A Twelve-Week, Double-Blind, Placebo-Controlled, Randomized, Parallel-Group, Multicenter Study of the Safety and Efficacy of JZP-110 [(R)-2-amino-3-phenylpropylcarbamate Hydrochloride] in the Treatment of Excessive Sleepiness in Subjects With Obstructive Sleep Apnea (OSA)
Phase: PHASE3
Conditions: Obstructive Sleep Apnea
Sponsor: Jazz Pharmaceuticals

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Clinical Trial Protocol: 14-003 Amendment 3 
 
  
 
 
 
 
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Clinical Trial Protocol: 14-003 
Study Title: 
A Twelve-Week, Double-Blind, Placebo-Controlled, Randomized, 
Parallel-Group, Multicenter Study of the Safety and Efficacy of 
JZP-110 [(R)-2-amino-3-phenylpropylcarbamate hydrochloride] in the 
Treatment of Excessive Sleepiness in Subjects with Obstructive Sleep 
Apnea (OSA) 
Study Phase: 
3 
Product Name: 
JZP-110 [(R)-2-amino-3-phenylpropylcarbamate hydrochloride] 
IND Number: 
122,590 
EUDRACT 
Number: 
2014-005514-31 
Indication: 
Treatment of excessive sleepiness in adult patients with obstructive 
sleep apnea; to increase the ability to stay awake throughout the day. 
Investigators: 
Multicenter 
Sponsor: 
Jazz Pharmaceuticals 
3180 Porter Drive 
Palo Alto, CA 94304 
(650) 496-3777 
Sponsor’s 
Medical Director: 
Contract 
Research 
Organization: 
Original Protocol: 
17 December 2014 
Amendment 1: 
18 February 2015 
Amendment 2: 
10 September 2015 
Amendment 3: 
08 February 2016 
 
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document constitutes an agreement by the recipient(s) that no unpublished information 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. 
CONFIDENTIAL
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Clinical Trial Protocol: 14-003 Amendment 3 
 
  
 
 
 
