IV 
The Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease 
Rating Scale (MDS-UPDRS) is a 4-part clinical rating scale for patients with Parkinson’s 
disease. Part III measures motor function by examination and Hoehn and Yahr staging, and 
Part IV measures dyskinesias, motor fluctuations, and “off dystonia” (Goetz et al. 2008; 
Appendix 14). Subjects will complete the MDS-UPDRS Parts III and IV at Baseline and at 
Visits 3, 4, 5, and 6. 
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6.12.3 
Maintenance of Wakefulness Test  
The MWT is the standard objective measure of an individual’s ability to remain awake in a 
darkened, quiet environment and is commonly used to assess response to treatment 
(Doghramji et al. 1997, Mitler et al. 1982, AASM 2014). Only for subjects enrolled in 
Group 1, a 3-trial (with the option to do a fourth trial), 40-minute MWT will be performed at 
the Baseline visit and at Visits 3, 4, 5, and 6.  
Each MWT during the study should be started at approximately the same time of the day. 
During the MWT trials, subjects should be seated in bed in a darkened room with the back 
and head supported by a bedrest (bolster pillow) such that their neck is not uncomfortably 
flexed or extended (Littner et al. 2005). Subjects will be instructed to sit still and remain 
awake for as long as possible during each of the three (or four) 40-minute trials separated by 
2-hour intervals. The first MWT trial should occur approximately 1 hour after dosing with 
study drug at all visits at which the MWT will be conducted. If the subject falls asleep during 
a trial, they will be awakened and instructed to remain awake until the next trial. If the 
subject does not fall asleep, then the specific trial is terminated at 40 minutes and a sleep 
latency of 40 minutes is recorded. The subject is then instructed to remain awake (and will be 
awoken if they fall asleep) until the next trial.  
Data from the MWT should be recorded and saved electronically, and any technician notes 
should also be maintained for potential transfer to Jazz Pharmaceuticals at the end of the 
study. A central reader will also evaluate all Baseline and Post-Baseline MWT trials for 
calculation of changes from Baseline.  
Before the start of the first MWT on a given day, subjects will be asked the following 
question: “How long did you sleep last night?” This information should be recorded and may 
be used as a factor in the statistical analysis. 
6.12.4 
Clinician Global Impression of Severity  
The CGIs is a 7-point Likert-type rating scale and a widely used assessment in clinical 
psychopharmacology trials to assess severity of illness (Appendix 15). The responses of this 
investigator-completed scale range from 1 = normal, no signs of illness to 7 = among the 
most extremely ill patients. The investigator will rate his/her impression of the severity of the 
subject’s current condition at Baseline relative to his/her experience with this patient 
population. 
6.12.5 
Clinician Global Impression of Change  
The CGIc is a 7-point Likert-type rating scale and a widely used assessment to assess 
efficacy in clinical drug trials (Appendix 16). Investigators will rate their impression of any 
change from baseline in the subject’s condition on a 7-point scale ranging from 1 = very 
much improved to 7 = very much worse at Visits 3, 4, 5, and 6. 
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6.12.6 
Patient Global Impression of Change  
The PGIc is a 7-point Likert-type rating scale and a widely used assessment to assess 
efficacy in clinical drug trials (Appendix 17). Subjects will rate the change from baseline in 
their condition on a 7-point scale ranging from 1 = very much improved to 7 = very much 
worse at Visits 3, 4, 5, and 6. 
6.12.7 
Apathy Scale 
The Apathy Scale assesses apathy in patients with PD (Starkstein et al. 1992) (Appendix 18). 
The maximum total score possible is 42, with higher scores indicating more severe apathy. 
Subjects will complete the Apathy Scale at Baseline and at Visits 3, 4, 5, and 6. 
6.12.8 
Fatigue Severity Scale 
The FSS, a 7-point Likert-type rating scale, is the most commonly used fatigue scale across 
all conditions and is recommended by the Movement Disorders Society Task Force for both 
fatigue screening and severity ratings in Parkinson’s disease (Friedman et al. 2010; 
Krupp et al. 1989) (Appendix 19). The scale consists of 9 items and the total score represents 
the mean score of each of the 9 items, yielding a score range between 1 and 7, with higher 
scores indicating a higher level of fatigue. Subjects will complete the FSS at Baseline and at 
Visits 3, 4, 5, and 6. 
6.12.9 
Scales for Outcomes of Parkinson’s Disease-Cognition 
The SCOPA-cog evaluates the specific cognitive deficits in PD (Marinus et al. 2003) 
(Appendix 20). The scale consists of 10 items with a total possible score of 43, with higher 
scores indicative of better cognition. Subjects will complete the SCOPA-cog at the 
Screening, Baseline, and at Visits 3, 4, 5, and 6. 
6.13 Pharmacokinetic Assessments 
6.13.1 
Blood Samples 
Subjects who enrolled in the study prior to Amendment 2 implementation would have 
participated in PK evaluation. Refer to Protocol Amendment 1 for the details regarding blood 
sample collection. 
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6.13.2 
Pharmacokinetic Parameters  
Plasma PK parameters to be calculated for JZP-110 concentrations will include, but may not 
be limited to, the following, as appropriate: 
AUC0-t  
Area under the plasma concentration versus time curve from time 0 to t hours, the 
last detectable concentration, calculated by means of the trapezoidal rule 
AUC0-inf  
Area under the plasma concentration versus time curve from time 0 to infinity, 
calculated as AUC = AUC0-t + Ct /Kel, where Ct is concentration at time t, and 
Kel is the elimination rate constant estimated from the fitted terminal elimination 
phase (see Kel) 
Cmax    
Maximum plasma drug concentration 
Tmax    
Time to reach Cmax 
t1/2   
Apparent terminal elimination half-life, calculated as ln(2)/ Kel 
Kel   
Apparent elimination rate constant estimated by unweighted log-linear regression 
of the last portion of the plasma concentration profile. This log-linear regression 
will be fitted according to the least-squares approach. Starting with the last 
3 quantifiable measurements and stepping back, the best fit will be determined by 
minimizing the residual sums of squares; the time interval and the number of 
time points used for this optimal fit will be provided. 
CL/F 
Apparent oral clearance (calculated as Dose/AUCinf) 
Vd/F 
Apparent oral volume of distribution (calculated as oral clearance/Kel) 
 
6.14 Adverse Event Reporting 
6.14.1 
Adverse Events  
An AE is any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered related to study drug or procedure.  
Adverse events include, but are not limited to: (1) a worsening or change in nature, severity, 
or frequency of conditions present at the start of the study; (2) subject deterioration due to 
primary illness; (3) intercurrent illness; (4) drug interaction; and/or (5) clinically significant 
laboratory findings that represent a worsening from the Screening visit. 
• Symptoms of the subject’s Parkinson’s disease or the underlying medical condition of 
excessive sleepiness in subjects with Parkinson’s disease are not considered as AEs 
unless there is an exacerbation of the symptoms from baseline at entry into the study. 
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• During the study, clinically significant adverse changes in ECGs, routine laboratory tests, 
vital signs, and physical examinations are considered AEs.  
 
All AEs, whether observed by the investigator, reported by the subject, determined from 
laboratory findings, or other means, should be documented. 
Subjects should be questioned in a general way, without asking about the occurrence of any 
specific symptom. The investigator should attempt to establish a diagnosis of the event based 
on signs, symptoms, and/or other clinical information. In such cases, the diagnosis, not the 
individual signs/symptoms, should be documented as the AE.  
Following questioning and evaluation, all AEs, whether believed by the investigator to be 
related or unrelated to the study drug or procedure, must be documented in the subject’s 
medical records, in accordance with the investigator’s normal clinical practice. Adverse 
events in randomized subjects must also be recorded on the eCRF in accordance with the 
eCRF completion guidelines. Each such AE is to be evaluated for duration, severity, 
seriousness, and causal relationship to the study drug and to study procedure. 
6.14.1.1 
Severity Assessment 
Adverse events will be classified by the investigator as mild, moderate, severe, 
life-threatening or fatal as defined below.  
Mild 
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Moderate 
Minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL)a. 
Severe 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting age-appropriate self-care ADLb. 
Life-
threatening 
Life-threatening consequences; urgent intervention indicated. 
Fatal 
Death related to AE. 
a  Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
b  Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden. 
6.14.1.2 
Serious Adverse Events  
Serious AEs (SAEs) must be reported to Jazz Pharmaceuticals or its designee using the SAE 
Reporting form within 24 hours of first knowledge of the event by study personnel. SAE 
Reporting forms and contact information will be provided to the study sites. For randomized 
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subjects, the event must also be entered on the AE eCRF in accordance with the eCRF 
completion guidelines. 
An SAE is an AE that fulfills any of the following criteria, as per Title 21 Code of Federal 
Regulations (CFR) 312.32 and ICH E2A.II.B.  
• Is fatal (results in death) 
• Is life-threatening (Note: the term “life-threatening” refers to an event in which the 
subject was at immediate risk of death at the time of the event; it does not refer to an 
event that could hypothetically have caused death had it been more severe) 
• Requires inpatient hospitalization or prolongs existing hospitalization 
• Results in persistent or significant incapacity or disability, defined as substantial 
disruption of the ability to conduct normal life functions 
• Is a congenital anomaly/birth defect 
• Is an important medical event  
−Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based on appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above in the definition of an 
SAE.  
−Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that 
do not result in inpatient hospitalization, and the development of drug dependency 
or drug abuse. 
−Additionally, any suspected transmission of an infectious agent via a medicinal 
product should be reported as an important medical event. 
 
A hospitalization is NOT considered an SAE if: 
• It is planned prior to subject entering trial 
• It is for social reasons and respite care in the absence of any deterioration in the subject’s 
general condition 
• It is elective in nature and not related to worsening of an underlying condition 
 
Complications that occur during hospitalizations are AEs. If a complication prolongs the 
hospitalization, it is an SAE. 
“In-patient hospitalization” means the subject has been formally admitted to a hospital for 
medical reasons, for any length of time. Emergency room care without admission to a 
hospital is considered outpatient care. 
Overdose of study drug (i.e., anything exceeding the dose prescribed in the protocol, either 
intentional or unintentional), medication error, or drug misuse are SAEs only if any of the 
seriousness criteria are met. 
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The SAE Reporting form must be completed as thoroughly as possible before transmittal to 
the contact provided. The investigator must provide his/her assessment of causality 
(relationship) to study drug and procedure at the time of the initial report. Where the 
investigator does not provide causality assessment of the SAE at the time of the initial report, 
the event by default will be presumed “Related.” Follow-up SAE information must be 
provided to Jazz Pharmaceuticals or its designee if there are any updates to the SAE 
information previously provided, including any change in the investigator’s assessment of 
causality. 
6.14.1.3 
Causal Relationship to Study Drug or Procedure 
The investigator’s assessment of the relationship of an AE to study drug and to study 
procedure is required. The relationship or association of the study drug or procedure in 
causing or contributing to the AE will be characterized using the following classification and 
criteria:  
Related 
or 
Suspected 
to be 
Related 
to Study 
Drug or 
Procedure 
There is a reasonable possibility that the study drug or procedure 
caused the event—i.e., there is evidence to suggest a causal 
relationship between the study drug or procedure and the AE.  
Some temporal relationship exists between the event and the 
administration of the study drug or procedure and the event is 
unlikely to be explained by the subject’s medical condition, other 
therapies, or accident.  
The event follows a reasonable temporal sequence from 
administration of the study drug or procedure and at least one of the 
following instances of clinical evidence: 
• The event follows a known or suspected response pattern to the 
study drug or procedure. 
• The event improves upon stopping the study drug or procedure 
or decreasing the dose (positive dechallenge). 
• The event reappears upon repeated exposure (positive 
rechallenge) if medically appropriate.  
Not 
Related 
to Study 
Drug or 
Procedure 
There is not a reasonable possibility or clinical evidence that the 
study drug or procedure caused the event. 
The event can be readily explained by other factors such as the 
subject’s underlying medical conditions, concomitant therapy, or 
accident; or there is no temporal relationship between study drug or 
procedure and the event. 
 
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6.14.1.4 
Other Immediately Reportable Experiences 
The following immediately reportable experiences may occur during participation in this 
clinical trial and must be reported within 24 hours of first knowledge of the event by study 
personnel to the appropriate Jazz Pharmaceuticals contact or designee: 
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) with a 3-fold or 
greater elevation above the ULN in addition to an elevation of serum total bilirubin 
greater than 2 times the ULN, with no other identifiable etiology 
• Liver enzyme (AST, ALT) value greater than or equal to 5 times the ULN 
• An overdose of study drug defined as anything exceeding the dose prescribed in the 
protocol (either intentional or unintentional), medication error, or drug misuse 
• Active suicidal ideation or behavior (e.g., a positive response to Question 4 or 5 on the 
C-SSRS)  
 
As with SAEs (Section 6.14.1.2), immediately reportable experiences must be reported on 
the SAE Reporting form, which should be completed as thoroughly as possible before 
transmittal to the contact provided. The investigator must provide his/her assessment of 
causality to study drug and study procedure at the time of the initial report.  For randomized 
subjects, these experiences must also be entered as AEs on the AE eCRF in accordance with 
the eCRF completion guidelines. 
6.14.1.5 
Adverse Event and Serious Adverse Event Recording and Reporting Timeframe 
The investigator must document all AEs and SAEs that occur during the study from the time 
written informed consent is obtained until the final study visit or early termination, regardless 
of their relationship to study drug or procedure. Adverse events and SAEs in randomized 
subjects must also be recorded on the eCRF in accordance with the eCRF completion 
guidelines. 
SAEs and immediately reportable experiences must be reported within 24 hours of first 
knowledge of the event by study personnel as described in Section 6.14.1.2 and 6.14.1.4. 
If an investigator becomes aware of an SAE within 30 days after the last dose of study drug, 
the event must be documented and reported as described in Section 6.14.1.2. 
Any SAE assessed as related to study drug or procedure by the investigator must be reported 
regardless of time after study termination. 
6.14.1.6 
Follow-up of Adverse Events and Serious Adverse Events 
AEs and SAEs assessed as not related to study drug or procedure, including clinically 
significant laboratory tests, ECGs, or physical examination findings, must be followed until 
the event resolves, the condition stabilizes, the event is otherwise explained, or the final 
study visit occurs, whichever comes first.  
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AEs and SAEs assessed as related to study drug or procedure will be followed for as long as 
necessary to adequately evaluate the subject’s safety, or until the event resolves, the 
condition stabilizes, the event is otherwise explained, or the subject is lost to follow up. 
If the event resolves, a resolution date should be provided. For SAEs, a follow-up SAE 
Reporting form must be submitted to provide the final outcome of the event and if the event 
resolves, the resolution date.  
The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations indicated to elucidate the nature and/or causality of the AE. This may include 
additional clinical laboratory testing or investigations, examinations, histopathological 
examinations, or consultation with other health care professionals as is practical. 
6.14.2 
Regulatory Reporting 
Jazz Pharmaceuticals or its designee is responsible for safety reporting to the applicable 
regulatory authorities, concerned central ethics committees (CECs), and participating 
investigators, in accordance with ICH guidelines, the US CFR, the EU Clinical Trial 
Directive (2001/20/EC) and/or local regulatory requirements. 
The reference safety information for the determination of expectedness for JZP-110 is the 
Investigator’s Brochure. 
All suspected unexpected serious adverse reactions (SUSARs) will be reported to the 
applicable regulatory authorities, CECs, and all participating investigators no later than 
15 days after first knowledge of the event. 
SUSARs that are fatal or life-threatening will be reported to the applicable regulatory 
authorities, IRBs, and investigators (if required by local regulation) no later than 7 days after 
knowledge of such a case, and relevant follow-up information provided within an additional 
8 days. 
Once a year throughout the study, a report listing of all SUSARs (and SAEs if required by 
local regulation) that have occurred during the period and a report of the subject’s safety will 
be submitted to the applicable regulatory authorities and CECs. 
The subject’s treatment assignment may be unblinded for regulatory reporting purposes. 
Notification of the treatment assignment is only made known to those who require it for 
safety reporting and submission processes. All other individuals involved in the study, 
including the investigator, will remain blinded to the treatment assignment. Subjects will not 
be withdrawn from the study solely based on unblinding for safety reporting. 
Reporting of SAEs by the investigator to his or her local institutional review board 
(IRB)/ethics committee will be done in accordance with the standard operations procedures 
and policies of the IRB/ethics committee. Adequate documentation must be maintained 
showing that the IRB/ethics committee was properly notified. 
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6.14.3 
Pregnancy   
Pregnancy of a subject or a male subject’s partner is an immediately reportable event and 
must be reported within 24 hours of first knowledge of the event by study personnel to the 
appropriate Jazz Pharmaceuticals contact or designee.  
If a subject or a male subject’s partner becomes pregnant any time after the first dose of 
study drug is taken until 30 days after the last dose of study drug is taken, the pregnancy 
form will be used to report the pregnancy to Jazz Pharmaceuticals or its designee. 
The pregnancy of a subject or a male subject’s partner will be followed until the outcome of 
the pregnancy is known, and in the case of a live birth, for 6 months following the birth of 
the child. The infant follow-up form will be used to report information regarding the status of 
the infant. 
6.14.4 
Emergency Unblinding 
A subject’s treatment assignment should only be unblinded when knowledge of the treatment 
is necessary for immediate medical management of the subject. In the case of an immediate 
medical emergency, an investigator or his/her designee will be able to unblind a subject at 
any time via the IVRS/IWRS. Every attempt should be made to contact Jazz Pharmaceuticals 
or its designee before unblinding a subject as long as this does not compromise the safety of 
the subject. If a request for unblinding is received from an investigator, the medical monitor 
will discuss with the investigator the rationale for the request. A comment must be entered in 
the source documentation to specify the reason for unblinding, along with the date on which 
the blind was broken and the identity of the person authorizing the unblinding. Subjects for 
whom the blind is broken will be withdrawn from the study. 
If the request for unblinding is related to the occurrence of an SAE, all procedures for the 
reporting of an SAE must be followed (Section 6.14.1.2).  
6.14.5 
Removal of Subjects from the Trial or Study Drug 
All subjects are free to withdraw from participation in this study at any time, for any reason, 
and without prejudice. The investigator must withdraw any subject from the study if the 
subject states that he/she wants to stop participating in the study. 
The investigator, Jazz Pharmaceuticals or its designee may remove a subject from the study 
at any time and for any reason.  
If any of the criteria below are met during the study, study drug administration must be 
stopped and the subject must be discontinued from the study. 
• Active suicidal ideation or behavior (e.g., a positive response to Question 4 or 5 on the 
C-SSRS) 
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Clinical Trial Protocol: JZP166-201 Amendment 2 
 
 
 
 
 
 
 
CONFIDENTIAL 
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• 3-fold or greater elevation above the ULN of ALT or AST accompanied by an elevation 
of serum total bilirubin greater than 2 times the ULN 
• Liver enzyme (AST, ALT) value greater than or equal to 5 times the ULN 
• Serum creatinine ≥2 mg/dL 
• Positive urine drug screen (unless due to a prescription medication that is allowed by the 
protocol) 
• Positive pregnancy test 
• Subject demonstrates a QTcF interval of >450 msec for males and >470 msec for females 
(determinations should be based on at least 2 ECG recordings performed in close 
proximity prior to study drug discontinuation) 
• Subject experiences a serious adverse event that is considered related to study drug or 
procedure 
 
For all subjects who prematurely discontinue, an attempt should be made to perform all early 
termination assessments as indicated in Section 7.6. Subjects should be asked to return 
1 week later for a Safety Follow-up visit.  
The specific reason for the discontinuation should be documented on the termination eCRF. 
If a subject withdraws informed consent, the specific reason for withdrawing the informed 
consent should be stated. 
Adverse events resulting in termination will be followed to the satisfactory resolution and 
determination of outcome as ascertained by the investigator (and/or Jazz Pharmaceuticals or 
its designee). The data will be recorded on the appropriate eCRF. 
6.14.6 
Handling of Early Terminations 
If a subject terminates early from the study, either at his or her request or at the investigator’s 
discretion, the investigator will record the reason(s) for early termination on the relevant 
eCRF page and notify the medical monitor immediately. All subjects who terminate from the 
study early should undergo all Early Termination visit assessments as described in 
Section 7.5. 
It is vital to obtain follow-up data on any subject who terminated because of an AE, 
abnormal laboratory test, or ECG finding. In any case, every effort must be made to 
undertake safety follow-up procedures. 
6.14.7 
Jazz Pharmaceuticals’ Termination of Study 
Jazz Pharmaceuticals reserves the right to discontinue the study at any time for clinical or 
administrative reasons. 
Such a termination must be implemented by the investigator, if instructed to do so by Jazz 
Pharmaceuticals in a time frame that is compatible with the subject’s well-being. 
 
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Jazz Pharmaceuticals 
Clinical Trial Protocol: JZP166-201 Amendment 2 
 
 
 
 
 
 
 
CONFIDENTIAL 
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6.15 Appropriateness of Measurements 
The ESS is a validated measure with high specificity and sensitivity for assessing subjective 
sleepiness (Johns 1991; Broderick et al. 2013). While the ESS has been most frequently used 
as the primary or only assay of excessive sleepiness in PD studies, in a smaller number of 
studies the MWT has also been used as an additional assay (Bliwise et al. 2012; 
Hogl et al. 2002; Stevens et al. 2004; Razmy et al. 2004). The MWT is a validated objective 
measure of the ability to stay awake for a defined period of time and is particularly useful for 
determining efficacy of treatment in sleep disorder populations such as narcolepsy 
(Doghramji et al. 1997; Mitler et al. 1982). However, the MWT has not been specifically 
validated in PD, a population that experiences fluctuating nonmotor symptoms including 
greater day-to-day variability in sleepiness (Roth et al. 2003). Additionally, the CGIc and 
PGIc have been used extensively in clinical trials to assess efficacy and quality of life. 
For subjects who enroll in the study prior to Amendment 2 implementation, the PK profile of 
JZP-110 will be evaluated over an 8-hour period based on blood samples (4 mL) collected at 
predose and at 1, 2, 3, 4, 5, 6, and 7 to 8 (if feasible) hours after dosing at Visits 3, 4, 5, and 
6. PK/pharmacodynamic modeling or population PK/pharmacodynamic modeling may be 
used to explore exposure-response relationships in subjects with PD. 
The use of vital signs, clinical laboratory tests, standard AE reporting, and the questionnaires 
that have been selected to assess the safety of the study drug are appropriate since they are 
routinely used to assess the safety profile of drugs in clinical studies and pertinent to known 
risks of JZP-110. The C-SSRS is able to determine clinically meaningful points at which a 
person may be at risk for an impending suicide attempt (Posner et al. 2011). 
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Jazz Pharmaceuticals 
Clinical Trial Protocol: JZP166-201 Amendment 2 
 
 
 
 
 
 
 
CONFIDENTIAL 
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7 
STUDY ACTIVITIES 
The schedule of events for subjects enrolling in the MWT component of the study (Group 1) 
is presented in Appendix 1. Sample schedules for Group 1 are presented in Appendix 2 and 
Appendix 3. The schedule of events for subjects opting out of the MWT component of the 
study (Group 2) is presented in Appendix 4. Sample schedules for Group 2 are presented in 
Appendix 5 and Appendix 6. 
Visit windows and approximate times for assessments are provided below and in 
Appendix 1, Appendix 2, Appendix 3, Appendix 4, Appendix 5, and Appendix 6. In the case 
that an efficacy assessment is missed, not conducted within the specified number of days, 
failed, or conducted incorrectly, the investigator may conduct the assessment outside of the 
specified time window or repeat the assessment only with prior permission from Jazz 
Pharmaceuticals. Scheduled safety assessments should always be conducted, even if outside 
of the specified windows, and the date and time of their conduct should be recorded. Sites 
should complete informed consent procedures and collect a signed ICF from the subject prior 
to the conduct of any study procedures. Refer to Section 6 for full descriptions of all study 
assessments. 
7.1 
Screening/Visit 1 (Days –31 to -3) (For subjects in Both Groups 1 
and 2) 
Subjects may be screened over a maximum period of 29 days.  
Prior to performing any study procedures the subject will read the informed consent form and 
study personnel will address all questions. The subject will sign the consent form and study 
personnel will document that the subject read, expressed an understanding of, signed the 
informed consent form, and was given a copy of the signed document. 
• Obtain demographics. 
• Administer the ESS 
• Administer the Berlin Sleep Apnea Questionnaire and record results. 
• Assess the subject using the UK PDS Brain Bank Criteria.  
• Obtain medical history, including details of sleepiness symptoms, diagnosis, and any past 
and current primary and adjunctive therapies for excessive sleepiness. 
• Record all prior and concomitant medications, including OTC medications, health, and 
dietary supplements taken during the 30 days before screening; also record any 
medications used for the treatment of excessive sleepiness and PD since diagnosis. 
• Perform a physical examination including a full examination of body systems (excluding 
a full genitourinary exam) and a brief neurological examination. Record height and 
weight in ordinary indoor clothes (without shoes). 
• Calculate body mass index. 
• Obtain vital signs (systolic and diastolic blood pressure [seated and standing], pulse rate 
[seated and standing], respiratory rate, and body temperature), including at least 2 sets of 
blood pressure and pulse rate measurements in the seated position after the subject has 
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Jazz Pharmaceuticals 
Clinical Trial Protocol: JZP166-201 Amendment 2 
 