 
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SYNOPSIS 
SPONSOR 
Jazz Pharmaceuticals 
PRODUCT 
JZP-110 [(R)-2-amino-3-phenylpropylcarbamate 
hydrochloride] 
TITLE 
A Twelve-Week, Double-Blind, Placebo-Controlled, 
Randomized, Parallel-Group, Multicenter Study of the Safety 
and Efficacy of JZP-110 [(R)-2-amino-3-
phenylpropylcarbamate hydrochloride] in the Treatment of 
Excessive Sleepiness in Subjects with Obstructive Sleep 
Apnea (OSA) 
STUDY NUMBER 
14-003 
STUDY PHASE 
Phase 3 
LOCATION 
This trial will be conducted at approximately 60 sites in 
North America and Europe. 
PRIMARY 
OBJECTIVE 
To evaluate the efficacy of JZP-110 administered once daily 
for up to 12 weeks in doses of 37.5, 75, 150, and 300 mg 
compared to placebo in the treatment of excessive sleepiness 
in adult subjects with OSA. 
SECONDARY 
OBJECTIVES 
To evaluate the safety and tolerability of JZP-110 
administered once daily for up to 12 weeks in doses of 
37.5, 75, 150, and 300 mg compared to placebo in the 
treatment of excessive sleepiness in adult subjects with OSA. 
To characterize the pharmacokinetics (PK) of JZP-110 in 
subjects with OSA using sparse sampling methods. 
DESIGN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This trial is a 12 week, randomized, double-blind, placebo-
controlled, multicenter, 5-arm parallel group study of safety 
and efficacy of JZP-110 in the treatment of excessive 
sleepiness in adult subjects with OSA. Following the 
successful completion of Screening and Baseline visits, 
stratified randomization on the basis of subjects’ compliant 
or non-compliant use of their primary OSA therapy will be 
used to assign subjects in a 1:1:2:2:2 ratio to JZP-110 37.5, 
75, 150, or 300 mg, or placebo. Treatment will be 
administered once daily over a Treatment Phase of 12 weeks. 
Subjects randomized to the 150 mg dose will initially receive 
75 mg from Day 1 through Day 3 of the first week of the 
Treatment Phase and will receive 150 mg starting on Day 4. 
Subjects randomized to the 300 mg dose will initially receive 
150 mg from Day 1 through Day 3 of the first week of the 
Treatment Phase and will receive 300 mg starting on Day 4. 
Subjects randomized to the other treatment groups will not 
require titration. 
During the Treatment Phase, subjects will return to the 
investigative site to complete efficacy and safety assessments 
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at the end of Weeks 1, 4, 8, and 12; the 4 and 12 Week Visits 
will also include an overnight stay at the investigational site 
for nocturnal polysomnography (PSG) followed by a 
Maintenance of Wakefulness Test (MWT), and the Week 8 
Visit will include 24-hour ambulatory blood pressure 
monitoring. Subjects will take their final dose of study drug 
at the Week 12 visit prior to the Week 12 visit assessments. 
Subjects will return at the end of Week 14 for follow-up 
assessments. Unless there are any outstanding safety issues 
that require follow-up, subjects will be discharged from the 
study at the Week 14 visit. 
Efficacy will be assessed by changes in the mean sleep 
latency on the first 4 trials of a 5-trial, 40-minute MWT and 
by changes in the mean Epworth Sleepiness Scale (ESS) 
score as co-primary endpoints, percentage of patients 
improved on the Patient Global Impression of Change (PGIc) 
as a key secondary endpoint, and Clinical Global Impression 
of Change (CGIc), Functional Outcomes of Sleep 
Questionnaire Short Version (FOSQ-10), 36-Item Short 
Form Health Survey (SF-36v2), EuroQoL EQ-5D-5L, and 
the Work Productivity and Activity Impairment 
Questionnaire: Specific Health Problem V2.0 (WPAI:SHP) 
as other endpoints. 
Four blood samples will be collected from each subject for 
PK evaluations; one sample during the Week 1 visit, one 
sample during the Week 4 visit, and two samples during the 
Week 8 visit. The samples collected at the Week 1 and Week 
8 visits will be within 1-8 hours of dosing. The samples 
collected at the Week 4 visit will be within 8-12 hours of 
dosing. 
Safety will be assessed by the incidence of observed and 
reported adverse events (AEs), and changes in physical 
examination findings, electrocardiograms (ECGs), clinical 
laboratory tests, vital signs, 24-hour ambulatory blood 
pressure monitoring, and the Columbia-Suicide Severity 
Rating Scale (C-SSRS). Safety will be assessed throughout 
the study. 
ESTIMATED 
DURATION OF 
STUDY 
The estimated duration of the study is up to 31 days for the 
Screening and Baseline visits, 12 weeks for the Treatment 
Phase, and 2 weeks for a Safety Follow-up (the 2 week 
Safety Follow-up visit is not required for subjects who enter 
the Open-label Safety Study [14-005] at the Final Clinic 
Visit). 
It is estimated that enrollment across all sites will be 
completed in 12 months. 
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STUDY POPULATION Subjects must have a documented diagnosis of OSA 
according to the International Classification of Sleep 
Disorders, Third Edition (ICSD-3) and have sleepiness and 
an inability to stay awake as demonstrated by objective and 
subjective criteria. In addition, subjects must currently use or 
have a history of an attempt to use an accepted therapy for 
the primary treatment of OSA. Approximately 440 subjects 
are planned for enrollment. Approximately 110 subjects will 
be randomized to each of the JZP-110 150 mg, 300 mg, and 
placebo groups. These sample sizes will provide at least 90% 
power to detect a difference of 5 minutes in the mean sleep 
latency time as determined from the MWT (mean of the first 
four trials) and a difference of 3.5 points on the ESS changes 
from Baseline to Week 12 between each of these JZP-110 
treatment dose groups and placebo. This calculation assumes 
common standard deviations of 10 minutes for the MWT and 
6 points for the ESS changes from Baseline and a two-sided 
significance level of 0.05 using a t-test. Approximately 
55 subjects will be randomized to each of the JZP-110 
37.5 mg and 75 mg groups.  
DIAGNOSIS AND 
MAIN CRITERIA FOR 
INCLUSION 
Inclusion Criteria 
Each subject must meet the following criteria to be enrolled 
in the study. 
1. Male or female between 18 and 75 years of age, 
inclusive. 
2. Diagnosis of OSA according to ICSD-3 criteria 
3. Subject report (with clinician concurrence) of at least 
minimal use of a primary therapy for OSA or an 
attempt to use a primary therapy for OSA as follows: 
a. Use of a primary therapy for OSA (i.e., 
positive airway pressure, oral pressure 
therapy, oral appliance, or upper airway 
stimulator) on at least 1 night/week, or 
b. History of at least 1 month of an attempt to 
use one or more primary OSA therapies with 
at least one documented adjustment that was 
made in an attempt to optimize the primary 
OSA therapy, or 
c. History of a surgical intervention intended to 
treat OSA symptoms. 
4. Subject report (with clinician concurrence) of a stable 
level of compliance with a primary OSA therapy for 
at least 1 month prior to Baseline as follows: 
a. A stable level of use of a primary OSA 
therapy, or 
b. A lack of use of a primary OSA therapy 
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following a history of attempted use, or 
c. A history of a surgical intervention intended 
to treat OSA symptoms. 
5. Baseline Epworth Sleepiness Scale (ESS) score ≥10. 
6. Baseline mean sleep latency <30 minutes as 
documented by the mean of the first four trials of the 
MWT. 
7. Usual nightly total sleep time of at least 6 hours. 
8. Body mass index from 18 to <45 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. 
10. Willing and able to comply with the study design 
schedule and other requirements. 
11. Willing and able to provide written informed consent. 
Exclusion Criteria 
Subjects who demonstrate any of the following will be 
excluded from the study. 
1. Unwilling to attempt to use one or more primary OSA 
therapies. 
2. Female subjects who are pregnant, nursing, or 
lactating. 
3. Usual bedtime later than 1 AM (0100 hours). 
4. Occupation requiring nighttime shift work or variable 
shift work.  
5. Any other clinically relevant medical, behavioral, or 
psychiatric disorder other than OSA that is associated 
with excessive sleepiness. 
6. History or presence of bipolar disorder, bipolar 
related disorders, schizophrenia, schizophrenia 
spectrum disorders, or other psychotic disorders 
according to DSM-5 criteria. 
7. History or presence of any acutely unstable medical 
condition, behavioral or psychiatric disorder 
(including active suicidal ideation), or surgical 
history that could affect the safety of the subject or 
interfere with study efficacy, safety, PK assessments, 
or the ability of the subject to complete the trial per 
the judgment of the Investigator. 
8. History of bariatric surgery within the past year or a 
history of any gastric bypass procedure. 
9. Presence of renal impairment or calculated creatinine 
clearance <60 mL/min. 
10. Clinically significant ECG abnormality in the opinion 
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of the Investigator.  
11. This criterion has been removed.  
12. Presence of significant cardiovascular disease 
including but not limited to: myocardial infarction 
within the past year, unstable angina pectoris, 
symptomatic congestive heart failure (ACC/AHA 
stage C or D), revascularization procedures within the 
past year, ventricular cardiac arrhythmias requiring 
an automatic implantable cardioverter defibrillator 
(AICD) or medication therapy, uncontrolled 
hypertension, 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. 
13. Laboratory value(s) outside the laboratory reference 
range that are considered to be clinically significant 
by the Investigator (clinical chemistry, hematology, 
and urinalysis); NOTE: Screening labs may be 
repeated once. 
14. Excessive caffeine use one week prior to Baseline 
assessments or anticipated excessive use during the 
study defined as >600 mg/day of caffeine. 
15. Use of any over-the-counter (OTC) or prescription 
medications that could affect the evaluation of 
excessive sleepiness within a time period prior to the 
Baseline Visit corresponding to at least five half-lives 
of the drug(s) or planned use of such drug(s) at some 
point throughout the duration of the study. Examples 
of excluded medications include OTC sleep aids or 
stimulants (e.g., pseudoephedrine), methylphenidate, 
amphetamines, modafinil, armodafinil, sodium 
oxybate, pemoline, trazodone, hypnotics, 
benzodiazepines, barbiturates, and opioids. 
Medications should be discontinued such that the 
subject has returned to his/her baseline level of 
daytime sleepiness at least 7 days prior to the 
Baseline visit, in the opinion of the Investigator. 
16. Use of a monoamine oxidase inhibitor (MAOI) in the 
past 14 days or five half-lives (whichever is longer) 
prior to the Baseline Visit, or plans to use an MAOI 
during the study. 
17. Received an investigational drug in the past 30 days 
or five half-lives (whichever is longer) prior to the 
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Clinical Trial Protocol: 14-003 Amendment 3 
 