 
 
 
 
 
 
CONFIDENTIAL 
Page 65 of 115 
been resting and seated for at least 5 minutes. Next, standing blood pressure and pulse 
rate should be taken at 1 and 3 minutes after the subject has been standing. 
• Administer the QUIP-RS and record results. 
• Administer the BDI-2. 
• Administer the C-SSRS Baseline/Screening Version and record results. 
• Administer the SCOPA-cog. 
• Obtain a 12-lead ECG after the subject has been resting supine for at least 5 minutes. 
• Complete safety laboratory tests, including the following: 
◦ 
Obtain blood samples for serum chemistry and hematology tests including a 
serum pregnancy test for all females of childbearing potential (see Table 1 for 
definitions of childbearing potential). 
• Obtain a urine sample for urinalysis and urine drug screens. 
• Complete breath alcohol screen test. 
• A light breakfast may be served. 
• Document any AEs that occurred after the ICF was signed. 
• Review the inclusion and exclusion criteria (Section 4). 
• After eligibility criteria have been confirmed, provide eligible subjects with instructions 
on how to discontinue any excluded medications.  
• Schedule a Baseline/Randomization visit after the investigator has thoroughly reviewed 
results of all screening procedures and has confirmed all eligibility criteria. 
7.2 
Group 1: Baseline and Treatment Phase Study Activities (Subjects 
Participating in the MWT Component of the Study) 
IF THE SUBJECT IS NOT IN GROUP 1, GO TO SECTION 7.3. 
7.2.1 
Group 1: Baseline/Randomization/Visit 2 (Day -2 to -1) 
After a subject has successfully completed the screening procedures he or she will return to 
the investigative site to complete his or her baseline procedures. The subject may be admitted 
to the study center the day before (Day -2) the MWT to complete selected assessments 
provided that it falls within the visit window (listed in Appendix 2). Individual assessments 
should be performed on the same study day at approximately the same time of day across 
study visits. 
On admission to the study center in the morning (at approximately 8:00 AM on Day -1), 
complete the following (as listed in Appendix 2): 
• Document the date(s) that excluded medications were discontinued and any other 
changes to concomitant medications since screening. Record all AEs that occur after the 
ICF was signed. Verify and ensure PD and sleep medications were taken and continue to 
be taken at the same dose and regimen. For subjects currently receiving treatment for 
OSA, review OSA therapy device usage to ensure adequate compliance. 
• Administer the ESS Questionnaire. 
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Jazz Pharmaceuticals 
Clinical Trial Protocol: JZP166-201 Amendment 2 
 
 
 
 
 
 
 
CONFIDENTIAL 
Page 66 of 115 
•  Administer the MDS-UPDRS (Parts III and IV). When feasible, the MDS-UPDRS 
(Parts III and IV) is to be performed on the same study day and approximate same time 
for each subsequent visit while the subject is in the “on” state.  
• Complete the CGIs. 
• Perform physical examination. 
◦ 
Obtain weight in ordinary indoor clothes (without shoes). 
• Obtain vital signs (systolic and diastolic blood pressure [seated and standing], pulse rate 
[seated and standing], respiratory rate, and body temperature), including at least 2 sets of 
blood pressure and pulse rate measurements in the seated position after the subject has 
been resting and seated for at least 5 minutes. Next, standing blood pressure and pulse 
rate should be taken at 1 and 3 minutes after the subject has been standing. 
• 12-lead ECG after the subject has been resting supine for at least 5 minutes. 
• If the Baseline visit occurs outside of the screening window (i.e., >29 days after the 
Screening Visit), obtain safety laboratory blood samples for serum chemistry and 
hematology tests and a urine sample for urinalysis. Record if the samples were collected 
with the subject fasted or nonfasted. 
• Obtain a urine sample for a pregnancy test for all females of childbearing potential (see 
Table 1 for definitions of childbearing potential). 
• Complete breath alcohol screen test. 
• A light breakfast may be served. Breakfast should be completed within 15 to 20 minutes. 
• Obtain vital signs (systolic and diastolic blood pressure [seated and standing] and pulse 
rate [seated and standing]), including at least 2 sets of blood pressure and pulse rate 
measurements in the seated position after the subject has been resting and seated for at 
least 5 minutes. Next, standing blood pressure and pulse rate should be taken at 1 and 
3 minutes after the subject has been standing. 
• Initiate the first trial of the MWT. Before starting the MWT, ask the subject the following 
question: “How long did you sleep last night?” The first MWT trial should be started 
approximately 1.5 to 3 hours after the time of the subject arising that morning. 
• Obtain vital signs (systolic and diastolic blood pressure [seated and standing] and pulse 
rate [seated and standing]), including at least 2 sets of blood pressure and pulse rate 
measurements in the seated position after the subject has been resting and seated for at 
least 5 minutes. Next, standing blood pressure and pulse rate should be taken at 1 and 
3 minutes after the subject has been standing. 
• Complete the FSS, Apathy Scale, and SCOPA-cog. 
• Administer the C-SSRS Since Last Visit Version and record the results. 
• Approximately 2 hours after the start of the first MWT, initiate the second trial of the 
MWT.  
• Subjects should be served a light lunch immediately after the second trial of the MWT. 
• After the subject finishes lunch, obtain vital signs (systolic and diastolic blood pressure 
[seated and standing] and pulse rate [seated and standing]), including at least 2 sets of 
blood pressure and pulse rate measurements in the seated position after the subject has 
been resting and seated for at least 5 minutes. Next, standing blood pressure and pulse 
rate should be taken at 1 and 3 minutes after the subject has been standing. 
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Signature Date:
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JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: JZP166-201 Amendment 2 
 
 
 
 
 
 
 
CONFIDENTIAL 
Page 67 of 115 
• Approximately 2 hours after the start of the second MWT, initiate the third trial of the 
MWT. 
• [Optional Assessment] If feasible, approximately 2 hours after the start of the third 
MWT, initiate the fourth trial of the MWT. 
• Review the inclusion and exclusion criteria, including ESS results, to determine the 
subject’s continuing eligibility to participate in the study (Section 4). 
• Randomize to study Treatment Sequence A, B, or C (access IVRS/IWRS). 
• Document any AEs that occurred after the ICF was signed. 
• Dispense study drug and instruct subject on the daily dose administration to begin on the 
following morning (Day 1). 
• Remind the subject to bring the last dose of their study drug supply to the study center at 
their next visit. The subject will take their last dose of their study drug supply at the study 
center during the next visit. 
• Schedule the next return clinic visit. 
 
7.2.2 
Group 1: Treatment Phase (Day 7 [±1 day], Day 14 [±1 day], 
Day 21 [±1 day], and Day 28 [±1 day]) 
The subject may be admitted to the study center the day before the MWT to complete 
selected assessments (listed in Appendix 3), provided it falls within the visit window. 
Individual assessments should be performed on the same study day at approximately the 
same time of day across study visits.  
Subjects enrolling in the study after Amendment 2 implementation will not undergo PK 
evaluation. 
On admission to the investigative site in the morning (at approximately 8:00 AM) on 
Days 7 (±1), 14 (±1), 21 (±1), and 28 (±1), complete the following (as listed in Appendix 3): 
• Record all concomitant medications, including OTC medications, health, and dietary 
supplements taken since the last visit. Record all AEs. Verify PD medications, sleep 
medications allowed by the protocol, and study drug (as specified in Section 5.3 of the 
protocol) were taken and continue to be taken appropriately. For subjects currently 
receiving treatment for OSA, review OSA therapy device usage to ensure adequate 
compliance. 
• Administer the ESS Questionnaire. 
• Administer the MDS-UPDRS (Parts III and IV). When feasible, the MDS-UPDRS 
(Parts III and IV) is to be performed on the same study day and approximate same time 
for each subsequent visit while the subject is in the “on” state. 
• Complete the CGIc. 
• Perform physical examination. 
◦ 
Obtain weight in ordinary indoor clothes (without shoes). 
• Approximately 1 hour before dosing, obtain vital signs (systolic and diastolic blood 
pressure [seated and standing], pulse rate [seated and standing], respiratory rate, and body 
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Signature Date:
JP: JZP166-201 Protocol Amendment 2.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: JZP166-201 Amendment 2 
 
 
 
 
 
 
 
CONFIDENTIAL 
Page 68 of 115 
temperature), including at least 2 sets of blood pressure and pulse rate measurements in 
the seated position after the subject has been resting and seated for at least 5 minutes. 
Next, standing blood pressure and pulse rate should be taken at 1 and 3 minutes after the 
subject has been standing. 
• 12-lead ECG after the subject has been resting supine for at least 5 minutes. 
• Obtain safety laboratory blood samples for serum chemistry and hematology tests and a 
urine sample for urinalysis. 
• Obtain a urine sample for a pregnancy test for all females of childbearing potential (see 
Table 1 for definitions of childbearing potential). 
• Complete breath alcohol screen test. 
• Observe study drug administration by the subject. 
• Approximately 15 minutes after dosing, subjects may be served a light breakfast. 
Breakfast should be completed within 15 to 20 minutes. 
• Approximately 50 minutes after dosing, obtain vital signs (systolic and diastolic blood 
pressure [seated and standing] and pulse rate [seated and standing]), including at least 
2 sets of blood pressure and pulse rate measurements in the seated position after the 
subject has been resting and seated for at least 5 minutes. Next, standing blood pressure 
and pulse rate should be taken at 1 and 3 minutes after the subject has been standing. 
• Approximately 1 hour after dosing, initiate the first trial of the MWT. Before starting the 
MWT, ask the subject the following question: “How long did you sleep last night?” The 
first MWT trial should be started approximately 1.5 to 3 hours after the time of the 
subject arising that morning. 
• Approximately 2 hours after dosing, obtain vital signs (systolic and diastolic blood 
pressure [seated and standing] and pulse rate [seated and standing]), including at least 
2 sets of blood pressure and pulse rate measurements in the seated position after the 
subject has been resting and seated for at least 5 minutes. Next, standing blood pressure 
and pulse rate should be taken at 1 and 3 minutes after the subject has been standing. 
• Complete the PGIc, FSS, Apathy Scale, and the SCOPA-cog. 
• Administer the C-SSRS Since Last Visit Version and record the results. 
• Approximately 3 hours after dosing, initiate the second trial of the MWT. 
• Subjects should be served a light lunch immediately after the second trial of the MWT. 
• Approximately 4 hours after dosing, obtain vital signs (systolic and diastolic blood 
pressure [seated and standing] and pulse rate [seated and standing]), including at least 
2 sets of blood pressure and pulse rate measurements in the seated position after the 
subject has been resting and seated for at least 5 minutes. Next, standing blood pressure 
and pulse rate should be taken at 1 and 3 minutes after the subject has been standing. 
• Approximately 5 hours after dosing, initiate the third trial of the MWT. 
• Approximately 6 hours after dosing, obtain vital signs (systolic and diastolic blood 
pressure [seated and standing] and pulse rate [seated and standing]), including at least 
2 sets of blood pressure and pulse rate measurements in the seated position after the 
subject has been resting and seated for at least 5 minutes. Next, standing blood pressure 
and pulse rate should be taken at 1 and 3 minutes after the subject has been standing. 
• Approximately 6 hours after dosing, obtain a 12-lead ECG after the subject has been 
resting supine for at least 5 minutes. 
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Signature Date:
JP: JZP166-201 Protocol Amendment 2.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: JZP166-201 Amendment 2 
 
 
 
 
 
 
 
CONFIDENTIAL 
Page 69 of 115 
• [Optional Assessment] If feasible, approximately 7 hours after dosing, initiate the fourth 
trial of the MWT. 
• Document any AEs that occurred since the last visit. 
• The safety findings will be reviewed by the investigator, who will decide whether or not 
to proceed to the next dose. 
• Dispense study drug and instruct subject on the daily dose administration to begin on the 
following morning. 
• Complete drug accountability. 
• Schedule the next return clinic visit.  
 
7.3 
Group 2: Baseline and Treatment Phase Study Activities (Subjects 
Opting Out of the MWT Component of the Study) 
7.3.1 
Group 2: Baseline/Randomization/Visit 2 (Day -1) 
After a subject has successfully completed the screening procedures, he or she will return to 
the investigative site to complete his or her baseline procedures. 
On admission to the study center in the morning (at approximately 8:00 AM on Day -1), 
complete the following (as listed in Appendix 5): 
• Document the date(s) that excluded medications were discontinued and any other 
changes to concomitant medications since screening. Record all AEs that occur after the 
ICF was signed. Verify and ensure PD and sleep medications were taken and continue to 
be taken at the same dose and regimen. For subjects currently receiving treatment for 
OSA, review OSA therapy device usage to ensure adequate compliance. 
• Administer the ESS Questionnaire. 
• Administer the C-SSRS Since Last Visit Version and record the results. 
• Obtain vital signs (systolic and diastolic blood pressure [seated and standing], pulse rate 
[seated and standing], respiratory rate, and body temperature), including at least 2 sets of 
blood pressure and pulse rate measurements in the seated position after the subject has 
been resting and seated for at least 5 minutes. Next, standing blood pressure and pulse 
rate should be taken at 1 and 3 minutes after the subject has been standing. 
• Perform physical examination. 
◦ 
Obtain weight in ordinary indoor clothes (without shoes). 
• If the Baseline visit occurs outside of the screening window (i.e., >29 days after the 
Screening Visit), obtain safety laboratory blood samples for serum chemistry and 
hematology tests and a urine sample for urinalysis. Record if the samples were collected 
with the subject fasted or nonfasted. 
• Obtain a urine sample for a pregnancy test for all females of childbearing potential (see 
Table 1 for definitions of childbearing potential). 
• Complete breath alcohol screen test. 
• A light breakfast may be served. Breakfast should be completed within 15 to 20 minutes. 
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Signature Date:
JP: JZP166-201 Protocol Amendment 2.pdf
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Jazz Pharmaceuticals 
Clinical Trial Protocol: JZP166-201 Amendment 2 
 
 
 
 
 
 
 
CONFIDENTIAL 
Page 70 of 115 
• Approximately 2 hours after the first set of vital signs are taken, obtain a second set of 
vital signs (systolic and diastolic blood pressure [seated and standing] and pulse rate 
[seated and standing]), including at least 2 sets of blood pressure and pulse rate 
measurements in the seated position after the subject has been resting and seated for at 
least 5 minutes. Next, standing blood pressure and pulse rate should be taken at 1 and 
3 minutes after the subject has been standing. 
• Complete the FSS, Apathy Scale, and SCOPA-cog. 
• Approximately 1 hour after the second set of vital signs are taken, obtain a third set of 
vital signs (systolic and diastolic blood pressure [seated and standing] and pulse rate 
[seated and standing]), including at least 2 sets of blood pressure and pulse rate 
measurements in the seated position after the subject has been resting and seated for at 
least 5 minutes. Next, standing blood pressure and pulse rate should be taken at 1 and 
3 minutes after the subject has been standing. 
• 12-lead ECG after the subject has been resting supine for at least 5 minutes. 
• Complete the CGIs. 
• Administer the MDS-UPDRS (Parts III and IV). When feasible, the MDS-UPDRS 
(Parts III and IV) is to be performed at approximately the same time for each subsequent 
visit while the subject is in the “on” state.  
• Review the inclusion and exclusion criteria, including ESS results, to determine the 
subject’s continuing eligibility to participate in the study (Section 4). 
• Randomize to study Treatment Sequence A, B, or C (access IVRS/IWRS). 
• Document any AEs that occurred after the ICF was signed. 
• Dispense study drug and instruct subject on the daily dose administration to begin on the 
following morning (Day 1). 
• Remind the subject to bring the last dose of their study drug supply to the study center at 
their next visit. The subject will take their last dose of their study drug supply at the study 
center during the next visit. 
• Schedule the next return clinic visit. 
 
7.3.2 
Group 2: Treatment Phase (Day 7 [±1 day], Day 14 [±1 day], 
Day 21 [±1 day], and Day 28 [±1 day]) 
Individual assessments should be performed at approximately the same time of day across 
study visits. 
Subjects enrolling in the study after Amendment 2 implementation will not undergo PK 
evaluation. 
On admission to the investigative site in the morning (at approximately 8:00 AM) on 
Days 7 (±1), 14 (±1), 21 (±1), and 28 (±1), complete the following (as listed in Appendix 6): 
• Record all concomitant medications, including OTC medications, health, and dietary 
supplements taken since the last visit. Record all AEs. Verify PD medications, sleep 
medications allowed by the protocol, and study drug (as specified in Section 5.3 of the 
Confidential
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Signature Date:
JP: JZP166-201 Protocol Amendment 2.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: JZP166-201 Amendment 2 
 
 
 
 
 
 
 
CONFIDENTIAL 
Page 71 of 115 
protocol) were taken and continue to be taken appropriately. For subjects currently 
receiving treatment for OSA, review OSA therapy device usage to ensure adequate 
compliance. 
• Approximately 1 hour before dosing, obtain vital signs (systolic and diastolic blood 
pressure [seated and standing], pulse rate [seated and standing], respiratory rate, and body 
temperature), including at least 2 sets of blood pressure and pulse rate measurements in 
the seated position after the subject has been resting and seated for at least 5 minutes. 
Next, standing blood pressure and pulse rate should be taken at 1 and 3 minutes after the 
subject has been standing. 
• 12-lead ECG after the subject has been resting supine for at least 5 minutes. 
• Perform physical examination. 
◦ 
Obtain weight in ordinary indoor clothes (without shoes). 
• Obtain safety laboratory blood samples for serum chemistry and hematology tests and a 
urine sample for urinalysis. 
• Obtain a urine sample for a pregnancy test for all females of childbearing potential (see 
Table 1 for definitions of childbearing potential). 
• Complete breath alcohol screen test. 
• Observe study drug administration by the subject. 
• Approximately 15 minutes after dosing, subjects may be served a light breakfast. 
Breakfast should be completed within 15 to 20 minutes. 
• Approximately 1 hour after dosing, obtain vital signs (systolic and diastolic blood 
pressure [seated and standing] and pulse rate [seated and standing]), including at least 
2 sets of blood pressure and pulse rate measurements in the seated position after the 
subject has been resting and seated for at least 5 minutes. Next, standing blood pressure 
and pulse rate should be taken at 1 and 3 minutes after the subject has been standing. 
• Administer the ESS Questionnaire. 
• Complete the PGIc, FSS, Apathy Scale, and the SCOPA-cog. 
• Administer the C-SSRS Since Last Visit Version and record the results. 
• Approximately 2 hours after dosing, obtain vital signs (systolic and diastolic blood 
pressure [seated and standing] and pulse rate [seated and standing]), including at least 
2 sets of blood pressure and pulse rate measurements in the seated position after the 
subject has been resting and seated for at least 5 minutes. Next, standing blood pressure 
and pulse rate should be taken at 1 and 3 minutes after the subject has been standing. 
• Approximately 2 hours after dosing, 12-lead ECG after the subject has been resting 
supine for at least 5 minutes. 
• Complete the CGIc. 
• Administer the MDS-UPDRS (Parts III and IV). When feasible, the MDS-UPDRS 
(Parts III and IV) is to be performed at approximately the same time for each subsequent 
visit while the subject is in the “on” state. 
• Document any AEs that occurred since the last visit. 
• The safety findings will be reviewed by the investigator, who will decide whether or not 
to proceed to the next dose. 
• Dispense study drug and instruct subject on the daily dose administration to begin on the 
following morning. 
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• Complete drug accountability. 
• Schedule the next return clinic visit.  
 
7.4 
Follow-up (Day 35 [±1 day]) (For Subjects in Both Groups 1 and 2) 
At the Follow-up Visit, perform the following: 
• Record all concomitant medications, including OTC medications, health, and dietary 
supplements taken since the last visit. 
• Complete physical examination. 
◦ 
Obtain weight in ordinary indoor clothes (without shoes). 
• Obtain vital signs (systolic and diastolic blood pressure [seated and standing], pulse rate 
[seated and standing], respiratory rate, and body temperature), including at least 2 sets of 
blood pressure and pulse rate measurements in the seated position after the subject has 
been resting and seated for at least 5 minutes. Next, standing blood pressure and pulse 
rate should be taken at 1 and 3 minutes after the subject has been standing.  
• Obtain a 12-lead ECG after the subject has been resting supine for at least 5 minutes. 
• Obtain safety laboratory blood samples for serum chemistry and hematology tests and a 
urine sample for urinalysis.  
• Obtain a urine sample for a pregnancy test for all females of childbearing potential (see 
Table 1 for definitions of childbearing potential). 
• Complete breath alcohol screen test. 
• Administer the C-SSRS Since Last Visit Version and record the results. 
• Complete the ESS Questionnaire. 
• Document any AEs that occurred since the last visit. Document the outcome of any 
ongoing AEs. 
 
Unless any safety issues are identified that require follow-up, the study will be considered 
completed and the subject will be discharged from the study. Subjects will be instructed to 
follow-up with their healthcare provider regarding the resumption of any medications that 
were discontinued prior to study participation. 
7.5 
Early Termination Visit (For Subjects in Both Groups 1 and 2) 
If a subject withdraws and is unable or unwilling to take additional study drug, the following 
safety and final assessments should be conducted.  
• Record all concomitant medications, including OTC medications, health, and dietary 
supplements taken since the last visit. 
• Perform a physical examination including a full examination of body systems (excluding 
a full genitourinary exam) and a brief neurological examination. 
◦ 
Obtain weight in ordinary indoor clothes (without shoes). 
• Obtain vital signs (systolic and diastolic blood pressure [seated and standing], pulse rate 
[seated and standing], respiratory rate, and body temperature), including at least 2 sets of 
blood pressure and pulse rate measurements in the seated position after the subject has 
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been resting and seated for at least 5 minutes. Next, standing blood pressure and pulse 
rate should be taken at 1 and 3 minutes after the subject has been standing. 
• Obtain a 12-lead ECG after the subject has been resting supine for at least 5 minutes. 
• Obtain safety laboratory blood samples for serum chemistry and hematology tests and a 
urine sample for urinalysis. 
• Obtain a urine sample for a pregnancy test for all females of childbearing potential (see 
Table 1 for definitions of childbearing potential). 
• Complete breath alcohol screen test.  
• A light breakfast may be served after blood samples are collected. 
• Administer the C-SSRS Since Last Visit Version and record the results. 
• Document any AEs that occurred since the last visit. Document the outcome of any 
ongoing AEs. 
• Complete drug accountability. 
• Schedule a 1-week Safety Follow-up visit, if the subject is willing to continue with 
follow-up procedures. 
 
7.6 
Discontinuations 
If a subject is withdrawn before completing the study, the reason for withdrawal will be 
entered on the appropriate eCRF. The specific reason for the withdrawal should be 
documented on the eCRF. For instance, rather than stating “withdrew informed consent,” the 
specific reason for withdrawing the informed consent should be stated. Whenever possible 
and reasonable, the evaluations that were to be conducted during the final study visit should 
be performed at the time of premature discontinuation.  
It is vital to obtain follow-up data on any subject who terminated because of an AE, 
abnormal laboratory test, or ECG finding. In any case, every effort must be made to ensure 
safety follow-up procedures are completed. 
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8 
QUALITY CONTROL AND ASSURANCE 
The study will be conducted according to GCP guidelines and according to national law. 
Quality control audits may be performed at the discretion of Jazz Pharmaceuticals. 
 
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9 
PLANNED STATISTICAL METHODS 
9.1 
General Considerations 
All study data will be summarized by treatment or treatment sequence as appropriate. 
Categorical variables will be reported as frequency and percent (e.g., gender, race). 
Continuous variables will be reported as number of subjects with observations, mean, 
standard deviation (SD), median, minimum and maximum (e.g., age, weight). Listings will 
include the group number (e.g., Group 1 or Group 2) in which a subject was enrolled. All 
summaries, statistical analyses, and individual subject data listings described in this section 
will be produced using Version 9.3 or later of the SAS Statistical Analysis System (SAS 
Institute, Inc. Cary, NC). 
9.2 
Tests of Hypotheses and Significance Levels 
Safety and tolerability of JZP-110 is the primary objective of this study. No inferential 
statistics will be provided for safety endpoints.  
To address the key efficacy objective of treatment effect on the change in ESS in an 
exploratory manner, pairwise treatment difference against placebo will be tested as part of 
the mixed-effects model described in Section 9.12 using a 2-sided test at 0.05 level.  
9.3 
Determination of Sample Size 
Approximately 49 subjects will be randomized to the 3 sequence groups (A, B, and C) with 
the goal of 40 subjects completing the study: 34 subjects each in Sequences A and B, and up 
to 6 subjects in sequence C. The randomization ratio implemented will be 3:3:1 with 
expected randomization of subjects to sequences being approximately 21:21:7. 
Although the primary objective of this study is to assess safety, efficacy endpoint-based 
power calculations were performed for reference. A sample size of 34 subjects (assuming 
17 completing in each of the Sequences A and B) will provide 80% power to detect a 
difference of 3 points in the change from baseline in ESS score between 1 of the JZP-110 and 
placebo groups not adjusting for multiple comparisons. This calculation assumes a common 
SD of 6 points for the change from baseline in ESS score and a 2-sided significance level of 
0.05 using an analysis of variance (ANOVA)-based t-test for difference of means in a 
crossover design. The primary purpose of placebo Sequence C is to preserve study blinding. 
9.4 
Analysis Populations  
The safety population will consist of all subjects who received at least 1 dose of study drug. 
This population will be analyzed for safety evaluations and will be presented in the tables 
and listings of safety data.  
The modified intent-to-treat (mITT) Population will include subjects who were randomized, 
received at least 1 dose of study medication and have baseline and at least 1 postbaseline 
evaluation of ESS. This population will also be analyzed for exploratory efficacy endpoints.  
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The PK population will consist of all subjects who enrolled under the Original Protocol or 
Amendment 1 and received study drug and provided postdose PK data for at least 1 time 
point.  
The key efficacy population will consist of subjects in the mITT population from Sequences 
A and B only. Exploratory efficacy analyses will be performed on subjects from sequences 
A, B, and C. The details of how these populations are defined will be specified in the 
Statistical Analysis Plan. 
9.5 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized for the safety population and 
the mITT population. The summaries of data will include frequencies and percentages for 
categorical variables and mean, SD, median, minimum and maximum for continuous 
variables. 
9.6 
Handling of Dropouts and Missing Data 
All available data will be presented in descriptive summaries and included in statistical 
models as appropriate. All subjects who are included in the safety, mITT, or PK population 
will be included in analyses, and their missing data will not be imputed.  
9.7 
Pooling of Investigation Centers 
Data from all investigational centers will be pooled together for all analyses. 
9.8 
Primary Objective 
The primary objective of this study is the safety and tolerability of JZP-110 administered to 
subjects with excessive sleepiness and PD. This will be assessed by the occurrence of and/or 
clinically significant changes in: 
• Treatment-emergent AEs 
• Discontinuations due to AEs 
• Clinical laboratory tests (chemistry, hematology, and urinalysis) 
• Vital signs 
• 12-lead ECGs 
• Physical examination 
• C-SSRS 
 
9.9 
 Key Efficacy Endpoint 
The key efficacy endpoint is defined in terms of change from study baseline (prior to first 
dose in Period 1) to the end of each Treatment Period (Weeks 1, 2, 3, and 4); and consists of 
the following: 
• Change from Baseline in ESS (Epworth Sleepiness Scale) score   
 
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9.10 Exploratory Endpoints 
Exploratory efficacy endpoints include the following as measured by the change from 
Baseline in scores (prior to first dose in Period 1) to the end of each Treatment Period 
(Weeks 1, 2, 3, and 4) for each of the following assessments: 
• Mean sleep latency time (in minutes), as determined from the 40-minute MWT 
• MDS-UPDRS Parts III and IV 
• CGIc 
• PGIc 
• FSS 
• Apathy Scale 
• SCOPA-cog 
 
9.11 Pharmacokinetic Analysis 
Pharmacokinetic analysis will include estimation of the following parameters of interest: 
Cmax, Tmax, t1/2, and area under the curve (AUC), as appropriate. Pharmacokinetic parameters 
will be estimated for subjects in the PK population who have evaluable PK data. 
9.12 Efficacy Analysis 
For the analysis of the key efficacy endpoints of change from baseline in ESS, a 
mixed-effects model will be used as the primary method of analysis. This model will include 
fixed effects for treatment (dose), sequence, treatment-by-sequence interaction, and baseline 
value of the efficacy endpoint. The model will also include a random effect for subject within 
sequence.  
SAS procedure PROC MIXED will be used to carry out this analysis. All available data will 
be included in the model. The estimates of treatment difference versus placebo and 
associated 95% confidence intervals will be presented.  
Additional statistical methodologies will be explored to aid in the interpretation of the study 
results due to treatment-by-sequence interaction and carryover effects. The details will be 
provided in the Statistical Analysis Plan. 
For the analysis of the MWT exploratory endpoint, a similar mixed-effects model as for ESS 
will be used. However, because the MWT will be optional and consequently result in a 
reduced sample size, there may be convergence issues associated with the mixed-effects 
model. In the event such issues do arise, an analysis of covariance (ANCOVA) model 
without accounting for treatment sequence may be used at each visit. 
For the analysis of efficacy endpoints of improvement in PGIc and CGIc, the chi-squared test 
will be used to test the hypotheses of difference between placebo and each active dose  
A mixed-effects model similar to the model described above will be used for the analysis of 
MDS-UPDRS, FSS, Apathy Scale, and SCOPA-cog endpoints. Details of the analyses will 
be specified in the Statistical Analysis Plan.    
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As a sensitivity analysis, the efficacy endpoint summary may be reported separately for 
Groups 1 and 2 to address any potential selection bias. 
In addition, due to the removal of MWT as an eligibility criterion in Protocol Amendment 2, 
the efficacy endpoint summary may also be reported separately for subjects with eligible 
MWT at study entry versus those with either ineligible or missing MWT at study entry. 
No adjustment for multiple testing will be performed. 
Summary statistics for all efficacy assessments/endpoints will be presented by treatment 
dose. 
9.13 Safety Analysis 
9.13.1 
Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities system 
to classify events under primary system organ class and preferred term. The number and 
percent of subjects who experienced TEAEs, TEAEs related to study drug, or SAEs; who 
died during the study; or who discontinued study drug or withdrew from the study due to an 
AE will be summarized by treatment at onset. Results will be presented by system organ 
class, and preferred term.  
A TEAE is defined as an AE that either began after first study drug dose or worsened after 
the first dose. When determining the percent of subjects who experience an AE, multiple 
increases in severity are only counted as one AE. For example, a subject who develops a mild 
headache after the first study drug dose (that was not present during screening or at baseline), 
which subsequently worsens to moderate, then severe, is only counted once under the 
preferred term of headache.  
For all AE summaries, if a subject has more than one AE within a preferred term on a given 
dose, the subject is counted only once at the maximum severity and with the closest 
relationship to study drug. If a subject has more than one AE within a system organ class, the 
subject is similarly counted once when reporting results for that system organ class. 
All AE data will be listed.   
9.13.2 
Vital Signs 
Vital signs will be summarized at baseline, at each postbaseline visit, and within each visit 
across time. Change from baseline to each postbaseline visit in each vital sign parameter will 
also be summarized. The summaries will include descriptive statistics (i.e., mean, median, 
minimum, maximum, SD, and number of subjects) as well as graphs, and will be presented 
by treatment (dose) group, and by sequence. 
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The number and percentage of subjects with clinically significant changes from baseline to 
each postbaseline visit in blood pressure and heart rate will be summarized. The ranges will 
be prespecified in the Statistical Analysis Plan. 
Blood pressure and heart rate will also be categorized as falling within or outside of normal 
ranges. Frequency counts and percentages will be presented by treatment (dose) group, and 
by sequence. In addition, shifts in these categories from baseline to each postbaseline visit 
will be summarized by treatment (dose) group and by sequence group. The ranges will be 
prespecified in the Statistical Analysis Plan. 
The blood pressure and pulse results obtained on MWT days will be summarized separately, 
in a similar fashion. 
In addition, blood pressure and heart rate will be analyzed separately for the subset of 
subjects who meet criteria for clinically significant orthostatic hypotension. 
A listing of subjects who have clinically significant vital sign values will be generated.  
Detailed vital signs analyses, and the statistical derivation of the algorithms to be used to 
derive variables for clinically significant changes will be specified in the Statistical Analysis 
Plan based on data observed in other JZP-110 studies during the conduct of this study. 
9.13.3 
Laboratory Evaluation 
The number and percent of subjects with abnormal values post-baseline will be tabulated by 
treatment. In addition, summary statistics (i.e., mean, minimum, maximum, SD, and number 
of subjects) will be presented by treatment/dose group for each laboratory. An additional 
listing of subjects with clinically significant laboratory values will be generated. Detailed 
laboratory value analyses, and the algorithms to derive variables for the clinically significant 
changes will be specified in the Statistical Analysis Plan. 
 
9.13.4 
12-Lead Electrocardiograms 
Electrocardiogram intervals and durations will be reviewed for notable abnormalities, and 
clinically notable abnormalities and findings considered to be clinically significant will be 
listed. The number and percent of subjects who have a clinically notable ECG interval 
abnormality or other clinically significant ECG finding will be summarized. A listing of 
abnormal ECG values will also be provided. Detailed ECG value analyses and the algorithms 
to derive variables for the clinically significant changes will be specified in the Statistical 
Analysis Plan. 
Electrocardiogram parameter values (HR, RR, PR, QRS, QT, and QT corrected with 
Fridericia’s formula [QTcF]) will be summarized at baseline, at each postbaseline visit, and 
within each visit across time by treatment group (dose) and by sequence. The number and 
percentage of subjects with QT and QTcF values falling within or outside of normal ranges 
will be summarized by treatment (dose) groups and by sequence. The number and percentage 
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of subjects with other clinically significant ECG findings will also be summarized at each 
postbaseline time point by treatment (dose) and by sequence group. 
9.13.5 
Physical Examinations 
For randomized subjects, a finding identified by the investigator as abnormal on the physical 
examination at the Screening visit will be recorded on the Medical History eCRF; whereas, a 
clinically significant adverse change (i.e., worsening) of a physical examination finding after 
screening will be recorded as an AE. 
 
9.13.6 
Columbia-Suicide Severity Rating Scale  
Data from the Since Last Visit Version of the C-SSRS will be summarized by treatment 
(dose) group according to the Columbia Classification Algorithm of Suicide Assessment 
(Posner et al. 2007). 
 
9.14 Analysis of Pharmacokinetic and Pharmacodynamic Variables 
PK analyses will be performed for subjects in the PK population who have evaluable PK 
data. 
Individual plasma JZP-110 concentrations and corresponding PK parameters will be listed by 
treatment. Descriptive statistics including number of subjects, mean, SD, minimum, median, 
maximum, coefficient of variation, geometric mean, and geometric SD will be used to 
summarize concentration data and PK parameters by treatment, as appropriate. For Tmax, a 
frequency table will also be provided. 
Plasma concentrations of JZP-110 will be displayed as mean (with SD included) and 
individual plasma concentration-time curves using linear and log scales. If appropriate, all 
curves will be displayed using a unique concentration axis. 
All statistical summaries and displays will be based on scheduled sampling times unless there 
are significant deviations of actual sampling times from scheduled sampling times. 
Differences between scheduled and actual sampling times will be listed for all subjects. 
PK/pharmacodynamic modeling or population PK/pharmacodynamic modeling may be used 
to explore exposure-response relationships in subjects with PD. 
9.15 Subgroup Analyses 
Exploratory analyses of safety and efficacy will be conducted in subgroups of subjects 
including but not limited to disease severity (by Hoehn and Yahr stage), treatment with 
levodopa, dopamine agonists, or a combination of dopamine agonist with levodopa. As 
sensitivity analyses, efficacy and exploratory analyses may be reported separately for 
Group 1 and Group 2.  
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9.16 Interim Analysis and Data Monitoring 
There is no interim analysis planned for this study. 
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10 DATA QUALITY ASSURANCE 
Steps to assure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator 
and associated personnel prior to the study, and periodic monitoring visits by Jazz 
Pharmaceuticals or its designee. Data are reviewed throughout the study through 
programmed checks, reports, and manual review. Any discrepancies will be resolved with the 
investigator or designees as appropriate. 
10.1 Clinical Data Management 
The standard procedures for handling and processing records will be followed in compliance 
with 21 CFR Part 11, FDA and ICH Regulations and Guidelines, Good Clinical Practices, 
and the Standard Operating Procedures (SOPs) of Jazz Pharmaceuticals or the Contract 
Research Organization (CRO).  A comprehensive Data Management Plan (DMP) will be 
developed to document data sources, systems, and handling. 
10.2 Electronic Case Report Forms 
All subject data required by the protocol to be reported to the sponsor on each trial subject 
will be recorded by clinical site staff in eCRFs developed by Jazz Pharmaceuticals or its 
designee, unless such data are transmitted to the sponsor or designee electronically (e.g., 
central laboratory data, data from an interactive response technology system, electronic 
clinical outcome assessment data, etc.). Electronic data sources will be identified in the 
DMP. The principal investigator must review the eCRFs and provide his/her signature 
certifying that he/she has reviewed the data and considers them complete and accurate to the 
best of his/her knowledge. Regardless of who signs or completes the forms, it is the principal 
investigator’s responsibility to ensure their completeness and accuracy. 
10.3 Retention of Data 
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Trial (ICH E6 Good Clinical Practice) and as required by the 
applicable regulatory requirement(s). The investigator/institution should take measures to 
prevent accidental or premature destruction of these documents.  
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period if required by the applicable regulatory requirements or 
by an agreement with Jazz Pharmaceuticals. It is the responsibility of Jazz Pharmaceuticals to 
inform the investigator/institution when these documents no longer need to be retained. 
10.4 Data Safety Monitoring Board 
A data safety monitoring board is not planned for this trial. The sponsor meets regularly to 
discuss overall safety with JZP-110. 
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11 ADMINISTRATIVE CONSIDERATIONS 
11.1 Investigators and Study Administrative Structure 
11.2 Ethics Committee Approval 
The final approved protocol and the informed consent form will be reviewed by the ethics 
committee (e.g., Institutional Review Board [IRB]).  In addition, the ethics committee will 
review any other written information to be provided to the subject, advertisements for subject 
recruitment (if used), and subject compensation (if any). The committee’s decision 
concerning conduct of the study will be sent in writing to the investigator and a copy will be 
forwarded to Jazz Pharmaceuticals. The investigator agrees to make any required progress 
reports, as well as reports of SAEs, life-threatening problems, death, or any significant 
protocol deviations, as required by the ethics committee. 
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A list of the ethics committee members who actually participated in the review, their 
respective titles (occupational identification), and institutional affiliations or an ethics 
committee assurance number must be provided to Jazz Pharmaceuticals. The approval letter 
or notice must be provided on ethics committee letterhead and contain the date of the 
meeting and sufficient information to identify the version of the protocol unambiguously (by 
name and number) and state that the informed consent form was also reviewed. 
A clinical trial may not be initiated before the proposed protocol and informed consent form 
have been reviewed and unconditionally approved/given favorable opinion by an ethics 
committee meeting country or local regulations. The clinical study remains subject to 
continuing review by the ethics committee. Jazz Pharmaceuticals or its designee will supply 
all necessary data for the investigator to submit to the ethics committee. Jazz Pharmaceuticals 
will not ship clinical supplies to an investigational site until written signed 
approval/favorable opinion from the site’s ethics committee has been received by Jazz 
Pharmaceuticals. 
The investigator is responsible for ensuring initial and continued review and approval of the 
clinical trial by the ethics committee at his/her site. The investigator must also ensure that 
he/she will promptly report to the ethics committee and Jazz Pharmaceuticals all changes in 
the research activity and all unanticipated problems involving risk to human subjects or 
others, and that he/she will not make any changes in the research without ethics committee 
approval/favorable opinion, except where necessary to eliminate apparent hazards to human 
subjects. If the trial remains in progress for more than 1 year, documentation of annual 
renewal must be submitted to Jazz Pharmaceuticals or its designee. Within 3 months of trial 
completion or termination, a final report must be provided to the ethics committee by the 
clinical site. 
11.3 Ethical Conduct of the Study 
The study will be conducted in accordance with applicable local regulations relating to GCP 
and with the SOPs of the CRO or Jazz Pharmaceuticals, as applicable. These standards 
respect the following guidelines or laws: 
• Guideline for Good Clinical Practice E6 (R1): ICH, May 1996). 
• United States (US) Code of Federal Regulations (CFR) pertaining to conduct and 
reporting of clinical studies (Title 21 CFR Parts 11, 50, 54, 56, 312, and 314). 
• Clinical Trials Directive (European Medicines Agency) Directive 2001/20/EC 
Endorsement of the ethical principles embedded in the above guidances and regulations 
ensures that the rights, safety, and well-being of trial subjects are protected and are consistent 
with the principles that have their origin in the Declaration of Helsinki, World Medical 
Association –“Ethical Principles for Medical Research Involving Human Subjects.” 
11.4 Subject Information and Consent 
All subjects will provide their written informed consent before the performance of any 
study-related procedures. 
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Each subject's chart will have his/her signed ICF for study participation attached to it. When 
the study treatment is completed and the eCRF has been monitored, the ICF will be kept in 
the investigator’s central study file.   
11.5 Subject Confidentiality  
All reports and communications relating to the subjects in the study will identify each subject 
only by his/her initials and by the subject’s study number. These documents will be treated 
with strict adherence to professional standards of confidentiality and will be filed at the study 
site under adequate security and restricted access.  
Portions of the subject's medical records pertinent to the study will be reviewed by Jazz 
Pharmaceuticals personnel or its designee and possibly by governmental agency personnel to 
ensure adequate source documentation, accuracy, and completeness of the eCRFs. The ethics 
committee has the authority to review subject records. 
11.6 Protocol Adherence – Amendments 
The protocol must be read thoroughly and the instructions must be followed exactly. 
Any changes in the protocol will require a formal amendment. Such amendments will be 
agreed upon and approved in writing by the investigator and the Jazz Pharmaceuticals 
designees. The ethics committee and the FDA will be notified of all amendments to the 
protocol. Amendments to the protocol will not be implemented until written ethics committee 
approval has been received.  
11.7 Required Documents 
The investigator must provide Jazz Pharmaceuticals or its designee with the applicable 
regulatory documents before the enrollment of any subject (copies should be kept by the 
investigator in the investigator’s regulatory document binder).  
11.8 Study Monitoring 
Throughout the course of the study, the study monitor will make frequent contacts with the 
investigator. This will include telephone calls and onsite visits.  During the onsite visits, the 
eCRFs will be reviewed for completeness and adherence to the protocol. As part of the data 
audit, source documents will be made available for review by the site. The study monitor will 
also perform drug accountability checks and may periodically request review of the 
investigator study file to assure completeness of documentation in all respects of clinical trial 
conduct. 
Upon completion of the study, the study monitor will arrange for a final review of the study 
files after which the files should be secured for the appropriate time period. The investigator 
or appointed delegate will receive the study monitor during these onsite visits and will 
cooperate in providing the documents for inspection and respond to inquiries. In addition, the 
investigator will permit inspection of the study files by authorized representatives of the 
regulatory agencies. 
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11.9 Protocol Violations/Deviations 
All major protocol deviations (violations) must be reported to the ethics committee in an 
expedited fashion. Minor deviations are to be reported at continuing review. It is the 
responsibility of the principal investigator to ensure proper reporting to the ethics committee. 
Protocol violations and deviations must be reported to Jazz Pharmaceuticals or designee. 
11.10 Access to Source Documentation  
The investigator/institution will permit trial-related monitoring (Section 11.8), audits 
conducted by the Clinical Quality Assurance Department of Jazz Pharmaceuticals or 
designee, ethics committee review and regulatory inspections by providing direct access to 
source data and documents for the trial. 
11.11 Publication and Disclosure Policy  
Please refer to individual site contracts for specific contractual obligations and requirements. 
All information concerning JZP-110, Jazz Pharmaceuticals’ operations, patent applications, 
formulas, manufacturing processes, basic scientific data, and formulation information 
supplied by Jazz Pharmaceuticals to the investigator and not previously published, are 
considered confidential and remain the sole property of Jazz Pharmaceuticals. eCRFs also 
remain the property of Jazz Pharmaceuticals. The investigator agrees to use this information 
only to complete this study and will not use it for other purposes without written consent of 
Jazz Pharmaceuticals as further detailed in the Clinical Study Agreement signed by the 
investigator and/or institution. 
It is understood by the investigator that Jazz Pharmaceuticals will use the information 
obtained in this clinical trial in connection with the study of JZP166-201 and therefore may 
disclose this information as required to other Jazz Pharmaceuticals investigators; appropriate 
international regulatory agencies; or others. In agreeing to participate in this study, the 
investigator understands that he/she has an obligation to provide complete test results and all 
data developed during this trial to Jazz Pharmaceuticals. Jazz Pharmaceuticals requires that 
permission to publish details of this study must be obtained in writing as further detailed in 
the Clinical Study Agreement signed by the investigator and/or institution. It is intended that 
the results of this trial be published in scientific literature. The conditions noted here are 
intended to protect commercial confidential materials (patents, etc.) and not to restrict 
publication.   
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12 REFERENCE LIST 
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development of Parkinson disease. Neurology 2005;65:1442-1446. 
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treating subjective daytime sleepiness in patients with Parkinson’s disease. Mov Disord. 
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American Academy of Sleep Medicine (AASM). International Classification of Sleep 
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53-62, 143-155. 
Arnulf I. Excessive daytime sleepiness in parkinsonism. Sleep Medicine Reviews 
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Arnulf I, Leu-Semenescu S. Sleepiness in Parkinson’s disease. Parkinsonism and Related 
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Barone P, Antonini A, Colosimo C, et al. The Priamo study: a multicenter assessment of 
nonmotor symptoms and their impact on quality of life in Parkinson’s disease. Mov Disord. 
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Bliwise DL, Trotti LM, Wilson AG, et al. Daytime alertness in Parkinson’s disease: 
potentially dose-dependent, divergent effects by drug class. Mov Disord. 
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Brodsky MA, Godbold J, Roth T, Olanow CW. Sleepiness in Parkinson’s disease: a 
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Cheng HC, Ulane CM, Burke RE. Clinical progression in Parkinson disease and the 
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Christmann BL, Blutstein T, Hughes M. Disease landscape and forecast: Parkinson’s disease. 
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Ferreira JJ, Katzenschlager R, Bloem BR, et al. Summary of the recommendations of the 
EFNS/MDS-ES review on therapeutic management of Parkinson’s disease. European J of 
Neurology 2013;20:5-15. 
Friedman JH, Alves G, Hagell P, et al. Fatigue rating scales critique and recommendations by 
the movement disorders society task force on rating scales for Parkinson’s disease. Mov 
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Gao J, Huang X, Park Y, et al. Daytime napping, nighttime sleeping, and Parkinson disease. 
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sleepiness in Parkinson disease: is it the drugs or the disease? Neurology 2006;67:853-858. 
Goetz CG, Tilley BC, Shaftman SR, et al. Movement Disorder Society-sponsored revision of 
the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS): scale presentation and 
clinimetric testing results. Mov Disord. 2008;23(15):2129-2170. 
Halliday GM, McCann H. The progression of pathology in Parkinson’s disease. Ann NY 
Acad Sci. 2010;1184:188-195. 
Harsh JR, Hayduk R, Rosenberg R, et al. The efficacy and safety of armodafinil as treatment 
for adults with excessive sleepiness associated with narcolepsy. Curr Med Res Opin. 
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Hasan S, Pradervand S, Ahnaou A, Drinkenburg W, Tafti M, Franken P. How to keep the 
brain awake? The complex molecular pharmacogenetics of wake promotion. 
Neuropsychopharmacology. 2009;34:1625-1640. 
Herlofson K, Larsen JP. Measuring fatigue in patients with Parkinson's disease - the Fatigue 
Severity Scale. Eur J Neurol. 2002;9:595-600. 
Högl B, Saletu M, Brandauer E, et al. Modafinil for the treatment of daytime sleepiness in 
Parkinson’s disease: a double-blind, randomized crossover, placebo-controlled polygraphic 
trial. Sleep 2002;25(8):62-65. 
Ishibashi K, Oda K, Ishiwata K, Ishii K. Comparison of dopamine transporter decline in a 
patient with Parkinson’s disease and normal aging effect. J Neurol Sci. 2014;339:207-209. 
Johns, MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. 
Sleep. 1991;14(6):540-545. 
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Karlsen KH, Larsen JP, Tandberg E, Maeland JG. Influence of clinical and demographic 
variables on quality of life in patients with Parkinson’s disease. J Neurol Neurosurg 
Psychiatry 1999;66:431-535. 
Kirsch-Darrow L, Marsiske M, Okun MS, Bauer R, Bowers D. Apathy and depression: 
separate focus in Parkinson’s disease. J Int Neuropsychol Soc. 2011;17(6):1058-1066. 
Knie B, Mitra MT, Logishetty K, Chaudhuri KR. Excessive daytime sleepiness in patients 
with Parkinson’s disease. CNS Drugs 2011;25(3):203-212. 
Krupp LB, LaRocca NG Muir-Nash J, Steinberg AD. The fatigue severity scale: application 
to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol. 
1989;46:1121-1123. 
Littner MR, Kushida C, Wise M, et al. Practice parameters for clinical use of the multiple 
sleep latency test and the maintenance of wakefulness test. Sleep. 2005;28: 113-21. 
Lou JS, Dimitrova DM, Park BS, et al. Using modafinil to treat fatigue in Parkinson disease: 
a double-blind, placebo-controlled pilot study. Clin Neuropharm. 2009;32:305-310. 
Marinus J, Visser M, Verwey NA, et al. Assessment of cognition in Parkinson’s disease. 
Neurology 2003;61:1222-1228. 
Mitler MM, Gujavarty KS, Broman C. Maintenance of wakefulness test: A 
polysomnographic technique for evaluating treatment efficacy in patients with excessive 
somnolence. Electroencephalogr Clin Neurophysiol. 1982;53(6):658-661. 
Ondo WG, Fayle R, Atassi F, Jankovic J. Modafinil for daytime somnolence in Parkinson’s 
disease: double blind, placebo controlled parallel trial. J Neurol Neurosurg Psychiatry 
2005;76:1636-1639. 
Paus S, Brecht HM, Koster J, Seeger G, Klockgether T, Wullner U. Sleep attacks, daytime 
sleepiness, and dopamine agonists in Parkinson’s disease. Mov Disord. 2003;18(6):659-667. 
Pickering TG, Hall JE, Appel LJ, et al.; Subcommittee of Professional and Public Education 
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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;168:1266-1277. 
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Razmy A, Lang AE, Shapiro CM. Predictors of impaired daytime sleep and wakefulness in 
patients with Parkinson disease treated with older (ergot) vs newer (nonergot) dopamine 
agonists. Arch Neurol. 2004;61:97-102. 
Roth T, Rye DB, Borchert LD, et al. Assessment of sleepiness and unintended sleep in 
Parkinson’s disease patients taking dopamine agonists. Sleep Medicine 2003;4:275-280. 
Ruoff C, Swick TJ, Doekel R, et al. Effect of Oral JZP-110 (ADX-N05) on wakefulness and 
sleepiness in adults with narcolepsy: a Phase 2b study. Sleep 2016;39(7):1379.1387. 
Rye D. Excessive daytime sleepiness and unintended sleep in Parkinson’s disease. Current 
Neurology and Neuroscience Reports 2006;6:169-176. 
Schrag A, Barone P, Brown RG, et al. Depression rating scales in Parkinson’s disease: 
critique and recommendations. Mov Disord. 2007;22(8):1077-1092. 
Schwartz JR, Feldman NT, Bogan RK, Nelson MT, Hughes RJ. Dosing regimen effects of 
modafinil for improving daytime wakefulness in patients with narcolepsy. Clin 
Neuropharmacol. 2003;26(5):252-257. 
Seppi K, Weintraub D, Coelho M, et al. The Movement Disorder Society evidence-based 
medicine review Update: treatments for the non-motor symptoms of Parkinson’s disease. 
Mov Disord. 2011;26(3):S42-S80. 
Shulman LM, Taback RL, Rabinstein AA, Weiner WJ. Non-recognition of depression and 
other non-motor symptoms in Parkinson’s disease. Parkinsonism and Related Disorders 
2002;8:192-197. 
Starkstein SE, Mayberg HS, Preziosi TJ, Andrezejewski P, Leiguarda R, Robinson RG. 
Reliability, validity, and clinical correlates of apathy in Parkinson’s disease. J Neuropsych 
and Clin Neurosci. 1992;4:134-139. 
Stevens S, Comella CL, Stepanski EJ. Daytime sleepiness and alertness in patients with 
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Tandberg E, Larsen JP, Karlsen K. Excessive daytime sleepiness and sleep benefit in 
Parkinson’s disease: a community-based study. Mov Disord. 1999;14(6):922-927. 
US Food and Drug Administration (FDA) Patient-Focused Drug Development Initiative. The 
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US Modafinil in Narcolepsy Multicenter Study Group. Randomized trial of modafinil for the 
treatment of pathological somnolence in narcolepsy. Ann Neurol. 1998;43(1):88-97. 
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US Modafinil in Narcolepsy Multicenter Study Group. Randomized trial of modafinil as a 
treatment for the excessive daytime somnolence of narcolepsy. Neurology. 
2000;54(5):1166-1175. 
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with Parkinson’s disease: prevalence and effect on quality of life. J Am Geriatr Soc. 
2013;61:1714-1721. 
Weintraub D, Mamikonyan E, Papay K, Shea JA, Xie SX, Siderowf A. Questionnaire for 
Impulsive-Compulsive Disorders in Parkinson’s Disease-Rating Scale. Mov Disord. 
2012;27(2):242-247. 
Videnovic A, Golombek D. Circadian and sleep disorders in Parkinson’s disease. Exp 
Neurol. 2013;243:45-56. 
Zesiewicz TA, Sullivan KL, Arnulf I, et al. Practice parameter: treatment of nonmotor 
symptoms of Parkinson disease. Report of the Quality Standards Subcommittee of the 
American Academy of Neurology. Neurology 2010;74:924-931.
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Appendix 1 
Group 1: Schedule of Events 
 