  
 
 
 
 
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Baseline Visit, or plans to use an investigational drug 
(other than the study drug) during the study. 
18. Previous exposure to or participation in a clinical trial 
of JZP-110 (ADX-N05, R228060, or YKP10A). 
19. Current or past (within the past 2 years) diagnosis of 
a moderate or severe substance use disorder 
according to DSM-5 criteria. 
20. Nicotine dependence that has an effect on sleep (e.g., 
a subject who routinely awakens at night to smoke). 
21. Current, past (within the past 2 years), or seeking 
treatment for a substance related disorder. 
22. Urine drug screen positive for an illicit drug of abuse 
(including cannabinoids) at screening or at any point 
throughout the duration of the study, except for a 
prescribed drug (e.g., amphetamine) at screening. 
23. History of phenylketonuria (PKU) or history of 
hypersensitivity to phenylalanine-derived products. 
TEST PRODUCT, 
DOSE, AND MODE OF 
ADMINISTRATION 
JZP-110 [(R)-2-amino-3-phenylpropylcarbamate 
hydrochloride] will be supplied as 37.5, 75 mg, 150 mg, and 
300 mg tablets that will be overencapsulated in identical 
opaque gelatin capsules. The doses of JZP-110 will be based 
on the free base of the molecule. Subjects will be instructed 
to take a single oral daily dose of study drug in the morning, 
on an empty stomach within one hour of awakening. Subjects 
will also be instructed to abstain from eating or drinking 
(except for water) for 30 minutes after taking the study drug. 
REFERENCE 
THERAPY, DOSE, 
AND MODE OF 
ADMINISTRATION 
Placebo tablets will also be overencapsulated in opaque 
gelatin capsules that will be identical to those used for the 
active JZP-110 treatments. Mode of administration will be 
the same as for the test product above. 
DURATION OF 
TREATMENT 
The treatment duration of the study for each subject will be 
approximately 12 weeks. 
EFFICACY 
ASSESSMENTS 
 
Co-primary Efficacy Endpoints: 
• MWT: Change in the mean sleep latency time (in 
minutes) as determined from the first four trials of a 
40-minute MWT from Baseline to Week 12 
• ESS: Change in ESS score from Baseline to Week 12 
Key Secondary Efficacy Endpoint: 
• PGIc: Percentage of subjects reported as improved 
(minimally, much, or very much) on the PGIc at 
Week 12 
PHARMACOKINETIC 
ASSESSMENTS 
Concentration data for JZP-110 will be tabulated by sampling 
time point, and will be included in a population PK analysis. 
The population PK model will be used to characterize 
JZP-110 PK profile in OSA patients, and to explore 
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exposure-efficacy correlations. 
SAFETY 
ASSESSMENTS 
Safety and tolerability evaluations will consist of treatment-
emergent adverse events (TEAEs) and changes in clinical 
laboratory tests (chemistry, hematology, and urinalysis), vital 
signs, 24-hour ambulatory blood pressure monitoring, 
12-lead ECGs, physical exams, and C-SSRS assessments. 
STATISTICAL 
ANALYSIS 
For the analysis of the co-primary efficacy endpoints, a 
mixed-effect repeated measures (MMRM) model will be 
used as the primary method of analysis. This model will 
include fixed effects for treatment (i.e., dose group), time (as 
a discrete factor), treatment-by-time interaction, baseline 
value of the efficacy endpoint, and randomization 
stratification factor. SAS procedure PROC MIXED will be 
used to carry out this analysis. All available data will be 
included in the model. An unstructured covariance matrix 
will be used to model the correlation among repeated 
measurements. The estimates of treatment difference versus 
placebo and their 95% confidence intervals will be presented. 
In addition to the MMRM model, an analysis of covariance 
(ANCOVA) model will be used to analyze MWT and ESS to 
provide sensitivity analyses. This ANCOVA model will 
include the effect for treatment (i.e., dose group) as a fixed 
effect, and baseline value of the efficacy endpoint as the 
covariate.  
The chi-squared test will be used to test the hypotheses 
associated with the analysis of PGIc. 
DATE OF ORIGINAL 
PROTOCOL 
17 December 2014 
AMENDMENT 1 
18 February 2015 
AMENDMENT 2 
10 September 2015 
AMENDMENT 3 
08 February 2016 
 
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Clinical Trial Protocol: 14-003 Amendment 3 
 
  
 
 
 
 
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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................2 
TABLE OF CONTENTS ...........................................................................................................9 
LIST OF IN-TEXT TABLES ..................................................................................................13 
LIST OF IN-TEXT FIGURES.................................................................................................13 
LIST OF APPENDIXES..........................................................................................................13 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................14 
1 
INTRODUCTION ...........................................................................................................17 
1.1 
Background and Rationale .....................................................................................18 
1.2 
Nonclinical Experience ..........................................................................................20 
1.3 
Clinical Experience ................................................................................................20 
1.3.1 
Pharmacokinetics of JZP-110 ......................................................................20 
1.3.2 
Efficacy of JZP-110 in Clinical Studies of Narcolepsy ...............................21 
1.3.3 
Safety of JZP-110 in Clinical Studies of Narcolepsy ..................................21 
1.3.4 
Safety of JZP-110 in Clinical Studies of Major Depression and in Healthy 
Subjects ........................................................................................................22 
1.4 
Summary of Potential Benefits and Risks .............................................................23 
2 
STUDY OBJECTIVES ....................................................................................................24 
2.1 
Primary Objective ..................................................................................................24 
2.2 
Secondary Objective(s) ..........................................................................................24 
3 
STUDY DESIGN.............................................................................................................25 
3.1 
Overall Study Design and Plan ..............................................................................25 
3.1.1 
Rationale for Study Design and Control Group ...........................................27 
3.2 
Study Duration and Dates ......................................................................................27 
3.3 
End of Trial ............................................................................................................27 
4 
STUDY POPULATION SELECTION ...........................................................................27 
4.1 
Selection of Study Population ................................................................................27 
4.2 
Inclusion Criteria ...................................................................................................27 
4.3 
Exclusion Criteria ..................................................................................................28 
4.4 
Screening and Randomization Eligibility ..............................................................30 
5 
STUDY TREATMENT(S) ..............................................................................................30 
5.1 
Description of Treatment(s) ...................................................................................30 
5.1.1 
JZP-110 ........................................................................................................30 
5.1.2 
Placebo .........................................................................................................30 
5.2 
Treatments Administered .......................................................................................30 
5.3 
Selection and Timing of Dose for Each Subject ....................................................30 
5.4 
Method of Assigning Subjects to Treatment Groups .............................................31 
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5.5 
Randomization .......................................................................................................32 
5.6 
Blinding..................................................................................................................32 
5.7 
Prior and Concomitant Therapy .............................................................................32 
5.8 
Restrictions ............................................................................................................32 
5.8.1 
Prior Therapy ...............................................................................................32 
5.8.2 
Fluid and Food Intake ..................................................................................32 
5.8.3 
Other Restrictions ........................................................................................33 
5.9 
Investigational Medicinal Product Treatment Compliance ...................................33 
5.10 
Packaging and Labeling .........................................................................................33 
5.11 
Storage and Accountability ....................................................................................33 
5.12 
Investigational Medicinal Product Retention at Study Site ...................................34 
6 
STUDY PROCEDURES .................................................................................................34 
6.1 
Informed Consent...................................................................................................34 
6.2 
Demographics ........................................................................................................34 
6.3 
Medical History .....................................................................................................34 
6.4 
Physical Examination.............................................................................................35 
6.5 
Vital Signs ..............................................................................................................35 
6.6 
24-Hour Ambulatory Blood Pressure Monitoring .................................................36 
6.7 
Electrocardiography ...............................................................................................36 
6.8 
Polysomnography (PSG) .......................................................................................36 
6.9 
Columbia-Suicide Severity Rating Scale (C-SSRS) ..............................................37 
6.10 
Clinical Laboratory Tests .......................................................................................37 
6.10.1 
Laboratory Parameters .................................................................................37 
6.10.2 
Sample Collection, Storage, and Shipping ..................................................39 
6.10.2.1 
Clinical Laboratory Test Samples ......................................................39 
6.10.2.2 
Blood Samples for Pharmacokinetic Analysis ...................................40 
6.11 
Dispensing Study Drug ..........................................................................................40 
6.12 
Efficacy Assessments.............................................................................................40 
6.12.1 
Maintenance of Wakefulness Test (MWT) ..................................................40 
6.12.2 
Epworth Sleepiness Scale (ESS) ..................................................................41 
6.12.3 
Clinician Global Impression of Severity (CGIs) .........................................41 
6.12.4 
Clinician Global Impression of Change (CGIc) ..........................................41 
6.12.5 
Patient Global Impression of Change (PGIc) ..............................................42 
6.12.6 
Functional Outcomes of Sleep Questionnaire (FOSQ-10) ..........................42 
6.12.7 
36-Item Short Form Health Survey Version 2 (SF-36v2) ...........................42 
6.12.8 
EuroQoL EQ-5D-5L ....................................................................................42 
6.12.9 
Work Productivity and Activity Impairment Questionnaire: Specific Health 
Problem V2.0 (WPAI:SHP) .........................................................................42 
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6.12.10 Primary OSA Therapy Use ..........................................................................43 
6.13 
Pharmacokinetic Assessments ...............................................................................43 
6.13.1 
Blood Samples .............................................................................................43 
6.13.2 
Pharmacokinetic Parameters ........................................................................43 
6.14 
Adverse Event Reporting .......................................................................................44 
6.14.1 
Adverse Events (AEs) ..................................................................................44 
6.14.1.1 
Severity Assessment ..........................................................................44 
6.14.1.2 
Serious Adverse Events and Seriousness Assessment .......................45 
6.14.1.3 
Causal Relationship to Study Drug or Procedure ..............................46 
6.14.1.4 
Other Immediately Reportable Experiences ......................................46 
6.14.1.5 
Adverse Events Recording and Reporting .........................................47 
6.14.1.6 
Follow-up of Adverse Events and Serious Adverse Events ..............47 
6.14.2 
Post-Study Reporting Requirements ............................................................47 
6.14.3 
Pregnancy .....................................................................................................48 
6.14.4 
Emergency Unblinding ................................................................................48 
6.15 
Removal of Subjects from the Trial or Study Drug ...............................................48 
6.15.1 
Handling of Early Terminations ..................................................................49 
6.15.2 
Jazz Pharmaceuticals’ Termination of Study ...............................................49 
6.16 
Appropriateness of Measurements .........................................................................50 
7 
STUDY ACTIVITIES .....................................................................................................50 
7.1 
Screening Clinic Visit(s) ........................................................................................50 
7.1.1 
Screening Visit 1, Days -31 to -3 .................................................................50 
7.1.2 
Rescreening ..................................................................................................51 
7.2 
Baseline Clinic Visit ..............................................................................................52 
7.3 
End of Week 1 Visit ...............................................................................................54 
7.4 
End of Week 4 Clinic Visit ....................................................................................55 
7.5 
Phone Contact at the end of Weeks 2, 3, 5, 6, 7, 9, 10, and 11 ..............................57 
7.6 
End of Week 8 Clinic Visit ....................................................................................57 
7.7 
Final Clinic Visit Week 12 ....................................................................................58 
7.8 
Follow-up Clinic Visit Week 14 ............................................................................60 
7.9 
Early Termination Clinic Visit ...............................................................................61 
7.10 
Discontinuations ....................................................................................................62 
8 
QUALITY CONTROL AND ASSURANCE .................................................................62 
9 
PLANNED STATISTICAL METHODS ........................................................................62 
9.1 
General Considerations ..........................................................................................62 
9.2 
Tests of Hypotheses and Significance Levels ........................................................62 
9.3 
Determination of Sample Size ...............................................................................63 
9.4 
Analysis Populations ..............................................................................................63 
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9.5 
Demographics and Baseline Characteristics ..........................................................63 
9.6 
Handling of Dropouts and Missing Data ...............................................................64 
9.7 
Pooling of Investigation Centers ............................................................................64 
9.8 
Efficacy Endpoints .................................................................................................64 
9.8.1 
Co-primary Efficacy Endpoint .....................................................................64 
9.8.2 
Key Secondary Efficacy Endpoints: ............................................................64 
9.8.3 
Other Secondary Endpoints .........................................................................64 
9.8.4 
Functional Outcomes and Quality of Life Endpoints ..................................65 
9.8.5 
Exploratory Endpoints .................................................................................65 
9.9 
Safety Endpoints ....................................................................................................65 
9.10 
Multiplicity Issue ...................................................................................................66 
9.11 
Efficacy Analyses ..................................................................................................66 
9.12 
Safety Analyses ......................................................................................................67 
9.12.1 
Adverse Event ..............................................................................................67 
9.12.2 
Vital Signs and 24-Hour Ambulatory Blood Pressure Monitoring .............68 
9.12.3 
Laboratory Evaluation .................................................................................68 
9.12.4 
12-Lead Electrocardiograms ........................................................................68 
9.12.5 
Physical Examinations .................................................................................68 
9.12.6 
Columbia-Suicide Severity Rating Scale (C-SSRS) ....................................69 
9.13 
Analysis of Pharmacokinetic and Pharmacodynamic Variables ...........................69 
9.14 
Subgroup Analyses ................................................................................................69 
9.15 
Interim Analysis and Data Monitoring ..................................................................69 
10 DATA QUALITY ASSURANCE ...................................................................................69 
10.1 
Data Management ..................................................................................................69 
10.2 
Case Report Forms .................................................................................................70 
10.3 
Retention of Data ...................................................................................................70 
10.4 
Data Safety Monitoring Board ...............................................................................70 
11 ADMINISTRATIVE CONSIDERATIONS ....................................................................70 
11.1 
Investigators and Study Administrative Structure .................................................70 
11.1.1 
Contract Research Organization ..................................................................70 
11.1.2 
Jazz Pharmaceuticals Medical Monitors ......................................................70 
11.1.3 
EU Medical Monitor ....................................................................................71 
11.1.4 
Investigator ..................................................................................................71 
11.2 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval ................................................................................................................71 
11.3 
Ethical/Legal Conduct of the Study .......................................................................72 
11.4 
Subject Information and Consent...........................................................................72 
11.5 
Subject Confidentiality ..........................................................................................72 
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11.6 
Protocol Adherence – Amendments ......................................................................72 
11.7 
Required Documents ..............................................................................................73 
11.8 
Study Monitoring ...................................................................................................73 
11.9 
Protocol Violations/Deviations ..............................................................................73 
11.10 Access to Source Documentation ..........................................................................73 
11.11 Publication and Disclosure Policy .........................................................................74 
12 REFERENCE LIST .........................................................................................................75 
13 LIST OF UNPUBLISHED STUDY REPORTS .............................................................78 
 