Screen 
BL 
Treatment Phase 
ET 
Safety  
Follow-up 
Visit 
1 
2 
3 
4 
5 
6 
 
7 
Day 
End of Week 
Days 
 -31 to 
-3 
Day 
-2 to  
-1 
Day 7 
(±1) 
Week 1 
Day 14 
(±1) 
Week 2 
Day 21 
(±1)  
Week 3 
Day 28 
(±1) 
Week 4 
 
Day 35 
(±1) 
Week 5 
Clinic visit 
X 
X 
X 
X 
X 
X 
X 
X 
Informed Consent 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
ESS 
X 
X 
X 
X 
X 
X 
 
X 
Berlin Sleep Apnea 
Questionnaire 
X 
 
 
 
 
 
 
 
UK PDS Brain Bank Criteria 
X 
 
 
 
 
 
 
 
MDS-UPDRS Parts III and 
IVa (on-state) 
 
X 
X 
X 
X 
X 
 
 
CGIs 
 
X 
 
 
 
 
 
 
CGIc 
 
 
X 
X 
X 
X 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Prior and Concomitant 
Medications and Therapies 
X 
Xb 
Xb 
Xb 
Xb 
Xb 
X 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
Calculate BMI 
X 
 
 
 
 
 
 
 
Vital Signsc 
X 
X 
X 
X 
X 
X 
X 
X 
QUIP-RS 
X 
 
 
 
 
 
 
 
BDI-2 
X 
 
 
 
 
 
 
 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
X 
X 
X 
X 
X 
X 
X 
Safety Laboratory Testsd 
X 
Xe 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
Xe 
X 
X 
X 
X 
X 
X 
Serum Pregnancy Testf 
X 
 
 
 
 
 
 
 
Urine Pregnancy Testf 
 
X 
X 
X 
X 
X 
X 
X 
Urine Drug Screen 
X 
 
 
 
 
 
 
 
Alcohol Breath Test 
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug Administration 
Prior to MWT 
 
 
X 
X 
X 
X 
 
 
Light Breakfast and/or 
Lunchg 
X 
X 
X 
X 
X 
X 
X 
 
Record Duration of Previous 
Night’s Sleeph 
 
X 
X 
X 
X 
X 
 
 
MWT 
 
X 
X 
X 
X 
X 
 
 
PGIc 
 
 
X 
X 
X 
X 
 
 
FSS 
 
X 
X 
X 
X 
X 
 
 
Apathy Scale 
 
X 
X 
X 
X 
X 
 
 
SCOPA-cog 
X 
X 
X 
X 
X 
X 
 
 
Adverse Event Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
Review I/E Criteria 
X 
X 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
Dispense Study Drug 
 
X 
X 
X 
X 
 
 
 
Drug Accountability 
 
 
X 
X 
X 
X 
X 
 
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CONFIDENTIAL 
Page 93 of 115 
 
BDI-2 = Beck Depression Inventory-2; BL = baseline; BMI = body mass index; CGIc = Clinical Global Impression of 
Change; CGIs = Clinical Global Impression of Severity; C-SSRS = Columbia-Suicide Severity Rating Scale; 
ECG = electrocardiogram; ESS = Epworth Sleepiness Scale; ET = Early Termination; FSS = Fatigue Severity Scale; 
I/E = inclusion/exclusion; MDS-UPDRS = Movement Disorders Society-Unified Parkinson’s Disease Rating Scale; 
MWT = maintenance of wakefulness test; PDS = Parkinson’s Disease Society; PGIc = Patient Global Impression of Change; 
QUIP-RS = Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s disease Rating Scale; SCOPA-cog = Scales 
for Outcomes in Parkinson's disease-cognition; UK = United Kingdom  
a 
The Hoehn and Yahr stage is assessed in Part III of the MDS-UPDRS. 
b 
Review concomitant medications to verify PD medications, sleep medications allowed by the protocol, and when 
applicable, study drug (as specified in Section 5.3) were taken appropriately. For subjects currently receiving treatment 
for OSA, review OSA therapy device usage to ensure adequate compliance. 
c 
At the Baseline visit, vital signs (body temperature, respiratory rate, blood pressure [seated and standing], and pulse 
[seated and standing]) will be taken at approximately 1 hour before the first MWT. Additional blood pressure [seated 
and standing], and pulse [seated and standing] measurements will be taken at approximately 15 minutes before the first 
MWT, and after the completion of the first 2 MWT trials (see Section 7.2 for details). On MWT Visits 3, 4, 5, and 6, 
vital signs (body temperature, respiratory rate, blood pressure [seated and standing], and pulse [seated and standing]) 
will be taken approximately 1 hour prior to dosing at the clinic. Additional blood pressure [seated and standing], and 
pulse [seated and standing] measurements will be taken at approximately 1, 2, 4, and 6 hours after dosing (see 
Section 7.2.2 for details). On Safety Follow-Up, vital signs (body temperature, respiratory rate, blood pressure [seated 
and standing], and pulse [seated and standing]) will also be taken. 
d 
Additional safety laboratory samples may be obtained at the investigator’s discretion. 
e 
If the Baseline visit occurs outside of the screening window (i.e., >29 days after the Screening visit), obtain blood 
samples for serum chemistry, hematology and a urine sample for urinalysis. 
f 
Subjects who are not of childbearing potential (ie, postmenopausal, surgically sterile, or who have medically 
documented ovarian failure will not need to undergo pregnancy testing). 
g 
At the Screening and ET visits, subjects may be provided a light breakfast as described in Sections 7.1 and 7.5, 
respectively. At Visits 3, 4, 5, and 6, subjects may be provided a light breakfast and a light lunch as described in 
Section 7.2.2. 
h 
Before the start of the first MWT on a given day, subjects will be asked the following question: “How long did you 
sleep last night?”
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CONFIDENTIAL 
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Appendix 2 
Group 1: Example Time Schedule for Procedures 
During the Baseline Visit 
Note: This is a sample schedule and time of arrival at the study center can be shifted as 
needed based on the patient’s typical sleep periods and individual site logistics. Individual 
assessments should be performed at approximately the same time of day across study visits. 
Baseline Visit 
Approximate 
Time 
Procedure/Activity 
8:00 
Subject arrives at study centera 
Assess any updates to medical history and changes in concomitant medications. Record 
all AEs that occur after the ICF was signed. Verify and ensure PD and sleep medications 
were taken and continue to be taken appropriately. For subjects currently receiving 
treatment for OSA, review OSA therapy device usage to ensure adequate compliance.a 
Administer the ESS Questionnairea 
Administer the MDS-UPDRS (Parts III and IV)a,b 
Complete the CGIsa 
Physical examination and weighta 
Body temperature, respiratory rate, and at least 2 sets of blood pressure and pulse in 
seated position; then blood pressure and pulse at 1 and 3 minutes after standing 
ECGa 
Safety laboratory blood samplesa,c 
Urine sample for urinalysisa 
Urine pregnancy test (for all females of childbearing potential)a 
Alcohol breath screening testa 
9:15 
Light breakfast 
9:50 
At least 2 sets of blood pressure and pulse in seated position; then blood pressure and 
pulse at 1 and 3 minutes after standing 
10:00d 
Ask the subject the following question: “How long did you sleep last night?” 
Start first MWT triald 
11:00 
At least 2 sets of blood pressure and pulse in seated position; then blood pressure and 
pulse at 1 and 3 minutes after standing 
11:15 
Complete the FSS, Apathy Scale, SCOPA-cog, and C-SSRS Questionnairesa 
12:00 
Start second MWT trial 
 
Light lunch served immediately after the end of the second trial 
13:00 
At least 2 sets of blood pressure and pulse in seated position; then blood pressure and 
pulse at 1 and 3 minutes after standing 
14:00 
Start third MWT trial 
16:00 
Start fourth MWT trial (optional) 
CGIs = Clinical Global Impression of Severity; C-SSRS = Columbia-Suicide Severity Rating Scale; 
ECG = electrocardiogram; ESS = Epworth Sleepiness Scale; I/E = inclusion/exclusion; MDS-UPDRS = Movement 
Disorders Society-Unified Parkinson’s Disease Rating Scale; MWT = maintenance of wakefulness test; FSS = Fatigue 
Severity Scale; SCOPA cog = Scales for Outcomes in Parkinson's disease-cognition 
a 
These assessments can be performed the day before (Day -2) the MWT, provided it falls within the visit window.  
b 
When feasible, the MDS-UPDRS (Parts III and IV) is to be performed on the same study day and approximate same 
time for each subsequent visit while the subject is in the “on” state. 
c 
If the Baseline visit occurs outside of the screening window (i.e., >29 days after the Screening visit), obtain blood 
samples for serum chemistry and hematology and a urine sample for urinalysis.  
d 
The first MWT trial should be started approximately 1.5 to 3 hours after the time of the subject arising that morning.  
 
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CONFIDENTIAL 
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Appendix 3 
Group 1: Example Time Schedule for Procedures at 
Visits 3, 4, 5, or 6 
Note: This is a sample schedule and time of arrival at the study center can be shifted as 
needed based on the patient’s typical sleep periods and individual site logistics. Individual 
assessments should be performed at approximately the same time of day across study visits. 
Visits 3, 4, 5, and 6 
Time Relative 
to Dosing 
Approximate 
Time 
Procedure/Activity 
~ -1 h 
8:00 
Subject arrives at study centera 
Record all concomitant medications taken since last visit. Record all AEs. 
Verify and ensure PD medications, sleep medications allowed by the 
protocol, and study drug (as specified in Section 5.3 of the protocol) were 
taken and continue to be taken appropriately. For subjects currently 
receiving treatment for OSA, review OSA therapy device usage to ensure 
adequate compliance.a 
Administer the ESS Questionnairea 
Administer the MDS-UPDRS (Parts III and IV) a,b 
Complete the CGIca 
Physical examination and weighta 
Body temperature, respiratory rate, and at least 2 sets of blood pressure 
and pulse in seated position; then blood pressure and pulse at 1 and 
3 minutes after standing 
ECG 
Safety laboratory blood samplesa 
Urine sample for urinalysisa 
Urine pregnancy test (for all females of childbearing potential)a 
Alcohol breath screening testa 
0 h 
9:00 
Dosing 
~0.25 h 
9:15 
Light breakfast 
~1 h 
9:50 
At least 2 sets of blood pressure and pulse in seated position; then blood 
pressure and pulse at 1 and 3 minutes after standing 
~1 h 
10:00c 
Ask the subject the following question: “How long did you sleep last 
night?” 
Start first MWT trialc 
~2 h 
11:00 
At least 2 sets of blood pressure and pulse in seated position; then blood 
pressure and pulse at 1 and 3 minutes after standing 
~2.25 h 
11:15 
Complete the PGIc, FSS, Apathy Scale, SCOPA-cog, and C-SSRS 
Questionnairesa 
~3 h 
12:00 
Start second MWT trial 
 
 
Light lunch served immediately after the end of the second trial 
~4 h 
13:00 
At least 2 sets of blood pressure and pulse in seated position; then blood 
pressure and pulse at 1 and 3 minutes after standing 
~5 h 
14:00 
Start third MWT trial 
~6 h 
15:00 
At least 2 sets of blood pressure and pulse rate measurements in seated 
position; then standing blood pressure and pulse rate measurements at 
1 and 3 minutes after standing 
ECG 
~7 h 
16:00 
Start fourth MWT trial (optional) 
CGIc = Clinical Global Impression of Change; ECG = electrocardiogram; ESS = Epworth Sleepiness Scale; 
MDS-UPDRS = Movement Disorders Society-Unified Parkinson’s Disease Rating Scale; MWT = maintenance of 
wakefulness test; FSS = Fatigue Severity Scale; PGIc = Patient Global Impression of Change; SCOPA cog = Scales for 
Outcomes in Parkinson's disease-cognition 
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CONFIDENTIAL 
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a 
These assessments can be performed the day before the MWT, provided it falls within the visit window. Individual 
assessments should be performed on the same study day at approximately the same time of day across study visits. 
b 
When feasible, the MDS-UPDRS (Parts III and IV) is to be performed on the same study day and approximate same 
time for each subsequent visit while the subject is in the “on” state.  
c 
The first MWT trial should be started approximately 1.5 to 3 hours after the time of the subject arising that morning. 
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CONFIDENTIAL 
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Appendix 4 
Group 2: Schedule of Events 
 
Screen 
BL 
Treatment Phase 
ET 
Safety  
Follow-up 
Visit 
1 
2 
3 
4 
5 
6 
 
7 
Day 
End of Week 
Days 
 -31 to 
-3 
Day  
-1 
Day 7 
(±1) 
Week 1 
Day 14 
(±1) 
Week 2 
Day 21 
(±1)  
Week 3 
Day 28 
(±1) 
Week 4 
 
Day 35 
(±1) 
Week 5 
Clinic visit 
X 
X 
X 
X 
X 
X 
X 
X 
Informed Consent 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
ESS 
X 
X 
X 
X 
X 
X 
 
X 
Berlin Sleep Apnea 
Questionnaire 
X 
 
 
 
 
 
 
 
UK PDS Brain Bank Criteria 
X 
 
 
 
 
 
 
 
MDS-UPDRS Parts III and 
IVa (on-state) 
 
X 
X 
X 
X 
X 
 
 
CGIs 
 
X 
 
 
 
 
 
 
CGIc 
 
 
X 
X 
X 
X 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Prior and Concomitant 
Medications and Therapies 
X 
Xb 
Xb 
Xb 
Xb 
Xb 
X 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
Calculate BMI 
X 
 
 
 
 
 
 
 
Vital Signsc 
X 
X 
X 
X 
X 
X 
X 
X 
QUIP-RS 
X 
 
 
 
 
 
 
 
BDI-2 
X 
 
 
 
 
 
 
 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
X 
X 
X 
X 
X 
X 
X 
Safety Laboratory Testsd 
X 
Xe 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
Xe 
X 
X 
X 
X 
X 
X 
Serum Pregnancy Testf 
X 
 
 
 
 
 
 
 
Urine Pregnancy Testf 
 
X 
X 
X 
X 
X 
X 
X 
Urine Drug Screen 
X 
 
 
 
 
 
 
 
Alcohol Breath  Test 
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug Administration  
 
 
X 
X 
X 
X 
 
 
Light Breakfast and/or 
Lunchg 
X 
X 
X 
X 
X 
X 
X 
 
PGIc 
 
 
X 
X 
X 
X 
 
 
FSS 
 
X 
X 
X 
X 
X 
 
 
Apathy Scale 
 
X 
X 
X 
X 
X 
 
 
SCOPA-cog 
X 
X 
X 
X 
X 
X 
 
 
Adverse Event Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
Review I/E Criteria 
X 
X 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
Dispense Study Drug 
 
X 
X 
X 
X 
 
 
 
Drug Accountability 
 
 
X 
X 
X 
X 
X 
 
BDI-2 = Beck Depression Inventory-2; BL = baseline; BMI = body mass index; CGIc = Clinical Global Impression of 
Change; CGIs = Clinical Global Impression of Severity; C-SSRS = Columbia-Suicide Severity Rating Scale; 
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Clinical Trial Protocol: JZP166-201 Amendment 2 
 
 
 
 
 
 
CONFIDENTIAL 
Page 98 of 115 
 
ECG = electrocardiogram; ESS = Epworth Sleepiness Scale; ET = Early Termination; FSS = Fatigue Severity Scale; 
I/E = inclusion/exclusion; MDS-UPDRS = Movement Disorders Society-Unified Parkinson’s Disease Rating Scale; 
PDS = Parkinson’s Disease Society; PGIc = Patient Global Impression of Change;  QUIP-RS = Questionnaire for 
Impulsive-Compulsive Disorders in Parkinson’s disease Rating Scale; SCOPA-cog = Scales for Outcomes in Parkinson's 
disease-cognition; UK = United Kingdom  
a 
The Hoehn and Yahr stage is assessed in Part III of the MDS-UPDRS. 
b 
Review concomitant medications to verify PD medications, sleep medications allowed by the protocol, and when 
applicable, study drug (as specified in Section 5.3) were taken appropriately. For subjects currently receiving treatment 
for OSA, review OSA therapy device usage to ensure adequate compliance. 
c 
At the Baseline visit, vital signs (body temperature, respiratory rate, blood pressure [seated and standing], and pulse 
[seated and standing]) will be taken as soon as possible upon arrival at the study center. Additional blood pressure 
[seated and standing], and pulse [seated and standing] measurements will be taken at approximately 2 and 3 hours after 
the first set of vital signs (see Section 7.3 for details). On Treatment Visits 3, 4, 5, and 6, vital signs (body temperature, 
respiratory rate, blood pressure [seated and standing], and pulse [seated and standing]) will be taken approximately 
1 hour prior to dosing at the clinic. Additional blood pressure [seated and standing], and pulse [seated and standing] 
measurements will be taken at approximately 1 and 2 hours after dosing (see Section 7.3.2 for details). On Safety 
Follow-up, vital signs (body temperature, respiratory rate, blood pressure [seated and standing], and pulse [seated and 
standing]) will also be taken. 
d 
Additional safety laboratory samples may be obtained at the investigator’s discretion. 
e 
If the Baseline visit occurs outside of the screening window (i.e., >29 days after the Screening visit) obtain blood 
samples for serum chemistry, hematology and a urine sample for urinalysis. 
f 
Subjects who are not of childbearing potential (i.e., postmenopausal, surgically sterile, or who have medically 
documented ovarian failure will not need to undergo pregnancy testing). 
g 
At the Screening and ET visits, subjects may be provided a light breakfast as described in Sections 7.1 and 7.5, 
respectively. At Baseline and at Visits 3, 4, 5, and 6, subjects may be provided a light breakfast as described in 
Section 7.3.2. 
Confidential
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Signature Date: 20180129
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JZP-110 
 
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Clinical Trial Protocol: JZP166-201 Amendment 2 
 
 
 
 
 
 
CONFIDENTIAL 
Page 99 of 115 
 
Appendix 5 
Group 2: Example Time Schedule for Procedures 
During the Baseline Visit 
Note: This is a sample schedule and time of arrival at the study center can be shifted as 
needed. Individual assessments should be performed at approximately the same time of day 
across study visits. 
Baseline Visit 
Approximate 
Time 
Procedure/Activity 
8:00 
Subject arrives at study center 
Assess any updates to medical history and changes in concomitant medications. Record all 
AEs that occur after the ICF was signed. Verify and ensure PD and sleep medications were 
taken and continue to be taken appropriately. For subjects currently receiving treatment for 
OSA, review OSA therapy device usage to ensure adequate compliance. 
Administer the ESS Questionnaire 
Administer the C-SSRS Questionnaire 
Body temperature, respiratory rate, and at least 2 sets of blood pressure and pulse in seated 
position; then blood pressure and pulse at 1 and 3 minutes after standing 
Physical examination and weight 
Safety laboratory blood samplesa 
Urine sample for urinalysisa 
Urine pregnancy test (for all females of childbearing potential) 
Alcohol breath screening test 
9:15 
Light breakfast 
10:00 
At least 2 sets of blood pressure and pulse in seated position; then blood pressure and pulse 
at 1 and 3 minutes after standing 
10:30 
Complete the FSS, Apathy Scale, and SCOPA-cog Questionnaires 
11:00 
At least 2 sets of blood pressure and pulse in seated position; then blood pressure and pulse 
at 1 and 3 minutes after standing 
ECG 
Complete the CGIs 
Administer the MDS-UPDRS (Parts III and IV)b 
AE = adverse event; CGIs = Clinical Global Impression of Severity; C-SSRS = Columbia-Suicide Severity Rating Scale; 
ECG = electrocardiogram; ESS = Epworth Sleepiness Scale; ICF = informed consent form; I/E = inclusion/exclusion; 
MDS-UPDRS = Movement Disorders Society-Unified Parkinson’s Disease Rating Scale; FSS = Fatigue Severity Scale; 
PD = Parkinson’s disease; SCOPA cog = Scales for Outcomes in Parkinson's disease-cognition 
a 
If the Baseline visit occurs outside of the screening window (i.e., >29 days after the Screening visit), obtain blood 
samples for serum chemistry and hematology and a urine sample for urinalysis.  
b 
When feasible, the MDS-UPDRS (Parts III and IV) is to be performed at approximately the same time for each 
subsequent visit while the subject is in the “on” state.  
 