LIST OF IN-TEXT TABLES 
Table 1 
List of Laboratory Tests ...............................................................................38 
Table 2 
Schedule of Clinical Laboratory Samples and Estimated Blood Volume ...39 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Study Schema...............................................................................................26 
Figure 2 
Multiplicity Strategy ....................................................................................66 
 
LIST OF APPENDIXES 
Appendix 1 
Schedule of Events .............................................................................79 
Appendix 2 
Example Schedule of Times for Procedures During MWT Visits ....82 
Appendix 3 
DSM-5 Criteria for Psychiatric Disorders .........................................83 
Appendix 4 
DSM-5 Substance Use Disorder Diagnostic Criteria .........................90 
Appendix 5 
Epworth Sleepiness Scale (ESS) ........................................................91 
Appendix 6 
Functional Outcomes of Sleep Questionnaire Short Version (FOSQ-
                       10)........................................................................................................92 
Appendix 7 
36-Item Short Form Health Survey Version 2 (SF-36v2) .................96 
Appendix 8 
EuroQoL EQ-5D-5L ........................................................................103 
Appendix 9 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
                         Baseline/Screening Version ............................................................107 
Appendix 10 
Work Productivity and Activity Impairment Questionnaire: Specific 
                        Health Problem V2.0 (WPAI:SHP) .................................................111 
Appendix 11 
Columbia-Suicide Severity Rating Scale (C-SSRS) Since Last Visit 
                         Version.............................................................................................114 
Appendix 12 
Clinical Global Impression of Severity (CGIs) ...............................118 
Appendix 13 
Clinical Global Impression of Change (CGIc) ................................119 
Appendix 14 
Patient Global Impression of Change (PGIc) ..................................120 
Appendix 15 
ICSD-3 Diagnostic Criteria for OSA ...............................................121 
Appendix 16 
Signatures of Agreement for Protocol .............................................122 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AASM 
American Academy of Sleep Medicine 
AE 
Adverse event 
ACC 
American College of Cardiology 
AHA 
American Heart Association 
AHI 
Apnea hypopnea index 
AICD 
Automatic implantable cardioverter defibrillator 
ALB 
Albumin 
ALK-P 
Alkaline phosphatase 
ALT 
Alanine aminotransferase (SGPT) 
ANCOVA 
Analysis of covariance 
AR 
Adverse reaction 
AST 
Aspartate aminotransferase (SGOT) 
βHCG 
Βeta human chorionic gonadotropin 
bpm 
Beats per minute 
BUN 
Blood urea nitrogen 
Ca 
Calcium 
CBC 
Complete blood count 
C-CASA 
Columbia Classification Algorithm of Suicide Assessment 
CFR 
Code of Federal Regulations 
CGIc 
Clinical Global Impression of Change 
CGIs 
Clinical Global Impression of severity 
cGMP 
Current Good Manufacturing Practice 
Cl 
Chloride 
CPAP 
Continuous positive airway pressure 
C-SSRS 
Columbia-Suicide Severity Rating Scale  
CRO 
Contract Research Organization 
CRF 
Case report form 
DMP 
Data Management Plan 
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DSM-5 
Diagnostic and Statistical Manual of Mental Disorders 5th Edition 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EMA 
European Medicines Agency 
EQ-5D-5L 
EuroQoL 
EU 
European Union 
ESS 
Epworth Sleepiness Scale 
FDA 
Food and Drug Administration 
FOSQ-10 
Functional Outcomes of Sleep Questionnaire Short Version 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization  
ICSD 
International Classification of Sleep Disorders 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug  
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
K 
Potassium 
MCC 
Microcrystalline cellulose 
MDD 
Major depressive disorder 
mITT 
Modified intent-to treat 
MAOI 
Monoamine Oxidase Inhibitor 
MMRM 
Mixed-effect Repeated Measures 
MSLT 
Multiple Sleep Latency Test 
MWT 
Maintenance of Wakefulness Test 
OSA 
Obstructive Sleep Apnea 
OCST 
Out of center sleep test 
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OTC 
Over the counter 
PAP 
Positive airway pressure 
PGIc 
Patient Global Impression of change 
PK 
Pharmacokinetics 
PKU 
Phenylketonuria 
PSG 
Polysomnography 
QTc interval 
Q-T interval corrected for heart rate  
QTcB 
Q-T interval corrected for heart rate using Bazett’s formula 
QTcF 
Q-T interval corrected for heart rate using Fridericia’s formula 
SAE 
Serious adverse event 
SF-36v2 
36-Item Short Form Health Survey Version 2 
SGOT 
Serum glutamic oxaloacetic transaminase (AST) 
SGPT 
Serum glutamic pyruvic transaminase (ALT) 
SUSAR 
Suspected unexpected serious adverse reactions 
Suspected AR 
An AE for which there is a lesser degree of certainty about causality than 
an adverse reaction.  
TEAE 
Treatment emergent adverse event 
TST 
Total sleep time 
ULN 
Upper limit of normal 
UK 
United Kingdom 
US 
United States 
VAS 
Visual analogue scale 
WASO 
Wake after sleep onset 
WBC 
White blood cell (count) 
WPAI:SHP 
Work Productivity and Activity Impairment Questionnaire: Specific 
Health Problem V2.0 
 
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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 daytime 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). 
OSA is diagnosed according to The International Classification of Sleep Disorders, Third 
Edition (ICSD-3, American Academy of Sleep Medicine [AASM 2014]) or Diagnostic and 
Statistical Manual of Mental Disorders, Fifth Edition (DSM-5, American Psychiatric 
Association 2013) on the basis of the number of predominantly obstructive respiratory events 
that occur per hour of sleep during a nocturnal polysomnogram (PSG) or per hour of 
monitoring during an out of center sleep test (OCST); often in addition to a patient complaint 
of daytime sleepiness, non-restorative or unrefreshing sleep, or fatigue; or a report of a 
nocturnal breathing disturbance such as snoring, gasping, choking, or pauses in breathing. 
Essential features of OSA include repetitive episodes of complete (apnea) or partial 
(hypopnea) upper airway obstruction during sleep and excessive sleepiness that occurs 
during the day and is a major presenting complaint in many but not all cases (AASM 2014). 
Most patients with OSA awaken in the morning feeling tired and unrefreshed regardless of 
the duration of their time in bed. During the day, their sleepiness is most evident during 
relaxing or inactive situations; however, with extreme sleepiness, sleep may occur while 
actively conversing, eating, walking, or driving (AASM 2014). 
Positive airway pressure (PAP) applied through a nasal, oral, or oronasal interface during 
sleep is considered to be the reference- or gold-standard treatment for OSA by the AASM 
and the European Respiratory Society (Gay et al. 2006, Fietze et al. 2011, Randerath et al. 
2011). However, the effectiveness of PAP is limited by patient non-compliance or non-
adherence to therapy. Non-compliance with PAP is a widely recognized problem that limits 
its effectiveness (Weaver & Grunstein 2008, Weaver & Sawyer 2010, Sawyer et al. 2011). 
Compliance with PAP is typically defined as the use of PAP for ≥4 hours per night on ≥70% 
of nights (Gay et al. 2006). When compliance is defined as ≥4 hours of nightly use, it is 
estimated that 46-83% of patients with OSA are non-compliant with their prescribed 
continuous positive airway pressure (CPAP) therapy (Weaver & Grunstein 2008). 
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In addition to PAP, there are alternative therapies that are used for the primary treatment of 
OSA when PAP therapy is refused or is unsuccessful. The Clinical Guideline for the 
Evaluation, Management and Long-term Care of Obstructive Sleep Apnea in Adults that was 
authored by the Adult Obstructive Sleep Apnea Task Force of the AASM recommends that 
alternative therapies such as behavioral therapy, use of an oral appliance, surgical 
intervention, or adjunctive treatment should be discussed with a patient when PAP is not 
accepted by the patient or when the patient is either intolerant of PAP or unsuccessful with 
PAP therapy (Epstein et al. 2009). Similarly, the European Respiratory Society Task Force 
Report on Non-CPAP therapies in obstructive sleep apnoea states that evidence supports the 
use of mandibular advancement devices in mild to moderate OSA, that maxillomandibular 
osteotomy seems to be as efficient as CPAP in patients who refuse conservative treatment, 
and that there is a trend towards improvement in OSA symptoms after weight reduction 
(Randerath et al. 2011). 
 
Although PAP therapy is considered to be the international reference- or gold-standard 
treatment for OSA (Gay et al. 2006, Fietze et al. 2011, Randerath et al. 2011), the 
effectiveness of PAP therapy to adequately treat objective and subjective sleepiness 
associated with OSA is less definitive. The Positive Airway Pressure Task Force of the 
Standards of Practice Committee of the AASM has concluded that although PAP has been 
shown to be effective in eliminating respiratory disturbances and reducing the 
apnea/hypopnea index (AHI), Level I and Level II evidence for CPAP improving objective 
measures of wakefulness in patients with OSA is equivocal (Gay et al. 2006). In addition, 
data from a multicenter study on the relationships between hours of PAP use and measures of 
sleepiness showed that subjective sleepiness did not resolve with PAP therapy in 34% of 
OSA subjects who had ESS scores >10 at baseline and that objective sleepiness did not 
resolve with PAP therapy in 65% of OSA subjects who had an MSLT sleep latency 
<7.5 minutes at baseline (Weaver et al. 2007). Similarly, data from a multicenter study in 
France and from the French National Sleep Registry have estimated the prevalence of 
residual excessive sleepiness in OSA patients without major comorbidities who use CPAP to 
be 6 and 13%, respectively (Pepin et al. 2009, Gasa et al. 2013). 
These data are consistent with a consensus statement from the Medical Therapy for 
Obstructive Sleep Apnea Task Force of the Standards of Practice Committee of the American 
Academy of Sleep Medicine that concluded that many patients have residual sleepiness 
despite effective therapy with nasal PAP (Veasey et al. 2006). These findings highlight the 
unmet medical need for therapies that reduce excessive sleepiness and increase the ability to 
stay awake during the day in OSA. 
 