  
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Clinical Trial Protocol: JZP166-201 Amendment 2 
 
 
 
 
 
 
CONFIDENTIAL 
Page 100 of 115 
 
Appendix 6 
Group 2: Example Time Schedule for Procedures at 
Visits 3, 4, 5, or 6 
Note: This is a sample schedule and time of arrival at the study center can be shifted as 
needed. Individual assessments should be performed at approximately the same time of day 
across study visits. 
Visits 3, 4, 5, and 6 
Time Relative 
to Dosing 
Approximate 
Time 
Procedure/Activity 
~ -1 h 
8:00 
Subject arrives at study center 
Record all concomitant medications taken since last visit. Record all AEs. 
Verify and ensure PD medications, sleep medications allowed by the 
protocol, and study drug (as specified in Section 5.3 of the protocol) were 
taken and continue to be taken appropriately. For subjects currently 
receiving treatment for OSA, review OSA therapy device usage to ensure 
adequate compliance. 
Body temperature, respiratory rate, and at least 2 sets of blood pressure 
and pulse in seated position; then blood pressure and pulse at 1 and 
3 minutes after standing 
ECG 
Physical examination and weight 
Safety laboratory blood samples 
Urine sample for urinalysis 
Urine pregnancy test (for all females of childbearing potential) 
Alcohol breath screening test 
0 h 
9:00 
Dosing 
~ 0.25 h 
9:15 
Light breakfast 
~ 1 h 
10:00 
At least 2 sets of blood pressure and pulse in seated position; then blood 
pressure and pulse at 1 and 3 minutes after standing 
~ 1.5 h 
10:30 
Complete the ESS, PGIc, FSS, Apathy Scale, SCOPA-cog, and C-SSRS 
Questionnaires  
~ 2 h 
11:00 
At least 2 sets of blood pressure and pulse in seated position; then blood 
pressure and pulse at 1 and 3 minutes after standing 
ECG 
Complete the CGIc 
Administer the MDS-UPDRS (Parts III and IV)a 
AE = adverse event; CGIc = Clinical Global Impression of Change; C-SSRS = Columbia-Suicide Severity Rating Scale; 
ECG = electrocardiogram; ESS = Epworth Sleepiness Scale; MDS-UPDRS = Movement Disorders Society-Unified 
Parkinson’s Disease Rating Scale; FSS = Fatigue Severity Scale; PD = Parkinson’s disease; PGIc = Patient Global 
Impression of Change; SCOPA cog = Scales for Outcomes in Parkinson's disease-cognition 
a 
When feasible, the MDS-UPDRS (Parts III and IV) is to be performed at approximately the same time for each 
subsequent visit while the subject is in the “on” state.  
Confidential
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Signature Date: 20180129
JP: JZP166-201 Protocol Amendment 2.pdf
Signature Date:
JP: JZP166-201 Protocol Amendment 2.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: JZP166-201 Amendment 2 
 
 
 
 
 
 
CONFIDENTIAL 
Page 102 of 115 
 
Appendix 8 
Berlin Sleep Apnea Questionnaire 
 
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Signature Date:
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BERLIN QUESTIONNAIRE 
Height (m) ________       Weight (kg)________     Age______ 
 Male / Female 
Please choose the correct response to each question. 
CATEGORY 1 
1. Do you snore?
 a. Yes 
 b. No 
 c. Don’t know 
If you snore: 
2. Your snoring is:
 a. Slightly louder than breathing 
 b. As loud as talking 
 c. Louder than talking 
 d. Very loud – can be heard in adjacent 
rooms 
3. How often do you snore
 a. Nearly every day 
 b. 3-4 times a week 
 c. 1-2 times a week 
 d. 1-2 times a month 
 e. Never or nearly never 
4. Has your snoring ever bothered other
people?
 a. Yes 
 b. No 
 c. Don’t Know 
5. Has anyone noticed that you quit
breathing during your sleep?
 a. Nearly every day 
 b. 3-4 times a week 
 c. 1-2 times a week 
 d. 1-2 times a month 
 e. Never or nearly never 
CATEGORY 2 
6. How often do you feel tired or fatigued
after your sleep?
 a. Nearly every day 
 b. 3-4 times a week 
 c. 1-2 times a week 
 d. 1-2 times a month 
 e. Never or nearly never 
7. During your waking time, do you feel
tired, fatigued or not up to par?
 a. Nearly every day 
 b. 3-4 times a week 
 c. 1-2 times a week 
 d. 1-2 times a month 
 e. Never or nearly never 
8. Have you ever nodded off or fallen asleep
while driving a vehicle?
 a. Yes 
 b. No 
If yes: 
9. How often does this occur?
 a. Nearly every day 
 b. 3-4 times a week 
 c. 1-2 times a week 
 d. 1-2 times a month 
 e. Never or nearly never 
CATEGORY 3 
10. Do you have high blood pressure?
 Yes
 No
 Don’t know
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Confidential
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Signature Date: 20180129
JP: JZP166-201 Protocol Amendment 2.pdf
Signature Date:
JP: JZP166-201 Protocol Amendment 2.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: JZP166-201 Amendment 2 
 
 
 
 
 
 
CONFIDENTIAL 
Page 103 of 115 
 
Appendix 9 
Questionnaire for Impulsive-Compulsive Disorders 
in Parkinson’s Disease Rating Scale 
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QUIP-RATING SCALE
Version 1.0 (7/01/09) 
Copyright © 2010 University of Pennsylvania; All Rights Reserved.
1
Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease - Rating Scale 
(QUIP-RS)
Reported by:  
_____ Patient  
_____ Informant 
_____ Patient and Informant 
Patient / Subject: 
__________________________________________ 
Date:
__________________________________________ 
1. How much do you think about the following behaviors (such as having trouble keeping thoughts out of your mind or
feeling guilty)?
Gambling? 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Sex? 
 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Buying? 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Eating?  
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Performing tasks or hobbies? 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Repeating simple activities? 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Taking your PD medications? 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
2. Do you have urges or desires for the following behaviors that you feel are excessive or cause you distress (including
becoming restless or irritable when unable to participate in them)?  
Gambling? 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Sex? 
 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Buying? 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Eating?  
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Performing tasks or hobbies? 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Repeating simple activities? 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Taking your PD medications? 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
3. Do you have difficulty controlling the following behaviors (such as increasing them over time, or having trouble cutting
down or stopping them)? 
Gambling? 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Sex? 
 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Buying? 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Eating?  
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Performing tasks or hobbies? 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Repeating simple activities? 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Taking your PD medications? 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
4. Do you engage in activities specifically to continue the following behaviors (such as hiding what you are doing, lying,
hoarding things, borrowing from others, accumulating debt, stealing, or being involved in illegal acts)?   
Gambling? 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Sex? 
 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Buying? 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Eating?  
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Performing tasks or hobbies? 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Repeating simple activities? 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Taking your PD medications? 
___Never(0)   ___Rarely(1)   ___Sometimes(2)   ___Often(3)   ___Very often(4) 
Confidential
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Signature Date: 20180129
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Signature Date:
JP: JZP166-201 Protocol Amendment 2.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: JZP166-201 Amendment 2 
 
 
 
 
 
 
CONFIDENTIAL 
Page 104 of 115 
 
Appendix 10 
Beck Depression Inventory-2 Questionnaire 
 
Confidential
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Signature Date: 20180129
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Signature Date:
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_______ 
Subtotal Page 1
Continued on Back
Name: 
Marital Status:  
 
Age: 
Sex: 
Occupation: 
 
Education: 
1. Sadness
0 
I do not feel sad.
1 
I feel sad much of the time.
2 
I am sad all the time.
3 
I am so sad or unhappy that I can’t stand it.
2. Pessimism
0 
I am not discouraged about my future.
1 
 I feel more discouraged about my future than I 
used to be.
2 
I do not expect things to work out for me.
3 
 I feel my future is hopeless and will only get 
worse.
3. Past Failure
0 
I do not feel like a failure.
1 
I have failed more than I should have.
2 
As I look back, I see a lot of failures.
3 
I feel I am a total failure as a person.
4. Loss of Pleasure
0 
 I get as much pleasure as I ever did from the 
things I enjoy.
1 
I don’t enjoy things as much as I used to.
2 
 I get very little pleasure from the things I used 
to enjoy.
3 
 I can’t get any pleasure from the things I used to 
enjoy.
5. Guilty Feelings
0 
I don’t feel particularly guilty.
1 
 I feel guilty over many things I have done or 
should have done.
2 
I feel quite guilty most of the time.
3 
I feel guilty all of the time.
6. Punishment Feelings
0 
I don’t feel I am being punished.
1 
I feel I may be punished.
2 
I expect to be punished.
3 
I feel I am being punished.
7. Self-Dislike
0 
I feel the same about myself as ever.
1 
I have lost conﬁdence in myself.
2 
I am disappointed in myself.
3 
I dislike myself.
8. Self-Criticalness
0 
I don’t criticize or blame myself more than usual.
1 
I am more critical of myself than I used to be.
2 
I criticize myself for all of my faults.
3 
I blame myself for everything bad that happens.
9. Suicidal Thoughts or Wishes
0 
I don’t have any thoughts of killing myself.
1 
 I have thoughts of killing myself, but I would 
not carry them out.
2 
 I would like to kill myself.
3 
 I would kill myself if I had the chance.
10. Crying
0 
I don’t cry any more than I used to.
1 
I cry more than I used to.
2 
I cry over every little thing.
3 
I feel like crying, but I can’t.
Instructions:  This questionnaire consists of 21 groups of statements. Please read each group of statements carefully, and 
then pick out the one statement in each group that best describes the way you have been feeling during the past two  
weeks, including today. Circle the number beside the statement you have picked. If several statements in the group  
seem to apply equally well, circle the highest number for that group. Be sure that you do not choose more than one  
statement for any group, including Item 16 (Changes in Sleeping Pattern) or Item 18 (Changes in Appetite). 
Date:
%HFN'HSUHVVLRQ,QYHQWRU\6HFRQG(GLWLRQ%',,,Copyright © 1996 Aaron T. Beck.
Adapted and reproduced with permission of Published NCS Pearson, Inc. All rights reserved.
Product Number 0158018397 
24 25 26 27 28 29 30 A B C D E
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Signature Date: 20180129
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Signature Date:
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________ 
Subtotal Page 2
________ 
Subtotal Page 1
________ 
Total Score
11. Agitation
0 
I am no more restless or wound up than usual.
1 
I feel more restless or wound up than usual.
2 
 I am so restless or agitated that it’s hard to stay 
still.
3 
 I am so restless or agitated that I have to keep 
moving or doing something.
12. Loss of Interest
0 
 I have not lost interest in other people or 
activities.
1 
 I am less interested in other people or things  
than before.
2 
 I have lost most of my interest in other people 
or things.
3 
It’s hard to get interested in anything.
13. Indecisiveness
0 
I make decisions about as well as ever.
1 
 I ﬁnd it more difﬁcult to make decisions than 
usual.
2 
 I have much greater difﬁculty in making 
decisions than I used to.
3 
I have trouble making any decisions.
14. Worthlessness
0 
I do not feel I am worthless.
1 
 I don’t consider myself as worthwhile and useful 
as I used to.
2 
 I feel more worthless as compared to other 
people.
3 
I feel utterly worthless.
15. Loss of Energy
0 
I have as much energy as ever.
1 
I have less energy than I used to have.
2 
I don’t have enough energy to do very much.
3 
I don’t have enough energy to do anything.
16. Changes in Sleeping Pattern
0 
 I have not experienced any change in my 
sleeping pattern.
1a I sleep somewhat more than usual.
1b I sleep somewhat less than usual.
2a I sleep a lot more than usual.
2b I sleep a lot less than usual.
3a I sleep most of the day.
3b  I wake up 1–2 hours early and can’t get back 
 to sleep.
17. Irritability
0 
I am no more irritable than usual.
1 
I am more irritable than usual.
2 
I am much more irritable than usual.
3 
I am irritable all the time.
18. Changes in Appetite
0 
 I have not experienced any change in my 
appetite.
1a My appetite is somewhat less than usual.
1b My appetite is somewhat greater than usual.
2a My appetite is much less than before.
2b My appetite is much greater than usual.
3a I have no appetite at all.
3b I crave food all the time.
19. Concentration Difﬁculty
0 
I can concentrate as well as ever.
1 
I can’t concentrate as well as usual.
2 
 It’s hard to keep my mind on anything for  
very long.
3 
I ﬁnd I can’t concentrate on anything.
20. Tiredness or Fatigue
0 
I am no more tired or fatigued than usual.
1 
 I get more tired or fatigued more easily than 
usual.
2 
 I am too tired or fatigued to do a lot of the things 
I used to do.
3 
 I am too tired or fatigued to do most of the  
things I used to do.
21. Loss of Interest in Sex
0 
 I have not noticed any recent change in my 
interest in sex.
1 
I am less interested in sex than I used to be.
2 
I am much less interested in sex now.
3 
I have lost interest in sex completely.
NOTICE: This form is printed with green and black ink. If 
your copy does not appear this way, it has been photo-
copied in violation of copyright laws.
%HFN'HSUHVVLRQ,QYHQWRU\6HFRQG(GLWLRQ%',,,Copyright © 1996 
Aaron T. Beck.
Adapted and reproduced with permission of Published NCS Pearson, Inc. 
All rights reserved.
Confidential
Page 108 of 152


Signature Date: 20180129
JP: JZP166-201 Protocol Amendment 2.pdf
Signature Date:
JP: JZP166-201 Protocol Amendment 2.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: JZP166-201 Amendment 2 
 
 
 
 
 
 
CONFIDENTIAL 
Page 105 of 115 
 
Appendix 11 
Columbia-Suicide Severity Rating Scale 
Baseline/Screening Version 
Confidential
Page 109 of 152


Signature Date: 20180129
JP: JZP166-201 Protocol Amendment 2.pdf
Signature Date:
JP: JZP166-201 Protocol Amendment 2.pdf
COLUMBIA-SUICIDE SEVERITY
RATING SCALE
(C-SSRS) 
Screening 
Version 1/14/09 
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; 
Burke, A.; Oquendo, M.; Mann, J.  
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. The questions contained 
in the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of 
suicidal ideation or behavior depends on the judgment of the individual administering the scale. 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History 
Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., 
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First 
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside Drive, New 
York, New York, 10032; inquiries and training requirements contact posnerk@nyspi.columbia.edu
 
© 2008 The Research Foundation for Mental Hygiene, Inc. 
Confidential
Page 110 of 152


Signature Date: 20180129
JP: JZP166-201 Protocol Amendment 2.pdf
Signature Date:
JP: JZP166-201 Protocol Amendment 2.pdf
SUICIDAL IDEATION
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the answer to question 2 is “yes”,
ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is “yes”, complete “Intensity of Ideation” section below.
Past 
X Months
1.  Wish to be Dead
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up. 
Have you wished you were dead or wished you could go to sleep and not wake up? 
If yes, describe:
Yes   
No
□  □
2.  Non-Specific Active Suicidal Thoughts
General, non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing myself”) without thoughts of ways to kill 
oneself/associated methods, intent, or plan. 
Have you actually had any thoughts of killing yourself?
If yes, describe:
Yes      No
□    □
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a specific plan with time, 
place or method details worked out (e.g., thought of method to kill self but not a specific plan).  Includes person who would say, “I thought about taking an 
overdose but I never made a specific plan as to when, where or how I would actually do it…..and I would never go through with it.”
Have you been thinking about how you might do this?
If yes, describe:
Yes      No
□  □
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the thoughts but I 
definitely will not do anything about them.”
Have you had these thoughts and had some intention of acting on them?
If yes, describe:
Yes     No
□   □
5.  Active Suicidal Ideation with Specific Plan and Intent
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out.
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan?
   
If yes, describe:
Yes     No
□  □
INTENSITY OF IDEATION
The following features should be rated with respect to the most severe type of ideation (i.e., 1-5 from above, with 1 being the least severe 
and 5 being the most severe). Ask about time he/she was feeling the most suicidal. 
                                            
Most Severe Ideation:             _____                      _________________________________________________
                                             
                                                                                                           Type # (1-5)                                         Description of  Ideation
Most 
Severe
Frequency
How many times have you had these thoughts?
(1) Less than once a week    (2) Once a week   (3)  2-5 times in week    (4) Daily or almost daily    (5) Many times each day
____
Duration
When you have the thoughts, how long do they last?
(1) Fleeting - few seconds or minutes                                             
(4) 4-8 hours/most of day
(2) Less than 1 hour/some of the time                                                 (5) More than 8 hours/persistent or continuous
(3) 1-4 hours/a lot of time
____
Controllability
Could/can you stop thinking about killing yourself or wanting to die if you want to?
(1) Easily able to control thoughts                                                      (4) Can control thoughts with a lot of difficulty
(2) Can control thoughts with little difficulty                                   (5) Unable to control thoughts
(3) Can control thoughts with some difficulty                                   (0) Does not attempt to control thoughts
____
Deterrents
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from wanting to die or acting on 
thoughts of committing suicide?
(1) Deterrents definitely stopped you from attempting suicide            (4) Deterrents most likely did not stop you 
(2) Deterrents probably stopped you                                                
(5) Deterrents definitely did not stop you 
(3) Uncertain that deterrents stopped you                                            (0) Does not apply
____
Reasons for Ideation
What sort of reasons did you have for thinking about wanting to die or killing yourself?  Was it to end the pain or stop the way 
you were feeling (in other words you couldn’t go on living with this pain or how you were feeling) or was it to get attention,
revenge or a reaction from others? Or both?
(1) Completely to get attention, revenge or a reaction from others       (4) Mostly to end or stop the pain (you couldn’t go on
(2) Mostly to get attention, revenge or a reaction from others                     living with the pain or how you were feeling)
(3) Equally to get attention, revenge or a reaction from others               (5) Completely to end or stop the pain (you couldn’t go on 
       and to end/stop the pain                                                                         living with the pain or  how you were feeling)
                                                                                                             (0) Does not apply
____
© 2008 Research Foundation for Mental Hygiene, Inc.
        C-SSRS—Screening (Version 1/14/09)   
                                             Page 1 of 2
Confidential
Page 111 of 152


Signature Date: 20180129
JP: JZP166-201 Protocol Amendment 2.pdf
Signature Date:
JP: JZP166-201 Protocol Amendment 2.pdf
SUICIDAL BEHAVIOR
(Check all that apply, so long as these are separate events; must ask about all types)
Past X Years
or
Lifetime 
Actual Attempt:
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill oneself. Intent 
does not have to be 100%.  If there is any intent/desire to die associated with the act, then it can be considered an actual suicide attempt. There does not 
have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in mouth but gun is broken so no injury results,
this is considered an attempt.  
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For example, a highly lethal 
act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head, jumping from window of a high floor/story). Also, if 
someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred. 
Have you made a suicide attempt?
Have you done anything to harm yourself?
Have you done anything dangerous where you could have died?
What did you do?
Did you______ as a way to end your life? 
Did you want to die (even a little) when you_____? 
Were you trying to end your life when you _____?
Or did you think it was possible you could have died from_____?
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better, get sympathy, 
or get something else to happen)? (Self-Injurious Behavior without suicidal intent)
If yes, describe:
Has subject engaged in Non-Suicidal Self-Injurious Behavior?
Yes      No
□   □
Total # of
Attempts
______
Yes  No
□   □
Interrupted Attempt:
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt would have 
occurred).
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an attempt rather than an interrupted attempt. 
Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger. Once they pull the trigger, 
even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. Hanging: Person has noose around neck 
but has not yet started to hang - is stopped from doing so.
Has there been a time when you started to do something to end your life but someone or something stopped you before you 
actually did anything?
If yes, describe:
Yes      No
□   □
Total # of 
interrupted
______
Aborted Attempt:  
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-destructive behavior. 
Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by something else.
Has there been a time when you started to do something to try to end your life but you stopped yourself before you actually did 
anything?
If yes, describe:
Yes      No
□   □
Total # of
aborted
______
Preparatory Acts or Behavior:
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as assembling a specific 
method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving things away, writing a suicide note). 
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, getting a gun, 
giving valuables away or writing a suicide note)?
If yes, describe:
Yes      No
□   □
Suicidal Behavior:
Suicidal behavior was present during the assessment period?
Yes      No
□   □
Answer for Actual Attempts Only
Most Recent 
Attempt
Date:
Most Lethal         
Attempt
Date:
Initial/First 
Attempt
Date:
Actual Lethality/Medical Damage:  
0.  No physical damage or very minor physical damage (e.g., surface scratches).
1.  Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains).
2.  Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree 
burns; bleeding of major vessel).
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose with 
reflexes intact; third-degree burns less than 20% of body; extensive blood loss but can recover; major fractures).
4.  Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; third-
degree burns over 20% of body; extensive blood loss with unstable vital signs; major damage to a vital area).
5.  Death
Enter Code
______
Enter Code
______
Enter Code
______
Potential Lethality: Only Answer if Actual Lethality=0
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, 
had potential for very serious lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage;
laying on train tracks with oncoming train but pulled away before run over).
0 = Behavior not likely to result in injury
1 = Behavior likely to result in injury but not likely to cause death
2 = Behavior likely to result in death despite available medical care 
Enter Code
______
Enter Code
______
Enter Code
______
© 2008 Research Foundation for Mental Hygiene, Inc. 
 
        C-SSRS—Screening (Version 1/14/09)    
 
 
                                             Page 2 of 2 
Confidential
Page 112 of 152


Signature Date: 20180129
JP: JZP166-201 Protocol Amendment 2.pdf
Signature Date:
JP: JZP166-201 Protocol Amendment 2.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: JZP166-201 Amendment 2 
 
 
 
 
 
 
CONFIDENTIAL 
Page 106 of 115 
 
Appendix 12 
Columbia-Suicide Severity Rating Scale Since Last 
Visit Version 
 
Confidential
Page 113 of 152


Signature Date: 20180129
JP: JZP166-201 Protocol Amendment 2.pdf
Signature Date:
JP: JZP166-201 Protocol Amendment 2.pdf
COLUMBIA-SUICIDE SEVERITY
RATING SCALE
(C-SSRS) 
Since Last Visit 
Version 1/14/09 
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; 
Burke, A.; Oquendo, M.; Mann, J.  
 
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. The questions contained 
in the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of 
suicidal ideation or behavior depends on the judgment of the individual administering the scale. 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History 
Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., 
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First 
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside Drive, New 
York, New York, 10032; inquiries and training requirements contact posnerk@nyspi.columbia.edu
 
© 2008 The Research Foundation for Mental Hygiene, Inc. 
Confidential
Page 114 of 152


Signature Date: 20180129
JP: JZP166-201 Protocol Amendment 2.pdf
Signature Date:
JP: JZP166-201 Protocol Amendment 2.pdf
SUICIDAL IDEATION
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the answer to question 2 is “yes”,
ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is “yes”, complete “Intensity of Ideation” section below.
Since Last 
Visit
1.  Wish to be Dead
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up. 
Have you wished you were dead or wished you could go to sleep and not wake up? 
If yes, describe:
Yes   
No
□  □
2.  Non-Specific Active Suicidal Thoughts
General, non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing myself”) without thoughts of ways to kill 
oneself/associated methods, intent, or plan during the assessment period. 
Have you actually had any thoughts of killing yourself?
If yes, describe:
Yes      No
□    □
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a specific plan with time, 
place or method details worked out (e.g., thought of method to kill self but not a specific plan).  Includes person who would say, “I thought about taking an
overdose but I never made a specific plan as to when, where or how I would actually do it…and I would never go through with it.”
Have you been thinking about how you might do this?
If yes, describe:
Yes      No
□  □
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the thoughts but I 
definitely will not do anything about them.”
Have you had these thoughts and had some intention of acting on them?
If yes, describe:
Yes     No
□   □
5.  Active Suicidal Ideation with Specific Plan and Intent
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out.
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan?
   
If yes, describe:
Yes     No
□  □
INTENSITY OF IDEATION
The following features should be rated with respect to the most severe type of ideation (i.e., 1-5 from above, with 1 being the least severe 
and 5 being the most severe). 
                                            
Most Severe Ideation:             _____                      _________________________________________________
                                             
                                                                                                          Type # (1-5)                                         Description of  Ideation
Most 
Severe
Frequency
How many times have you had these thoughts?
(1) Less than once a week    (2) Once a week   (3)  2-5 times in week    (4) Daily or almost daily    (5) Many times each day
____
Duration
When you have the thoughts, how long do they last?
(1) Fleeting - few seconds or minutes                                             
(4) 4-8 hours/most of day
(2) Less than 1 hour/some of the time                                                 (5) More than 8 hours/persistent or continuous
(3) 1-4 hours/a lot of time                                                                   
____
Controllability
Could/can you stop thinking about killing yourself or wanting to die if you want to?
(1) Easily able to control thoughts                                                      (4) Can control thoughts with a lot of difficulty
(2) Can control thoughts with little difficulty                                   (5) Unable to control thoughts
(3) Can control thoughts with some difficulty                                   (0) Does not attempt to control thoughts
____
Deterrents
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from wanting to die or acting on 
thoughts of committing suicide?
(1) Deterrents definitely stopped you from attempting suicide            (4) Deterrents most likely did not stop you 
(2) Deterrents probably stopped you                                                
(5) Deterrents definitely did not stop you 
(3) Uncertain that deterrents stopped you                                            (0) Does not apply
____
Reasons for Ideation
What sort of reasons did you have for thinking about wanting to die or killing yourself?  Was it to end the pain or stop the way 
you were feeling (in other words you couldn’t go on living with this pain or how you were feeling) or was it to get attention,
revenge or a reaction from others? Or both?
(1) Completely to get attention, revenge or a reaction from others       (4) Mostly to end or stop the pain (you couldn’t go on
(2) Mostly to get attention, revenge or a reaction from others                     living with the pain or how you were feeling)
(3) Equally to get attention, revenge or a reaction from others               (5) Completely to end or stop the pain (you couldn’t go on 
       and to end/stop the pain                                                                         living with the pain or  how you were feeling)
                                                                                                                 (0) Does not apply
____
© 2008 Research Foundation for Mental Hygiene, Inc.
        C-SSRS—Since Last Visit (Version 1/14/09)
                         Page 1 of 2       
Confidential
Page 115 of 152


Signature Date: 20180129
JP: JZP166-201 Protocol Amendment 2.pdf
Signature Date:
JP: JZP166-201 Protocol Amendment 2.pdf
SUICIDAL BEHAVIOR
(Check all that apply, so long as these are separate events; must ask about all types)
Since Last 
Visit
Actual Attempt:
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill oneself. Intent 
does not have to be 100%.  If there is any intent/desire to die associated with the act, then it can be considered an actual suicide attempt. There does not 
have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in mouth but gun is broken so no injury results,
this is considered an attempt.  
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For example, a highly 
lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head, jumping from window of a high floor/story). 
Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred. 
Have you made a suicide attempt?
Have you done anything to harm yourself?
Have you done anything dangerous where you could have died?
What did you do?
Did you______ as a way to end your life? 
Did you want to die (even a little) when you_____? 
Were you trying to end your life when you _____?
Or did you think it was possible you could have died from_____?
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better, get
sympathy, or get something else to happen)? (Self-Injurious Behavior without suicidal intent)
If yes, describe:
Has subject engaged in Non-Suicidal Self-Injurious Behavior?
Yes      No
□   □
Total # of
Attempts
______
Yes
No
□   □
Interrupted Attempt:
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt would have 
occurred).
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an attempt rather than an interrupted attempt. 
Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger. Once they pull the trigger, 
even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. Hanging: Person has noose around 
neck but has not yet started to hang - is stopped from doing so.
Has there been a time when you started to do something to end your life but someone or something stopped you before you 
actually did anything?
If yes, describe:
Yes      No
□   □
Total # of 
interrupted
______
Aborted Attempt:  
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-destructive behavior. 
Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by something else.
Has there been a time when you started to do something to try to end your life but you stopped yourself before you 
actually did anything?
If yes, describe:
Yes      No
□   □
Total # of
aborted
______
Preparatory Acts or Behavior:
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as assembling a 
specific method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving things away, writing a suicide note). 
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, getting a gun, 
giving valuables away or writing a suicide note)?
If yes, describe:
Yes      No
□   □
Suicidal Behavior:
Suicidal behavior was present during the assessment period?
Yes      No
□   □
Suicide:
Yes    No
□   □
Answer for Actual Attempts Only
Most Lethal
Attempt
Date:
Actual Lethality/Medical Damage:  
0.  No physical damage or very minor physical damage (e.g., surface scratches).
1.  Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains).
2.  Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree burns; bleeding of major vessel).
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose with reflexes intact; third-degree burns 
less than 20% of body; extensive blood loss but can recover; major fractures).
4.  Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; third-degree burns over 20% of body; 
extensive blood loss with unstable vital signs; major damage to a vital area).
5.  Death
Enter Code
______
Potential Lethality: Only Answer if Actual Lethality=0
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had potential for very serious 
lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying on train tracks with oncoming train but pulled away 
before run over).
0 = Behavior not likely to result in injury
1 = Behavior likely to result in injury but not likely to cause death
2 = Behavior likely to result in death despite available medical care 
Enter Code
______
© 2008 Research Foundation for Mental Hygiene, Inc. 
 
        C-SSRS—Since Last Visit (Version 1/14/09)    
 
 
                          Page 2 of 2                               
Confidential
Page 116 of 152


Signature Date: 20180129
JP: JZP166-201 Protocol Amendment 2.pdf
Signature Date:
JP: JZP166-201 Protocol Amendment 2.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: JZP166-201 Amendment 2 
 
 
 
 
 
 
CONFIDENTIAL 
Page 107 of 115 
 
Appendix 13 
Epworth Sleepiness Scale 
 
Confidential
Page 117 of 152


Signature Date: 20180129
JP: JZP166-201 Protocol Amendment 2.pdf
Signature Date:
JP: JZP166-201 Protocol Amendment 2.pdf
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Confidential
Page 118 of 152


Signature Date: 20180129
JP: JZP166-201 Protocol Amendment 2.pdf
Signature Date:
JP: JZP166-201 Protocol Amendment 2.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: JZP166-201 Amendment 2 
 
 
 
 
 
 
CONFIDENTIAL 
Page 108 of 115 
 
Appendix 14 
Movement Disorders Society-Unified Parkinson’s 
Disease Rating Scale Parts III and IV 
Confidential
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Signature Date: 20180129
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Part III: Motor Examination
Overview: This portion of the scale assesses the motor signs of PD. In administering Part III of the MDS-UPDRS 
the examiner should comply with the following guidelines: 
At the top of the form, mark whether the patient is on medication for treating the symptoms of Parkinson's disease
and, if on levodopa, the time since the last dose. 
Also, if the patient is receiving medication for treating the symptoms of Parkinson’s Disease, mark the patient’s 
clinical state using the following definitions: 
ON is the typical functional state when patients are receiving medication and have a good response. 
OFF is the typical functional state when patients have a poor response in spite of taking medications.
The investigator should “rate what you see”. Admittedly, concurrent medical problems such as stroke, paralysis, 
arthritis, contracture, and orthopedic problems such as hip or knee replacement and scoliosis may interfere with 
individual items in the motor examination. In situations where it is absolutely impossible to test (e.g., amputations, 
plegia, limb in a cast), use the notation “UR” for Unable to Rate. Otherwise, rate the performance of each task as the 
patient performs in the context of co-morbidities. 
All items must have an integer rating (no half points, no missing ratings). 
Specific instructions are provided for the testing of each item. These should be followed in all instances. The 
investigator demonstrates while describing tasks the patient is to perform and rates function immediately thereafter. 
For Global Spontaneous Movement and Rest Tremor items (3.14 and 3.17), these items have been placed 
purposefully at the end of the scale because clinical information pertinent to the score will be obtained throughout the 
entire examination. 
At the end of the rating, indicate if dyskinesia (chorea or dystonia) was present at the time of the examination, and if 
so, whether these movements interfered with the motor examination.
3a
Is the patient on medication for treating the symptoms of Parkinson’s Disease? 
 No  Yes 
3b
If the patient is receiving medication for treating the symptoms of Parkinson’s Disease, 
mark the patient’s clinical state using the following definitions: 
 ON: On is the typical functional state when patients are receiving medication and have a good response. 
 OFF: Off is the typical functional state when patients have a poor response in spite of taking medications. 
3c
Is the patient on Levodopa ? 
 No  Yes 
3.C1 If yes, minutes since last levodopa dose:
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3.1 SPEECH
 
Instructions to examiner:
Listen to the patient’s free-flowing speech and engage in conversation if 
necessary. Suggested topics: ask about the patient’s work, hobbies, exercise, or how he got to the 
doctor’s office. Evaluate volume, modulation (prosody) and clarity, including slurring, palilalia (repetition 
of syllables) and tachyphemia (rapid speech, running syllables together).
 
0: Normal:
No speech problems.
 
1: Slight:
Loss of modulation, diction or volume, but still all words easy to understand.
 
2: Mild:
Loss of modulation, diction, or volume, with a few words unclear, but the overall 
sentences easy to follow.
 
3: Moderate: Speech is difficult to understand to the point that some, but not most, sentences are 
poorly understood.
 
4: Severe:
Most speech is difficult to understand or unintelligible.
SCORE
 
 
 
 
 
 
 
 
 
 
 
 
 
3.2 FACIAL EXPRESSION
 
Instructions to examiner: Observe the patient sitting at rest for 10 seconds, without talking and also 
while talking. Observe eye-blink frequency, masked facies or loss of facial expression, spontaneous 
smiling and parting of lips.
 
0: Normal:
Normal facial expression.
 
1: Slight:
Minimal masked facies manifested only by decreased frequency of blinking.
 
2: Mild:
In addition to decreased eye-blink frequency, Masked facies present in the lower 
face as well, namely fewer movements around the mouth, such as less 
spontaneous smiling, but lips not parted.
 
3: Moderate:  Masked facies with lips parted some of the time when the mouth is at rest.
 
4: Severe:
Masked facies with lips parted most of the time when the mouth is at rest.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3.3 RIGIDITY
 
Instructions to examiner: Rigidity is judged on slow passive movement of major joints with the patient in 
a relaxed position and the examiner manipulating the limbs and neck. First, test without an activation 
maneuver. Test and rate neck and each limb separately. For arms, test the wrist and elbow joints 
simultaneously. For legs, test the hip and knee joints simultaneously. If no rigidity is detected, use an 
activation maneuver such as tapping fingers, fist opening/closing, or heel tapping in a limb not being 
tested. Explain to the patient to go as limp as possible as you test for rigidity.
 
0: Normal:
No rigidity.
 
1: Slight:
Rigidity only detected with activation maneuver.
 
2: Mild:
Rigidity detected without the activation maneuver, but full range of motion is easily 
achieved.
 
3: Moderate:  Rigidity detected without the activation maneuver; full range of motion is achieved
with effort.
 
4: Severe:
Rigidity detected without the activation maneuver and full range of motion not 
achieved.
SCORE
Neck
RUE
LUE
RLE
LLE
3.4 FINGER TAPPING
 
Instructions to examiner: Each hand is tested separately. Demonstrate the task, but do not continue to 
perform the task while the patient is being tested. Instruct the patient to tap the index finger on the 
thumb 10 times as quickly AND as big as possible.  Rate each side separately, evaluating speed,
amplitude, hesitations, halts and decrementing amplitude.
 
0: Normal:
No problems.
 
1: Slight:        Any of the following: a) the regular rhythm is broken with one or two interruptions or 
hesitations of the tapping movement; b) slight slowing; c) the amplitude decrements 
near the end of the 10 taps.
 
2: Mild:
Any of the following: a) 3 to 5 interruptions during tapping; b) mild slowing; c) the 
amplitude decrements midway in the 10-tap sequence.
 
3: Moderate:  Any of the following: a) more than 5 interruptions during tapping or at least one 
longer arrest (freeze) in ongoing movement; b) moderate slowing; c) the amplitude
decrements starting after the 1st tap.
 
4: Severe:
Cannot or can only barely perform the task because of slowing, interruptions or 
decrements.
 
 
 
 
 
 
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3.5 HAND MOVEMENTS
 
Instructions to examiner: Test each hand separately. Demonstrate the task, but do not continue to 
perform the task while the patient is being tested. Instruct the patient to make a tight fist with the arm 
bent at the elbow so that the palm faces the examiner. Have the patient open the hand 10 times as fully 
AND as quickly as possible. If the patient fails to make a tight fist or to open the hand fully, remind him/ 
her to do so. Rate each side separately, evaluating speed, amplitude, hesitations, halts and 
decrementing amplitude.
 
0: Normal:
No problem.
 
1: Slight:
Any of the following: a) the regular rhythm is broken with one or two interruptions or 
hesitations of the movement; b) slight slowing; c) the amplitude decrements near
the end of the task.
 
2: Mild:
Any of the following: a) 3 to 5 interruptions during the movements; b) mild slowing;
c) the amplitude decrements midway in the task.
 
3: Moderate:  Any of the following: a) more than 5 interruptions during the movement or at least 
one longer arrest (freeze) in ongoing movement; b) moderate slowing; c) the 
amplitude decrements starting after the 1st open-and-close sequence.
 
4: Severe:
Cannot or can only barely perform the task because of slowing, interruptions or
decrements.
SCORE
 
 
 
 
 
 
 
 
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3.6
PRONATION-SUPINATION MOVEMENTS OF HANDS
 
Instructions to examiner: Test each hand separately. Demonstrate the task, but do not continue to 
perform the task while the patient is being tested. Instruct the patient to extend the arm out in front of 
his/her body with the palms down; then to turn the palm up and down alternately 10 times as fast and as 
fully as possible. Rate each side separately, evaluating speed, amplitude, hesitations, halts and
decrementing amplitude.
 
0: Normal:
No problems.
 
1: Slight:
Any of the following: a) the regular rhythm is broken with one or two interruptions or 
hesitations of the movement; b) slight slowing; c) the amplitude decrements near
the end of the sequence.
 
2: Mild:
Any of the following: a) 3 to 5 interruptions during the movements; b) mild slowing;
c) the amplitude decrements midway in the sequence.
 
3: Moderate:  Any of the following: a) more than 5 interruptions during the movement or at least 
one longer arrest (freeze) in ongoing movement; b) moderate slowing c) the
amplitude decrements starting after the 1st supination-pronation sequence.
 
4: Severe:
Cannot or can only barely perform the task because of slowing, interruptions or 
decrements.
 
 
 
 
 
 
 
 
 
 
 
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3.7 TOE TAPPING
 
Instructions to examiner: Have the patient sit in a straight-backed chair with arms, both feet on the floor. 
Test each foot separately. Demonstrate the task, but do not continue to perform the task while the 
patient is being tested. Instruct the patient to place the heel on the ground in a comfortable position and
then tap the toes 10 times as big and as fast as possible. Rate each side separately, evaluating speed, 
amplitude, hesitations, halts and decrementing amplitude.
 
0:
Normal:
No problem.
 
1: Slight:
Any of the following: a) the regular rhythm is broken with one or two interruptions 
or hesitations of the tapping movement; b) slight slowing; c) amplitude
decrements near the end of the ten taps.
 
2: Mild:
Any of the following: a) 3 to 5 interruptions during the tapping movements; b) mild
slowing; c) amplitude decrements midway in the task.
 
3: Moderate:
Any of the following: a) more than 5 interruptions during the tapping movements
or at least one longer arrest (freeze) in ongoing movement; b) moderate slowing;
c) amplitude decrements after the first tap.
 
4: Severe:
Cannot or can only barely perform the task because of slowing, interruptions or 
decrements.
SCORE
 
 
 
 
 
 
 
 
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3.8 LEG AGILITY
 
Instructions to examiner: Have the patient sit in a straight-backed chair with arms. The patient should 
have both feet comfortably on the floor. Test each leg separately. Demonstrate the task, but do not 
continue to perform the task while the patient is being tested. Instruct the patient to place the foot on the 
ground in a comfortable position and then raise and stomp the foot on the ground 10 times as high and 
as fast as possible. Rate each side separately, evaluating speed, amplitude, hesitations, halts and 
decrementing amplitude.
 
0: Normal:
No problems.
 
1: Slight:
Any of the following: a) the regular rhythm is broken with one or two interruptions 
or hesitations of the movement; b) slight slowing; c) amplitude decrements near
the end of the task.
 
2: Mild:
Any of the following: a) 3 to 5 interruptions during the movements; b) mild 
slowness; c) amplitude decrements midway in the task.
 
3: Moderate:     Any of the following: a) more than 5 interruptions during the movement or at least 
one longer arrest (freeze) in ongoing movement; b) moderate slowing in speed; c) 
amplitude decrements after the first tap.
 
4: Severe:
Cannot or can only barely perform the task because of slowing, interruptions or 
decrements.
 
 
 
 
 
 
 
 
 
 
 
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3.9 ARISING FROM CHAIR
Instructions to examiner: Have the patient sit in a straight-backed chair with arms, with both feet on the
floor and sitting back in the chair (if the patient is not too short). Ask the patient to cross his/her arms 
across the chest and then to stand up. If the patient is not successful, repeat this attempt a maximum
up to two more times. If still unsuccessful, allow the patient to move forward in the chair to arise with 
arms folded across the chest. Allow only one attempt in this situation. If unsuccessful, allow the patient 
to push off using his/her hands on the arms of the chair. Allow a maximum of three trials of pushing off. 
If still not successful, assist the patient to arise. After the patient stands up, observe the posture for item
3.13
0: Normal:
No problems. Able to arise quickly without hesitation.
1: Slight: 
Arising is slower than normal; or may need more than one attempt; or may 
need to move forward in the chair to arise. No need to use the arms of the 
chair.
2: Mild:
Pushes self up from arms of chair without difficulty.
3: Moderate:
Needs to push off, but tends to fall back; or may have to try more than one time 
using arms of chair, but can get up without help.
4: Severe:
Unable to arise without help.
SCORE
3.10 GAIT
Instructions to examiner: Testing gait is best performed by having the patient walking away from and 
towards the examiner so that both right and left sides of the body can be easily observed 
simultaneously. The patient should walk at least 10 meters (30 feet), then turn around and return to the 
examiner. This item measures multiple behaviors: stride amplitude, stride speed, height of foot lift, heel 
strike during walking, turning, and arm swing, but not freezing. Assess also for “freezing of gait” (next 
item 3.11) while patient is walking.  Observe posture for item 3.13
0: Normal:
No problems.
1: Slight:
Independent walking with minor gait impairment.
2: Mild:
Independent walking but with substantial gait impairment.
3: Moderate:
Requires an assistance device for safe walking (walking stick, walker) but not a 
person.
4: Severe:
Cannot walk at all or only with another person’s assistance.
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3.11 FREEZING OF GAIT
 
Instructions to examiner: While assessing gait, also assess for the presence of any gait freezing 
episodes. Observe for start hesitation and stuttering movements especially when turning and reaching
the end of the task. To the extent that safety permits, patients may NOT use sensory tricks during the 
assessment.
 
0: Normal:
No freezing.
 
1: Slight:            Freezes on starting, turning or walking through doorway with a single halt during 
any of these events, but then continues smoothly without freezing during straight 
walking.
 
2: Mild:
Freezes on starting, turning or walking through doorway with more than one halt 
during any of these activities, but continues smoothly without freezing during
straight walking.
 
3: Moderate:
Freezes once during straight walking.
 
4: Severe:
Freezes multiple times during straight walking.
SCORE
 
 
 
 
 
 
 
 
 
 
 
3.12 POSTURAL STABILITY
 
Instructions to examiner: The test examines the response to sudden body displacement produced by a 
quick, forceful pull on the shoulders while the patient is standing erect with eyes open and feet 
comfortably apart and parallel to each other. Test retropulsion. Stand behind the patient and instruct 
the patient on what is about to happen. Explain that s/he is allowed to take a step backwards to avoid 
falling. There should be a solid wall behind the examiner, at least 1-2 meters away to allow for the 
observation of the number of retropulsive steps. The first pull is an instructional demonstration and is 
purposely milder and not rated. The second time the shoulders are pulled briskly and forcefully towards
the examiner with enough force to displace the center of gravity so that patient MUST take a step 
backwards. The examiner needs to be ready to catch the patient, but must stand sufficiently back so as
to allow enough room for the patient to take several steps to recover independently. Do not allow the 
patient to flex the body abnormally forward in anticipation of the pull. Observe for the number of steps 
backwards or falling. Up to and including two steps for recovery is considered normal, so abnormal 
ratings begin with three steps. If the patient fails to understand the test, the examiner can repeat the
test so that the rating is based on an assessment that the examiner feels reflects the patient’s limitations 
rather than misunderstanding or lack of preparedness. Observe standing posture for item 3.13
 
0: Normal:
No problems: Recovers with one or two steps.
 
1: Slight:
3-5 steps, but subject recovers unaided.
 
2: Mild:
More than 5 steps, but subject recovers unaided.
 
3: Moderate:
Stands safely, but with absence of postural response; falls if not caught by 
examiner.
 
4: Severe:
Very unstable, tends to lose balance spontaneously or with just a gentle pull on
the shoulders.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3.13 POSTURE
 
Instructions to examiner: Posture is assessed with the patient standing erect after arising from a chair, 
during walking, and while being tested for postural reflexes. If you notice poor posture, tell the patient 
to stand up straight and see if the posture improves (see option 2 below). Rate the worst posture seen 
in these three observation points. Observe for flexion and side-to-side leaning.
 
0: Normal:
No problems.
 
1: Slight:
Not quite erect, but posture could be normal for older person.
 
2: Mild:
Definite flexion, scoliosis or leaning to one side, but patient can correct posture to 
normal posture when asked to do so.
 
3:
Moderate:
Stooped posture, scoliosis or leaning to one side that cannot be corrected
volitionally to a normal posture by the patient.
 
4:
Severe:
Flexion, scoliosis or leaning with extreme abnormality of posture.
SCORE
 
 
 
 
 
 
 
 
3.14 GLOBAL SPONTANEITY OF MOVEMENT (BODY BRADYKINESIA)
 
Instructions to examiner: This global rating combines all observations on slowness, hesitancy, and 
small amplitude and poverty of movement in general, including a reduction of gesturing and of crossing 
the legs. This assessment is based on the examiner’s global impression after observing for 
spontaneous gestures while sitting, and the nature of arising and walking.
 
0: Normal:
No problems.
 
1: Slight:
Slight global slowness and poverty of spontaneous movements.
 
2: Mild:
Mild global slowness and poverty of spontaneous movements.
 
3: Moderate:
Moderate global slowness and poverty of spontaneous movements.
 
4:
Severe:
Severe global slowness and poverty of spontaneous movements.
 
 
 
 
 
 
 
 
3.15 POSTURAL TREMOR OF THE HANDS
 
Instructions to examiner: All tremor, including re-emergent rest tremor, that is present in this posture is 
to be included in this rating. Rate each hand separately. Rate the highest amplitude seen. Instruct the 
patient to stretch the arms out in front of the body with palms down. The wrist should be straight and 
the fingers comfortably separated so that they do not touch each other. Observe this posture for 10 
seconds.
 
0: Normal:
No tremor.
 
1: Slight:
Tremor is present but less than 1 cm in amplitude.
 
2: Mild:
Tremor is at least 1 but less than 3 cm in amplitude.
 
3: Moderate:
Tremor is at least 3 but less than 10 cm in amplitude.
 
4:
Severe:
Tremor is at least 10 cm in amplitude.
 
 
 
 
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3.16 KINETIC TREMOR OF THE HANDS
Instructions to examiner: This is tested by the finger-to-nose maneuver. With the arm starting from the 
outstretched position, have the patient perform at least three finger-to-nose maneuvers with each hand
reaching as far as possible to touch the examiner’s finger. The finger-to-nose maneuver should be
performed slowly enough not to hide any tremor that could occur with very fast arm movements. Repeat
with the other hand, rating each hand separately. The tremor can be present throughout the movement 
or as the tremor reaches either target (nose or finger). Rate the highest amplitude seen.
0: Normal:
No tremor.
1: Slight:
Tremor is present but less than 1 cm in amplitude.
2: Mild:
Tremor is at least 1 but less than 3 cm in amplitude.
3: Moderate:
Tremor is at least 3 but less than 10 cm in amplitude.
4:
Severe:
Tremor is at least 10 cm in amplitude.
SCORE
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3.17
REST TREMOR AMPLITUDE
Instructions to examiner: This and the next item have been placed purposefully at the end of the 
examination to allow the rater to gather observations on rest tremor that may appear at any time during
the exam, including when quietly sitting, during walking and during activities when some body parts are 
moving but others are at rest. Score the maximum amplitude that is seen at any time as the final score. 
Rate only the amplitude and not the persistence or the intermittency of the tremor.
As part of this rating, the patient should sit quietly in a chair with the hands placed on the arms of the 
chair (not in the lap) and the feet comfortably supported on the floor for 10 seconds with no other
directives. Rest tremor is assessed separately for all four limbs and also for the lip/jaw. Rate only the 
maximum amplitude that is seen at any time as the final rating.
Extremity ratings
0: Normal:
No tremor.
1: Slight.:
≤1 cm in maximal amplitude.
2: Mild:
> 1 cm but < 3 cm in maximal amplitude.
3: Moderate:
3 - 10 cm in maximal amplitude.
4: Severe:
> 10 cm in maximal amplitude.
Lip/Jaw ratings
0: Normal:
No tremor.
1: Slight:
≤1 cm in maximal amplitude.
2: Mild:
> 1 cm but ≤2 cm in maximal amplitude.
3: Moderate:
> 2 cm but ≤3 cm in maximal amplitude.
4: Severe:
> 3 cm in maximal amplitude.
RUE
LUE
RLE
LLE
Lip/Jaw
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3.18 CONSTANCY OF REST TREMOR
 
Instructions to examiner: This item receives one rating for all rest tremor and focuses on the constancy 
of rest tremor during the examination period when different body parts are variously at rest. It is rated 
purposefully at the end of the examination so that several minutes of information can be coalesced into 
the rating.
 
0: Normal:
No tremor.
 
1: Slight:
Tremor at rest is present ≤25% of the entire examination period.
 
2: Mild:
Tremor at rest is present 26-50% of the entire examination period.
 
3: Moderate:
Tremor at rest is present 51-75% of the entire examination period.
 
4: Severe:
Tremor at rest is present > 75% of the entire examination period.
SCORE
 
 
 
 
 
 
 
 
 
 
DYSKINESIA IMPACT ON PART III RATINGS
 
A. Were dyskinesias (chorea or dystonia) present during examination?
 No  Yes
 
B. If yes, did these movements interfere with your ratings?
 No  Yes
 
 
 
HOEHN AND YAHR STAGE
 
0:  Asymptomatic.
 
1:  Unilateral involvement only.
 
2:  Bilateral involvement without impairment of balance.
 
3:  Mile 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.
 
 
 
 
 
 
 
 
 
 
 
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Part IV: Motor Complications
 
 
Overview and Instructions: In this section, the rater uses historical and objective information to assess two motor 
complications, dyskinesias and motor fluctuations that include OFF-state dystonia. Use all information from patient, 
caregiver, and the examination to answer the six questions that summarize function over the past week including 
today. As in the other sections, rate using only integers (no half points allowed) and leave no missing ratings. If the 
item cannot be rated, place UR for Unable to Rate. You will need to choose some answers based on percentages, 
and therefore you will need to establish how many hours generally are awake hours and use this figure as the 
denominator for “OFF” time and Dyskinesias. For “OFF dystonia”, the total “Off” time will be the denominator. 
Operational definitions for examiner’s use.
 
Dyskinesias: Involuntary random movements
Words that patients often recognize for dyskinesias include “irregular jerking”, “wiggling”, “twitching”. It is essential to
stress to the patient the difference between dyskinesias and tremor, a common error when patients are assessing
dyskinesias.
 
Dystonia: contorted posture, often with a twisting component:
Words that patients often recognize for dystonia include “spasms”, “cramps”, “posture”.
 
Motor fluctuation: Variable response to medication: 
Words that patients often recognize for motor fluctuation include “wearing out”, “wearing off”, “roller-coaster effect”, 
“on-off”, “uneven medication effects”.
 
OFF: Typical functional state when patients have a poor response in spite of taking mediation or the typical functional 
response when patients are on NO treatment for parkinsonism. Words that patients often recognize include “low
time”, “bad time”, “shaking time”, “slow time”, “time when my medications don’t work.”
 
ON: Typical functional state when patients are receiving medication and have a good response: 
Words that patients often recognize include “good time”, “walking time”, “time when my medications work.”
 
A . DYSKINESIAS [exclusive of OFF-state dystonia]
 
 
4.1 TIME SPENT WITH DYSKINESIAS
 
Instructions to examiner:  Determine the hours in the usual waking day and then the hours of 
dyskinesias. Calculate the percentage. If the patient has dyskinesias in the office, you can point them 
out as a reference to ensure that patients and caregivers understand what they are rating. You may also 
use your own acting skills to enact the dyskinetic movements you have seen in the patient before or
show them dyskinetic movements typical of other patients. Exclude from this question early morning
and nighttime painful dystonia. 
 
Instructions to patient [and caregiver].  Over the past week, how many hours do you usually sleep on a 
daily basis, including nighttime sleep and daytime napping? Alright, if you sleep   
 hrs, you are awake
  
 hrs. Out of those awake hours, how many hours in total do you have wiggling, twitching or jerking
movements? Do not count the times when you have tremor, which is a regular back and forth shaking
or times when you have painful foot cramps or spasms in the early morning or at nighttime. I will ask 
about those later.  Concentrate only on these types of wiggling, jerking and irregular movements. Add
SCORE
 
 
 
 
 
 
 
 
 
 
 
 
up all the time during the waking day when these usually occur. How many hours
number for your calculation).
(use this
 
0: Normal:
No dyskinesias.
 
 
1: Slight:
≤ 25% of waking day.
 
2: Mild:
26 - 50% of waking day.
1. Total Hours Awake:
 
3: Moderate:
51 - 75% of waking day.
2. Total Hours with Dyskinesia:
 
4: Severe:
> 75% of waking day.
3. % Dyskinesia = ((2/1)*100):
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1. Total Hours Awake:
2. Total Hours OFF:
3. % OFF = ((2/1)*100):
4.2 FUNCTIONAL IMPACT OF DYSKINESIAS
Instructions to examiner:  Determine the degree to which dyskinesias impact on the patient’s daily 
function in terms of activities and social interactions. Use the patient’s and caregiver’s response to your 
question and your own observations during the office visit to arrive at the best answer. 
Instructions to patient [and caregiver]: Over the past week, did you usually have trouble doing things or
being with people when these jerking movements occurred? Did they stop you from doing things or 
from being with people?
0: Normal: 
No dyskinesias or no impact by dyskinesias on activities or social interactions. 
1: Slight: 
Dyskinesias impact on a few activities, but the patient usually performs all 
activities and participates in all social interactions during dyskinetic periods. 
2: Mild: 
Dyskinesias impact on many activities, but the patient usually performs all 
activities and participates in all social interactions during dyskinetic periods. 
3: Moderate: 
Dyskinesias impact on activities to the point that the patient usually does not 
perform some activities or does not usually participate in some social activities 
during dyskinetic episodes. 
4: Severe: 
Dyskinesias impact on function to the point that the patient usually does not 
perform most activities or participate in most social interactions during 
dyskinetic episodes. 
SCORE
B . MOTOR FLUCTUATIONS
4.3 TIME SPENT IN THE OFF STATE
Instructions to examiner: Use the number of waking hours derived from 4.1 and determine the hours 
spent in the “OFF” state. Calculate the percentage. If the patient has an OFF period in the office, you 
can point to this state as a reference. You may also use your knowledge of the patient to describe a 
typical OFF period. Additionally you may use your own acting skills to enact an OFF period you have 
seen in the patient before or show them OFF function typical of other patients. Mark down the typical 
number of OFF hours, because you will need this number for completing 4.6 
Instructions to patient [and caregiver]:
Some patients with Parkinson's disease have a good effect
from their medications throughout their awake hours and we call that “ON” time.   Other patients take 
their medications but still have some hours of low time, bad time, slow time or shaking time. Doctors
call these low periods “OFF” time. Over the past week, you told me before that you are generally awake
hrs each day. Out of these awake hours, how many hours in total do you usually have this type of
low level or OFF function
(Use this number for your calculations).
0: Normal: 
No OFF time. 
1: Slight: 
≤ 25% of waking day. 
2: Mild: 
26 - 50% of waking day. 
3: Moderate: 
51 - 75% of waking day. 
4: Severe: 
> 75% of waking day. 
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Copyright © 2008 Movement Disorder Society. All rights reserved
This chart may not be copied, distributed or otherwise used in whole or in part without prior written consent of the Movement Disorder Society
 
 
 
4.4 FUNCTIONAL IMPACT OF FLUCTUATIONS
 
Instructions to examiner: Determine the degree to which motor fluctuations impact on the patient’s daily 
function in terms of activities and social interactions. This question concentrates on the difference 
between the ON state and the OFF state. If the patient has no OFF time, the rating must be 0, but if 
patients have very mild fluctuations, it is still possible to be rated 0 on this item if no impact on activities 
occurs. Use the patient’s and caregiver’s response to your question and your own observations during
the office visit to arrive at the best answer.
 
Instructions to patient [and caregiver]: Think about when those low or “OFF” periods have occurred over
the past week. Do you usually have more problems doing things or being with people than compared to 
the rest of the day when you feel your medications working? Are there some things you usually do
during a good period that you have trouble with or stop doing during a low period?
 
0: Normal:
No fluctuations or No impact by fluctuations on performance of activities or 
social interactions.
 
1: Slight:
Fluctuations impact on a few activities, but during OFF, the patient usually 
performs all activities and participates in all social interactions that typically 
occur during the ON state.
 
2: Mild:                 Fluctuations impact many activities, but during OFF, the patient still usually 
performs all activities and participates in all social interactions that typically 
occur during the ON state.
 
3: Moderate:
Fluctuations impact on the performance of activities during OFF to the point that 
the patient usually does not perform some activities or participate in some
social interactions that are performed during ON periods.
 
4: Severe:
Fluctuations impact on function to the point that, during OFF, the patient usually
does not perform most activities or participate in most social interactions that
are performed during ON periods.
SCORE
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.5 COMPLEXITY OF MOTOR FLUCTUATIONS
 
Instructions to examiner: Determine the usual predictability of OFF function whether due to dose, time 
of day, food intake or other factors. Use the information provided by the patients and caregiver and 
supplement with your own observations. You will ask if the patient can count on them always coming at
a special time, mostly coming at a special time (in which case you will probe further to separate slight
from mild), only sometimes coming at a special time or are they totally unpredictable? Narrowing down 
the percentage will allow you to find the correct answer.
 
Instructions to patient [and caregiver]: For some patients, the low or “OFF” periods happen at certain 
times during day or when they do activities like eating or exercising. Over the past week, do you usually 
know when your low periods will occur? In other words, do your low periods always come at a certain
time? Do they mostly come at a certain time? Do they only sometimes come at a certain time? Are 
your low periods totally unpredictable?”
 
0: Normal:
No motor fluctuations.
 
1: Slight:
OFF times are predictable all or almost all of the time (> 75%).
 
2: Mild:
OFF times are predictable most of the time (51-75%).
 
3: Moderate:
OFF times are predictable some of the time (26-50%).
 
4:
Severe:
OFF episodes are rarely predictable. (< 25%).
 
 
 
 
 
 
 
 
 
 
 
 
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This chart may not be copied, distributed or otherwise used in whole or in part without prior written consent of the Movement Disorder Society
 
 
 
 
C. “OFF” DYSTONIA
 
4.6 PAINFUL OFF-STATE DYSTONIA
 
Instructions to examiner: For patients who have motor fluctuations, determine what proportion of the 
OFF episodes usually includes painful dystonia? You have already determined the number of hours of 
“OFF” time (4.3). Of these hours, determine how many are associated with dystonia and calculate the 
percentage. If there is no OFF time, mark 0.
 
Instructions to patient [and caregiver]: 
In one of the questions I asked earlier, you said you generally
have 
hours of low or “OFF” time when your Parkinson's disease is under poor control. During these
low or “OFF” periods, do you usually have painful cramps or spasms? Out of the total 
hrs of this
low time, if you add up all the time in a day when these painful cramps come, how many hours would
this make?
 
0: Normal:
No dystonia OR NO OFF TIME.
 
1: Slight:
≤25% of time in OFF state.
 
2: Mild:
26-50% of time in OFF state.
 
3: Moderate:
51-75% of time in OFF state.
 
4: Severe:
> 75% of time in OFF state.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. Total Hours Off:
 
2. Total Off Hours w/Dystonia:
 
3. % Off Dystonia = ((2/1)*100):
 
 
 
 
 
 
 
 
 
 
 
 
Summary statement to patient: READ TO PATIENT
 
This completes my rating of your Parkinson’s disease.  I know the questions and tasks have taken several minutes, but 
I wanted to be complete and cover all possibilities. In doing so, I may have asked about problems you do not even 
have, and I may have mentioned problems that you may never develop at all. Not all patients develop all these 
problems, but because they can occur, it is important to ask all the questions to every patient. Thank you for your time 
and attention in completing this scale with me.
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Clinical Trial Protocol: JZP166-201 Amendment 2 
 
 
 
 
 
 
CONFIDENTIAL 
Page 109 of 115 
 
Appendix 15 
Clinical Global Impression of Severity 
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Clinical Global Impression of Severity (CGIs) 
Check if Not Done ڧ
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CGI – SEVERITY
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JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: JZP166-201 Amendment 2 
 
 
 
 
 
 
CONFIDENTIAL 
Page 110 of 115 
 
Appendix 16 
Clinical Global Impression of Change  
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Clinical Global Impression of Change (CGIc) 
Check if Not Done ڧ
CGI – CHANGE
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Signature Date: 20180129
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JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: JZP166-201 Amendment 2 
 
 
 
 
 
 
CONFIDENTIAL 
Page 111 of 115 
 
Appendix 17 
Patient Global Impression of Change  
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Patient Global Impression of Change (PGIc)
Check if Not Done ڧ
PGI – CHANGE
&KRRVHRQO\RQH
6LQFH\RXSTARTEDVWXG\WUHDWPHQW\RXUOVERALLFRQGLWLRQLV
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Signature Date: 20180129
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JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: JZP166-201 Amendment 2 
 
 
 
 
 
 
CONFIDENTIAL 
Page 112 of 115 
 
Appendix 18 
Apathy Scale 
 
 
 
 
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Apathy Scale
Name: ___________________________________________ 
Date: ___/___/___
For each statement, the examiner should read the question to the patient and give the patient the 
four possible answers: "not at all" "slightly" "some" or "a lot"
1.
Are you interested in learning new things?
NOT AT ALL
SLIGHTLY
SOME
2.
Does anything interest you?
3.
Are you concerned about your condition?
4.
Do you put much effort into things?
5.
Are you always looking for something to do?
6.
Do you have plans and goals for the future?
7.
Do you have motivation?
8.
Do you have the energy for daily activities?
9.
Does someone have to tell you what to do each day?
10.
Are you indifferent to things?
"-05
NOT AT ALL
SLIGHTLY
SOME
"-05
NOT AT ALL
SLIGHTLY
SOME
"-05
NOT AT ALL
SLIGHTLY
SOME
"-05
NOT AT ALL
SLIGHTLY
SOME
"-05
NOT AT ALL
SLIGHTLY
SOME
"-05
NOT AT ALL
SLIGHTLY
SOME
"-05
NOT AT ALL
SLIGHTLY
SOME
"-05
NOT AT ALL
SLIGHTLY
SOME
"-05
NOT AT ALL
SLIGHTLY
SOME
"-05
3FQSJOUFEXJUIQFSNJTTJPOGSPN5IF+PVSOBMPG/FVSPQTZDIJBUSZBOE$MJOJDBM/FVSPTDJFODFT	$PQZSJHIU
ª
"NFSJDBO1TZDIJBUSJD"TTPDJBUJPO"MM3JHIUT3FTFSWFE
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11.
Are you unconcerned with many things?
12.
Do you need a push to get started on things?
13.
Are you neither happy nor sad, just in between?
14.
Would you consider yourself apathetic?
NOT AT ALL
SLIGHTLY
SOME
"-05
NOT AT ALL
SLIGHTLY
SOME
"-05
NOT AT ALL
SLIGHTLY
SOME
"-05
NOT AT ALL
SLIGHTLY
SOME
"-05
3FQSJOUFEXJUIQFSNJTTJPOGSPN5IF+PVSOBMPG/FVSPQTZDIJBUSZBOE$MJOJDBM/FVSPTDJFODFT	$PQZSJHIU
ª
"NFSJDBO1TZDIJBUSJD"TTPDJBUJPO"MM3JHIUT3FTFSWFE
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Signature Date: 20180129
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JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: JZP166-201 Amendment 2 
 
 
 
 
 
 
CONFIDENTIAL 
Page 113 of 115 
 
Appendix 19 
Fatigue Severity Scale 
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Fatigue Severity Scale 
Please circle the number between 1 and 7 which you feel best fits the following statements. This 
refers to your usual way of life within the last week.  
1 indicates “strongly disagree” and 7 indicates “strongly agree”. 
Strongly 
Strongly 
disagree 
agree 
1. My motivation is lower when I am
fatigued.
1
2
3
4
5
6
7
2. Exercise brings on my fatigue.
1
2
3
4
5
6
7
3. I am easily fatigued.
1
2
3
4
5
6
7
4. Fatigue interferes with my physical
functioning.
1
2
3
4
5
6
7
5. Fatigue causes frequent problems for me.
1
2
3
4
5
6
7
6. My fatigue prevents sustained physical
functioning.
1
2
3
4
5
6
7
7. Fatigue interferes with carrying out
certain duties and responsibilities.
1
2
3
4
5
6
7
8. Fatigue is among my three most disabling
symptoms.
1
2
3
4
5
6
7
9. Fatigue interferes with my work, family,
or social life.
1
2
3
4
5
6
7
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TZTUFNJDMVQVTFSZUIFNBUPTVT"SDI/FVSPM
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Signature Date: 20180129
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Signature Date:
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JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: JZP166-201 Amendment 2 
 
 
 
 
 
 
CONFIDENTIAL 
Page 114 of 115 
 
Appendix 20 
Scales for Outcomes in Parkinson's Disease-
Cognition 
 
 
 
 
 
 
 
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SCOPA-COG
Memory and learning 
1.  
Verbal recall
Ten words are repeatedly shown for at least 4 seconds, get the patient to read them out 
loud, the time allowed for recall is unlimited. Underline each word that has been named. 
When words are named that were not shown, no penalty is given. When a false answer 
is changed (e.g. king into queen), it is correct.
Instruction: "Read the following 10 words aloud and try to remember as many as 
possible. After reading them all, name as many words as possible, the order of the words 
is not important". 
10 words: Butter arm shore letter queen cabin pole ticket grass engine 
(10 correct = 5, 8-9 correct = 4, 6-7 correct = 3, 5 correct = 2, 4 correct = 1, d 3 correct= 0) 
score ……../5 
2. 
Digit span backward
Ask the patient to repeat a series of numbers backwards; the numbers are read out 
separately, 1 second per number; if incorrectly repeated, the alternative in the second 
column is presented. Continue until both the first and the alternative series are repeated 
incorrectly. Make sure the time interval between numbers stays the same. Read the 
numbers calmly and make sure the time between numbers is equal. Record the highest 
series that is repeated correctly at least once; Give an example: "If I say 2-7-3, than you 
say (3-7-2) 
backwards 
 
 
 
 
 
 
score:
 
2-4 
 
 
 
5-8 
 
 
 
= 1 
 
6-2-9  
 
 
4-1-5  
 
 
= 2 
 
3-2-7-9 
 
 
4-9-6-8 
 
 
= 3 
 
1-5-2-8-6 
 
 
6-1-8-4-3 
 
 
= 4 
 
5-3-9-4-1-8 
 
 
7-2-4-8-5-6 
 
 
= 5 
 
8-1-2-9-3-6-5  
 
4-7-3-9-1-2-8  
 
= 6 
 
9-4-3-7-6-2-5-8                      7-2-8-1-9-6-5-3 
= 7 
 
 
 
score ……../7 
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SCOPA-COG
3. 
Indicate cubes
Point to the cubes in the order given below; the patient should copy this; do this slowly; 
the patient decides for himself with which hand he/she prefers. Indicate the cubes in the 
order as indicated. Observe carefully if the patient copies the order correctly. When a
patient wants to correct a mistake, let him/her do the complete order again. This is not 
counted as a mistake. However, if the patient forgets the order and would like to see the 
order a second time, the researcher does not repeat the order again but starts with the 
next order.
         1 
2
  3 
     4 
 
a. 
1-2-4-2
 
b. 
1-2-3-4-3
 
c. 
3-4-2-1-4
 
d. 
1-4-2-3-4-1
 
e. 
1-4-2-3
score ……../5 
Attention
4.
Counting backwards (30 to 0)
Instruction: "Would you subtract three from 30, and subtract three again from the result 
and continue till zero?".
Mistakes can be: the order, missing or not knowing a number, or not finishing off the 
series. Record the order of numbers named by the patient. If the patient asks where to 
start or how much to subtract, the researcher repeats the instructions but counts that as 
one mistake. If the patient makes a mistake but continues from that point to subtract
three, it is only one mistake. If the patient stops the order and starts all over again, it is
one mistake.
 (0 mistakes = 2, 1 mistake = 1, t 2 mistakes = 0)
score ……../2
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SCOPA-COG
5. 
Months backwards 
Instruction: "Name the months of the year in reverse order, starting with the last month 
of the year". 
Mistakes are: the order, missing or not knowing the next month, or not finishing off the 
series. Underline the months that are named correctly. When a month is passed over, 
this is a mistake, even if the patient corrects it later on. If the patient stops the order and 
starts all over again, it is one mistake. If the patient starts naming the month forward, 
repeat the instructions and count it as one mistake. 
Dec- Nov-Oct-Sept-Aug-July-June-May-April-March-Feb-Jan. 
(0 mistakes = 2, 1 mistake = 1, t 2 mistakes = 0) 
 
score ……../ 2 
Executive functions 
6. 
Fist-edge-palm 
1. fist with ulnar side down, 2. stretched fingers with ulnar side down, 3. stretched 
fingers with palm down; Practice 5 times together with the patient, the patient chooses 
which hand he/she prefers. Do it slowly and tell the patient to watch carefully and repeat 
what you are doing. Practice first 5 rounds, with verbal help, e.g. FIST- STRETCH-
PALM. Then tell the patient to make the movements alone.  
Instructions: “Now it is your turn to make the three movements, fist-stretch-palm, 10 
times in a row. You don’t have to count, I will tell you when to stop”.
Note the number of correct trios from a total of 10; Count carefully but not out loud. 
Every time a patient makes a wrong movement, count it as a mistake, even when the 
patient corrects it halfway. 
(10 correct = 3, 9 correct = 2, 8 correct = 1, d 7 correct = 0) 
score ……../3 
7.
Semantic fluency
Tell the patient to name as many animal as he/she knows in one minute. Note all 
answers that are given by the patient. No repetition or variations of words, such as lion-
lioness, tiger-tigress; categories are allowed, bird and pigeon are both correct. Count the 
number of animals correctly named. The purpose is that the patient generates the 
animals actively, therefore no clues are allowed. When the patient asks whether, for 
instance, naming different types of birds is allowed, this may be confirmed. When the 
patient almost immediately says he/she does not know any more animals, try to 
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SCOPA-COG
stimulate the patient by saying “there is still a lot of time left”, but do not give clues. 
When the patient starts naming other things than animals, do not correct the patient. 
Naming other things besides animals is not counted as an additional mistake.   
(t 25 correct = 6, 20-24 = 5, 15-19 = 4, 10-14 = 3, 5-9 = 2, 1-4 = 1 0=0) 
number of animals correct: ……. 
score ……../6 
Write down all animals named: 
8.  
Dice 
Use 2 cards, one with YES = EVEN, NO = ODD; one with YES = HIGHER, NO 
= LOWER. Put the correct card face up next to the explanation of the test and make sure 
that the other, irrelevant card is out of sight. The first round (situation 1) is not scored, 
and the patient is corrected if necessary. 
Situation 1: YES = EVEN 
Put the card “YES=EVEN, NO=ODD” on the table and leave it there during the test. 
Instruction: "Say YES for an even number on a dice and NO for an odd number, when 
you see a picture of a dice with an EVEN number of pips, I would like you to say YES, 
and NO when the number of pips is ODD”.  
Show the first two examples (3 even and 3 odd dices) and ask the patient “If you see one 
of these dice, do you say yes or no?” Tell the patient if the answer is correct or not. If 
the answer is not correct, explain why. It is important that the patient says YES or NO 
and not EVEN or ODD. Show the next two examples (with only one dice) and ask the 
patient “if you see this dice, do you say yes or no?” Tell the patient if the answer is 
correct or not. If the answer is not correct, explain why. 
Then show the patient the following 10 dices. Correct the patient if the answer is wrong. 
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Situation 2: YES = HIGHER 
With the card “example 1” (dice with 3 pips) the next condition starts. Put the card 
“YES=HIGHER, NO=LOWER” on the table and remove the former card. 
Instruction: “Now, we change the test a little. When you see a picture of a dice that is 
higher than de dice on the page before, you say YES. When the dice is lower, you say 
NO”.
Tell the patient you have an example (example 1). “Try to remember this dice” (turn the 
page) “Is this YES or NO?” Tell the patient whether the answer is correct or not. If the 
answer is not correct, explain why. Continue with example 2 and say “now remember 
this dice”(turn the page) “Is this YES or NO?” Tell the patient if the answer is correct or 
not. If the answer is not correct, explain why. 
Then start the test and show all 10 dices one after another. The first response counts and 
corrections are not allowed. Do NOT correct when a wrong answer is given. If a patient 
corrects a wrong answer, it is still counted as a mistake. If the patient asks for the 
instruction, the researcher explains but that is counted as one mistake. 
(10 correct = 3, 9 correct = 2, 8 correct =1, d 7 correct = 0) 
number correct: …./10 
score ……../3 
Visuo-spatial functions 
9. 
Assembling patterns
The patient is shown 5 incomplete patterns and has to choose 2 or 3 shapes out of 4 to 6 
possible alternatives in order to complete the pattern. First practice 2 figures. 
Show the patient example A and give the instruction to choose the shapes that form the 
pattern. Tell the patient if the answer is correct or not. If the answer is not correct, 
explain why and give the correct solution. Repeat this with example B. Then show the 5 
patterns. Do not tell the patient whether the answer is correct or not. There is no time 
limit. If the patient corrects a wrong answer, this is not counted as a mistake. 
a. 
b. 
 
c. 
 
d. 
 
e. 
 
 
      score ……../5
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SCOPA-COG
Memory 
10. Delayed recall 
Instruction: "Can you name as many as possible of the 10 words that you learned during 
the first test? " 
Underline each word that has been named. When words are named that were not shown, 
no penalty is given. When a false answer is changed (e.g. king into queen), it is correct.
10 words: butter  arm  shore  letter  queen  cabin  pole  ticket  grass  engine 
(10 correct = 5, 8-9 correct = 4, 6-7 correct = 3, 5 correct = 2, 4 correct = 1, d 3 correct= 0) 
number of correct words: …. /10 
score ……../5 
 Total COG score: … /43 
© This questionnaire is made available free of charge, with the permission of the authors, to all those undertaking non-
profit and profit making research. Future users may be requested to share data for psychometric purposes. Use of this 
questionnaire in studies should be communicated to the developers. No changes may be made to the questionnaire 
without written permission. Please use the following reference in publications: Marinus J, Visser M, Verwey NA, 
Verhey FRJ, Middelkoop HAM, Stiggelbout AM,  van Hilten JJ. Assessment of cognition in Parkinson’s disease. 
Neurology 2003;61:1222-1228. For further information, please contact Dr. J. Marinus, Leiden University Medical 
Center, Department of Neurology (K5Q), P.O. Box 9600, NL-2300 RC Leiden (email: j.marinus@lumc.nl). 
Confidential
Page 151 of 152


Signature Date: 20180129
JP: JZP166-201 Protocol Amendment 2.pdf
Signature Date:
JP: JZP166-201 Protocol Amendment 2.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: JZP166-201 Amendment 2 
 
 
 
 
 
 
CONFIDENTIAL 
Page 115 of 115 
 
Signatures of Agreement for Protocol 
Study Title: 
A 4-Week, Double-blind, Placebo-controlled, Randomized, 
Multicenter, Crossover Study of the Safety, Efficacy, and 
Pharmacokinetics of JZP-110 [(R)-2-amino-3-
phenylpropylcarbamate hydrochloride] in Subjects with Parkinson’s 
Disease and Excessive Sleepiness 
Study Number: 
JZP166-201 Amendment 2 
Final Date: 
26 January 2018  
 
This clinical study protocol was subject to critical review and has been approved by Jazz 
Pharmaceuticals.  
 
Confidential
Page 152 of 152


Signature Date: 20180129
JP: JZP166-201 Protocol Amendment 2.pdf
 
 
 
Signature Manifestation 
 
 

SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN 
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PROTOCOL 166-201 
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A 4-WEEK, DOUBLE-BLIND, PLACEBO-CONTROLLED, RANDOMIZED, MULTICENTER, 
CROSSOVER STUDY OF THE SAFETY, EFFICACY, AND PHARMACOKINETICS OF JZP-
110 [(R)-2-AMINO-3-PHENYLPROPYLCARBAMATE HYDROCHLORIDE] IN SUBJECTS 
WITH PARKINSON’S DISEASE AND EXCESSIVE SLEEPINESS 
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VERSION NUMBER AND DATE:  FINAL V1.0 , 10OCT2018 
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LIST OF ABBREVIATIONS 
10 
1. 
INTRODUCTION 
13 
2. 
STUDY OBJECTIVES 
13 
2.1. 
Primary Objective ........................................................................................................................ 13 
2.2. 
Secondary Objectives ................................................................................................................... 13 
2.3. 
Exploratory Objectives ................................................................................................................. 13 
3. 
STUDY DESIGN 
13 
3.1. 
General Description ..................................................................................................................... 13 
3.2. 
Blinding ........................................................................................................................................ 15 
3.3. 
Treatment Assignment and Randomization ................................................................................. 15 
3.4. 
Sample Size Justification .............................................................................................................. 16 
3.5. 
Schedule of Events ....................................................................................................................... 16 
3.6. 
Changes to Analysis from Protocol ............................................................................................... 21 
4. 
PLANNED ANALYSES 
21 
4.1. 
Data Monitoring Committee ........................................................................................................ 21 
4.2. 
Interim Analysis ........................................................................................................................... 21 


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4.3. 
Final Analysis ............................................................................................................................... 22 
5. 
ANALYSIS POPULATIONS 
22 
5.1. 
All Randomized Subjects Population ............................................................................................ 22 
5.2. 
Modified Intent-to-Treat Population ........................................................................................... 22 
5.3. 
Efficacy Population ...................................................................................................................... 22 
5.4. 
Per Protocol Population ............................................................................................................... 22 
5.5. 
Safety Population ........................................................................................................................ 23 
5.6. 
Pharmacokinetic Population ........................................................................................................ 23 
6. 
GENERAL CONSIDERATIONS 
23 
6.1. 
Study Day and Period Day ............................................................................................................ 23 
6.2. 
Baseline ....................................................................................................................................... 24 
6.3. 
Windowing Conventions .............................................................................................................. 24 
6.4. 
Common Calculations .................................................................................................................. 26 
6.5. 
Software Versions ........................................................................................................................ 26 
6.5.1. 
All Analyses Exception of PK Analysis ................................................................................................. 26 
6.5.2. 
PK Analysis .......................................................................................................................................... 26 
7. 
STATISTICAL CONSIDERATIONS 
26 
7.1. 
Multicenter Studies ..................................................................................................................... 26 
7.2. 
Missing data ................................................................................................................................ 27 
7.3. 
Adjustments for Covariate and Factor to be Included in Analyses ............................................... 27 
7.4. 
Multiple Comparisons/ Multiplicity and Significance Levels ........................................................ 27 
7.5. 
Examination of Subgroups ........................................................................................................... 27 
8. 
OUTPUT PRESENTATIONS 
28 


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9. 
DISPOSITION AND WITHDRAWALS 
28 
10. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
29 
10.1. 
Derivations .................................................................................................................................. 29 
11. 
PARKINSON’S DISEASE AND SLEEP DISORDERS HISTORY 
30 
11.1. 
Derivations .................................................................................................................................. 30 
12. 
SURGICAL AND MEDICAL HISTORY 
32 
13. 
PRIOR AND CONCOMITANT MEDICATIONS 
33 
14. 
STUDY DRUG EXPOSURE 
34 
14.1. 
Derivations .................................................................................................................................. 34 
15. 
STUDY DRUG COMPLIANCE 
34 
15.1. 
Derivations .................................................................................................................................. 35 
16. 
EFFICACY OUTCOMES 
35 
16.1. 
Key Efficacy Endpoint ................................................................................................................... 36 
16.1.1. 
Key Efficacy Endpoint & Derivation .................................................................................................... 36 
16.1.2. 
Hypothesis Testing .............................................................................................................................. 36 
16.1.3. 
Missing Data Methods for Key Efficacy Endpoint 7 ............................................................................ 36 
16.1.4. 
Primary Analysis of Key Efficacy Endpoint .......................................................................................... 36 
16.1.5. 
Sensitivity Analysis of Key Efficacy Endpoint ...................................................................................... 37 
16.1.6. 
Subgroup Analyses of Key Efficacy Endpoint ...................................................................................... 39 
16.2. 
Exploratory Efficacy Endpoints ..................................................................................................... 39 
16.2.1. 
Exploratory Efficacy Endpoints & Derivations .................................................................................... 39 
16.2.1.1. Mean sleep latency time (in minutes), as determined by the MWT 
39 
16.2.1.2. MDS-UPDRS Parts III and IV scores 
40 
16.2.1.3. CGIc 
41 
16.2.1.4. PGIc 
41 
16.2.1.5. FSS 
41 
16.2.1.6. Apathy Scale 
41 
16.2.1.7. SCOPA-cog 
42 


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16.2.2. 
Missing Data Methods for Exploratory Efficacy Endpoints ................................................................ 42 
16.2.3. 
Analysis of Exploratory Efficacy Endpoints ......................................................................................... 42 
16.2.3.1. Mean sleep latency time (in minutes), as determined by the MWT 
42 
16.2.3.2. CGIc and PGIc 
43 
16.2.3.3. MDS-UPDRS, FSS, Apathy Scale, and SCOPA-cog 
43 
16.2.4. 
Sensitivity to Exploratory Efficacy Endpoints ..................................................................................... 43 
16.2.5. 
Subgroup Analyses of Exploratory Efficacy Endpoint ......................................................................... 43 
16.3. 
Other Efficacy Analyses ................................................................................................................ 44 
17. 
SAFETY OUTCOMES 
44 
17.1. 
Adverse Events ............................................................................................................................ 45 
17.1.1. 
All TEAEs ............................................................................................................................................. 45 
17.1.1.1. Severity 
45 
17.1.1.2. Relationship to Study drug 
45 
17.1.2. 
Adverse Events with an Outcome of Death ........................................................................................ 46 
17.1.3. 
Serious Adverse Events ....................................................................................................................... 46 
17.1.4. 
TEAEs Leading to Discontinuation of Study drug and/or to Withdrawal from Study ......................... 46 
17.2. 
Laboratory Evaluations ................................................................................................................ 46 
17.2.1. 
Laboratory Standard Reference Ranges and Markedly Abnormal Criteria ........................................ 47 
17.3. 
ECG Evaluations ........................................................................................................................... 47 
17.3.1. 
ECG Specific Derivations ..................................................................................................................... 48 
17.3.2. 
ECG Markedly Abnormal Criteria ........................................................................................................ 48 
17.4. 
Vital Signs .................................................................................................................................... 49 
17.4.1. 
Body Temperature, Respiratory Rate, and Weight ............................................................................ 49 
17.4.2. 
Seated Blood Pressure and Pulse Rate ............................................................................................... 49 
17.4.3. 
Orthostatic Hypotension .................................................................................................................... 50 
17.4.4. 
Vital Signs Reference Ranges and Markedly Abnormal Criteria ......................................................... 50 
17.5. 
Columbia-Suicide Severity Rating Scale ........................................................................................ 51 
18. 
PHARMACOKINETIC DATA 
52 
18.1. 
General Considerations ................................................................................................................ 52 
18.2. 
Concentration Data ...................................................................................................................... 53 
18.3. 
Pharmacokinetic Parameters ....................................................................................................... 53 
18.4. 
Pharmacokinetic/Pharmacodynamic Modeling ........................................................................... 54 


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DATA NOT SUMMARIZED OR PRESENTED 
55 
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Algorithm for Treatment Emergence of Adverse Events ...................................................................................... 57 
Algorithm for Prior, Concomitant, And Post Medications .................................................................................... 58 
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61 
 Output Conventions .................................................................................................................................. 61 
Dates & Times ...................................................................................................................................................... 61 
Spelling Format .................................................................................................................................................... 61 
Presentation of Treatment Groups ...................................................................................................................... 61 
Number of Decimal Places To Be Presented......................................................................................................... 62 
Listings ................................................................................................................................................................. 62 
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1.INTRODUCTION 
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2.STUDY OBJECTIVES 
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PRIMARY OBJECTIVE 
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SECONDARY OBJECTIVES 
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 EXPLORATORY OBJECTIVES 
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3.STUDY DESIGN 
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GENERAL DESCRIPTION 
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BLINDING 
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TREATMENT ASSIGNMENT AND RANDOMIZATION 
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SAMPLE SIZE JUSTIFICATION 
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STUDY DAY AND PERIOD DAY 
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BASELINE 
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WINDOWING CONVENTIONS 
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COMMON CALCULATIONS 
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SOFTWARE VERSIONS 
6.5.1.
ALL ANALYSES EXCEPTION OF PK ANALYSIS 
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PK ANALYSIS 
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7.1.
MULTICENTER STUDIES 
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MISSING DATA 
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ADJUSTMENTS FOR COVARIATE AND FACTOR TO BE INCLUDED IN 
ANALYSES 
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MULTIPLE COMPARISONS/ MULTIPLICITY AND SIGNIFICANCE LEVELS 
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EXAMINATION OF SUBGROUPS 
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14. STUDY DRUG EXPOSURE 
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DERIVATIONS 
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15. STUDY DRUG COMPLIANCE  
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FKDQJH¶µPLQLPDOO\ZRUVH¶µPXFKZRUVH¶DQGµYHU\PXFKZRUVH¶FDWHJRULHV
16.2.1.4. PGIC 
7KH3DWLHQW*OREDO,PSUHVVLRQRI&KDQJH3*,FLVDSRLQW/LNHUWW\SHUDWLQJVFDOH6XEMHFWVZLOOUDWHWKH
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16.2.1.5. FSS 
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WRWDOVFRUHUHSUHVHQWVWKHPHDQVFRUHRIHDFKRIWKHLWHPV\LHOGLQJDVFRUHUDQJHEHWZHHQDQG
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VFRUHZLOOEHVHWWRPLVVLQJ6XEMHFWVZLOOFRPSOHWHWKH)66DW%DVHOLQHDQGDW9LVLWVDQG
7KHREVHUYHGDQGFKDQJHIURP%DVHOLQHLQ)66WRWDOVFRUHWRWKHHQGRISHULRGZLOOEHVXPPDUL]HG
16.2.1.6. APATHY SCALE 
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16.2.1.7. SCOPA-COG 
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16.2.2. MISSING DATA METHODS FOR EXPLORATORY EFFICACY ENDPOINTS 
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16.2.3. ANALYSIS OF EXPLORATORY EFFICACY ENDPOINTS 
16.2.3.1. MEAN SLEEP LATENCY TIME (IN MINUTES), AS DETERMINED BY THE MWT  
(DFKW\SHRIPHDQVOHHSODWHQF\WLPHPHDVXUHPHQWDVGHWHUPLQHGE\WKH0:7ZLOOEHVXPPDUL]HGDQG
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16.2.3.2. CGIC AND PGIC  
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16.2.3.3. MDS-UPDRS, FSS, APATHY SCALE, AND SCOPA-COG 
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16.2.4. SENSITIVITY TO EXPLORATORY EFFICACY ENDPOINTS 
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16.2.5. SUBGROUP ANALYSES OF EXPLORATORY EFFICACY ENDPOINT 
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16.3.
OTHER EFFICACY ANALYSES 
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17. SAFETY OUTCOMES 
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17.1.
ADVERSE EVENTS 
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Prior AEs are defined as AEs that started on or after the signature of the informed consent but prior to the 
first dose of study drug (i.e., first dose in Period 1) and have not worsened in severity on or after the first 
dose of study drug; 
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Treatment-emergent adverse events (TEAEs) are defined as any AEs that started or worsened in severity 
on or after the first dose of study drug; 
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17.1.1. ALL TEAES  
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17.1.1.1. SEVERITY 
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17.1.1.2. RELATIONSHIP TO STUDY DRUG 
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VXVSHFWHGWREHUHODWHGWRVWXG\GUXJ,IDVXEMHFWUHSRUWVWKHVDPH$(PRUHWKDQRQFHZLWKLQD62&RU


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17.1.2. ADVERSE EVENTS WITH AN OUTCOME OF DEATH 
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17.1.3. SERIOUS ADVERSE EVENTS 
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17.1.4. TEAES LEADING TO DISCONTINUATION OF STUDY DRUG AND/OR TO WITHDRAWAL 
FROM STUDY 
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17.2.
LABORATORY EVALUATIONS 
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x
Observed and change from Baseline by visit for quantitative (continuous) measurements 
x
Observed by visit for qualitative (categorical) measurements 
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SURYLGHG
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17.2.1. LABORATORY STANDARD REFERENCE RANGES AND MARKEDLY ABNORMAL CRITERIA 
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6,XQLWVDQGFDWHJRUL]HGDV
x
Low: result < LLN 
x
Normal: result within the laboratory normal reference range (upper and lower limit included) 
x
High: result > ULN 
17.3.
ECG EVALUATIONS 
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x
HR (beats per minute [bpm]) 
x
RR interval (msec) 
x
PR interval (msec) 
x
QRS interval (msec) 
x
QT interval (msec) 
x
QT Fridericia’s correction (QTcF) interval (msec) [derived] 
x
QT Bazett’s correction (QTcB) interval (msec) [derived] 
x
Overall evaluation of ECG: 
o
Normal 
o
Abnormal, not clinically significant 
o
Abnormal, clinically significant 
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x
Observed values and change from Baseline to end of period post-dose timepoint (for quantitative 
measurements) 
x
Observed values and change from end of period pre-dose timepoint to end of period post-dose timepoint 
(for quantitative measurements) 
x
Incidence of markedly abnormal criteria from Baseline to end of period post-dose timepoint (refer to 
Section 17.3.2 for details) by gender 
x
Incidence of markedly abnormal criteria from end of period pre-dose timepoint to end of period post-
dose timepoint (refer to Section 17.3.2 for details) by gender 
x
Shift from Baseline to end of period post-dose timepoint in ECG overall evaluation by gender 
x
Shift from end of period pre-dose timepoint to end of period post-dose timepoint in ECG overall 
evaluation by gender  


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x
Incidence of subjects for which their ECG overall evaluation improved, remained unchanged or worsened 
from Baseline to end of period post-dose timepoint by gender  
x
Incidence of subjects for which their ECG overall evaluation improved, remained unchanged or worsened 
from the end of period pre-dose timepoint to the end of period post-dose timepoint by gender 
x
Incidence of subjects with at least one ECG diagnosis by diagnosis category (i.e., rate/rhythm, conduction 
abnormalities, changes in ST segment, axis, chamber enlargement, myocardial infarction, and 
miscellaneous) and diagnosis by visit, timepoint, and gender 
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x
Listing of subjects with any observed QT, QTcB, or QTcF values >450 msec and/or change from Baseline in 
QT, QTcB, or QTcF >30 msec 
x
Listing of subjects with any abnormal ECG overall evaluation 
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x
Line plot of mean observed values across visit by sequence and treatment group; 
17.3.1. ECG SPECIFIC DERIVATIONS 
x
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17.3.2. ECG MARKEDLY ABNORMAL CRITERIA 
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x
Observed values for QT interval, QTcB and QTcF will be classified as: 
o
>450 msec with no pre-existing condition i.e., Baseline ≤450 msec 
o
>480 msec with no pre-existing condition i.e., Baseline ≤450 msec 
o
>500 msec with no pre-existing condition i.e., Baseline ≤450 msec 
x
Change from Baseline for QT interval and QTcF will be classified as: 
o
>30 msec increase from Baseline 
o
>60 msec increase from Baseline 


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17.4.
VITAL SIGNS 
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x
Seated and standing systolic blood pressure (SBP) (mmHg) 
x
Seated and standing diastolic blood pressure (DBP) (mmHg) 
x
Seated and standing pulse rate (bpm) 
x
Respiratory rate (breaths/min) 
x
Body temperature 
x
Weight 
17.4.1. BODY TEMPERATURE, RESPIRATORY RATE, AND WEIGHT  
7KHIROORZLQJVXPPDULHVZLOOEHSURYLGHG
x
Observed values and change from Baseline to end of period 
x
Shift from Baseline to end of period when observations are categorized into Low/Normal/High (refer to 
Table 6) 
17.4.2. SEATED BLOOD PRESSURE AND PULSE RATE 
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GXULQJWKHHQGRISHULRGYLVLWSRVWGRVHWLPHSRLQWVZLOOEHFRPSXWHGDQGWKHIROORZLQJVXPPDULHVZLOOEH
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Average observed values and average change from Baseline to the end of period visit; 
x
Shift from Baseline to end of period visit when average observed values are categorized into 
Low/Normal/High (refer to Table 6); 
x
Incidence of subjects with average change from Baseline to end of period visit meeting the following 
criteria: 
o
Decrease/increase in SBP ≥10, ≥20, and ≥30 mmHg 
o
Decrease/increase in DBP ≥10, ≥20, and ≥30 mmHg 
o
Decrease/increase in pulse rate (HR) ≥15 and ≥30 beats per minute 
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x
Average observed values and average changes from the end of period visit pre-dose timepoint to each 
end of the period visit post-dose timepoint; 


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x
Average observed values and average changes from each baseline visit timepoint to time-matched end of 
period visit timepoint, where the 0-hour baseline timepoint is matched with the pre-dose end of period 
visit timepoint, the 2-hour baseline timepoint with the 1-hour post-dose end of period timepoint, the 3-
hour baseline timepoint with the 2-hour post-dose end of period visit timepoint, and the 5-hour baseline 
timepoint with the 4-hour post-dose end of period timepoint; 
x
Shift from end of period visit pre-dose timepoint to each end of period post-dose timepoint when average 
observed values are categorized into Low/Normal/High (refer to Table 6); 
x
Shift from each baseline visit timepoint to time-matched end of period visit timepoint when average 
observed values are categorized into Low/Normal/High; 
x
Incidence of subjects with average change from end of period pre-dose timepoint to each end of period 
visit post-dose timepoint meeting the criteria described above; 
x
Incidence of subjects with average change from each Baseline timepoint to time-matched end of period 
visit timepoints meeting the criteria described above 
7KHIROORZLQJOLVWLQJVZLOOEHSURYLGHG
x
Listing of subjects with any abnormal average observed values for averages computed over the Baseline 
visit and end of period visit post-dose timepoints (low/ high); 
x
Listing of subjects with any abnormal average observed values for averages computed over each visit 
timepoint (low/ high); 
7KHIROORZLQJILJXUHVZLOOEHSURYLGHG
x
Lines plots of mean average time-matched observed values across visit by treatment group; 
17.4.3. ORTHOSTATIC HYPOTENSION 
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x
Summary of observed values and change from seated to standing (1 minute and 3 minutes, separately) 
position in observed values by timepoint and visit as well as changes from Baseline to time-matched end 
of period visit in change from seated to standing position 
x
Listing of subjects who meet the criteria for orthostatic hypotension (having a decrease in SBP ≥20 mmHg 
or decrease in DBP ≥10 mmHg) at any timepoint 
x
For the subset of subjects who meet the criteria for orthostatic hypotension: average observed values and 
average changes from each baseline visit timepoint to time-matched end of period visit timepoint 
17.4.4. VITAL SIGNS REFERENCE RANGES AND MARKEDLY ABNORMAL CRITERIA 
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x
Low: result < LLN 
x
Normal: result within the laboratory normal reference range (upper and lower limit included) 
x
High: result > ULN 
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17.5.COLUMBIA-SUICIDE SEVERITY RATING SCALE 
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GENERAL CONSIDERATIONS 
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