1.1 
Background and Rationale 
The MWT is the standard objective measure of an individual’s ability to remain awake 
during the daytime in a darkened, quiet environment and is commonly used to assess 
response to treatment (AASM 2014). Previous studies of modafinil and armodafinil 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 
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Study Group 1998, US Modafinil in Narcolepsy Multicenter Study Group 2000, Harsh et al. 
2006). In contrast, data for the 300 mg dose of JZP-110 from the Phase 2a Study 
ADX-N05 201 in narcolepsy patients using a 40-minute MWT resulted in a maximal 
difference in the means between drug and placebo of 11.8 minutes. Similarly, data from the 
Phase 2b Study ADX-N05 202 in narcolepsy patients resulted in maximal differences in the 
means of 8.1 and 10.7 minutes between 150 mg or 300 mg JZP-110 and placebo, 
respectively, on a 40-minute MWT. These data suggest that doses of 150 and 300 mg JZP-
110 could serve a significant unmet medical need to treat excessive sleepiness and to increase 
patients’ ability to stay awake throughout the day beyond what has been demonstrated with 
current available therapies. 
Modafinil and armodafinil are indicated in the US to improve wakefulness in adult patients 
with excessive sleepiness associated with narcolepsy or with OSA Provigil Prescribing 
Information, Nuvigil Prescribing Information). Although changes in sleep latency on the first 
four trials of a 20-minute MWT with modafinil were slightly lower in patients with OSA 
(mean changes of 1.5-1.6 minutes; Black & Hirshkowitz 2005) as compared to patients with 
narcolepsy (mean changes of 1.9-2.3 minutes; US Modafinil in Narcolepsy Multicenter 
Study Group 1998, US Modafinil in Narcolepsy Multicenter Study Group 2000), these data 
suggest that wake-promoting agents (such as JZP-110) should have similar therapeutic 
effects in the narcolepsy and OSA patient populations. 
 
Another limitation of modafinil and armodafinil is that the therapeutic effects of these drugs 
do not appear to last throughout the day and are markedly reduced by the fifth trial of a (5- or 
6-trial, 20- or 30-minute) MWT in patients with narcolepsy or OSA (Schwartz et al. 2003, 
Harsh et al. 2006, Roth et al. 2006). For example, the effects of 200 and 400 mg modafinil 
diminished throughout the day in narcolepsy patients, and the mean changes from baseline in 
sleep latency were almost zero on the fifth and sixth trials of a 6-trial, 20-minute MWT 
(5-7 PM) when modafinil was given once daily in the morning (Schwartz et al. 2003). 
Similarly, the effects of 150 and 250 mg armodafinil diminished by the fifth trial of a 6-trial, 
20-minute MWT in narcolepsy patients, resulting in a mean change from baseline in sleep 
latency of almost zero for 250 mg armodafinil at 1700 hours (5 pm) (Harsh et al. 2006). In 
addition, the effects of 150 and 250 mg modafinil on mean sleep latency across the last three 
trials (3-7 pm) were not statistically different from placebo (for the individual doses or when 
combined) at the end of this 12-week trial (Harsh et al. 2006). 
 
In contrast to the limited effects of modafinil and armodafinil on sleep latency on the fifth 
trial of a 20-minute MWT in narcolepsy patients, (Schwartz et al. 2003; Harsh et al. 2006), 
data from the 12-week, Phase 2b study of JZP-110 in 93 subjects with narcolepsy 
(44 subjects randomized to receive JZP-110) showed that 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 at p=0.0007). The mean change from 
baseline 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 at 5.4 minutes. The 4-week and 12-week 
JZP-110 studies found no unexpected drug-related toxicities and demonstrated that JZP-110 
was safe and well tolerated in narcolepsy patients under the parameters tested. Taken 
together, these data suggest that JZP-110 might offer an important advance in the treatment 
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of excessive sleepiness in OSA by increasing patients’ ability to stay awake throughout the 
day.  
1.2 
Nonclinical Experience  
Nonclinical studies have been conducted to characterize primary pharmacology, secondary 
and safety pharmacology, abuse liability, absorption, distribution, metabolism, excretion, and 
toxicology of JZP-110. 
JZP-110 was extensively absorbed and showed high oral bioavailability (71 to 100%) in 
mice, rats, and dogs. In humans, bioavailability was >90% as evidenced by plasma AUC for 
parent drug essentially matching AUC for total radioactivity in a human mass balance study, 
along with urinary recovery of >90% of the dose as unchanged drug. Plasma protein binding 
was low (8 to 17%) in mouse, rat, rabbit, dog, and human plasma. In the in vitro metabolism 
studies, no notable inhibition of CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, 
CYP2E1 and CYP3A4 occurred (15%) with concentrations up to 1000 μM. Notable 
inhibition of CYP1A2 (73%) and CYP2D6 (56%) activity was observed only at the highest 
concentration (1000 μM) investigated. However, this level of inhibition is unlikely to result 
in clinically significant drug-drug interactions with CYP1A2 or CYP2D6 substrates. The 
plasma Cmax level after oral administration to humans at 400 mg/day is approximately 7.6 μM 
(1482 ng/mL). JZP-110 (5 to 100 μM) did not inhibit P-glycoprotein–mediated transport. 
More detailed information is provided in the JZP-110 Investigators Brochure. 
1.3 
Clinical Experience  
At the start of Phase 3 program, nine clinical studies (six Phase 1 and three Phase 2a studies) 
had been conducted in 262 healthy subjects and 602 subjects (two of whom did not receive 
study drug) with major depressive disorder (MDD). Of these 862 subjects, 555 received JZP-
110, 185 received placebo, and 122 received paroxetine. Two Phase 2 studies have been 
conducted in 126 subjects with narcolepsy, in which 77 subjects received JZP-110 and 49 
subjects received placebo. 
1.3.1 
Pharmacokinetics of JZP-110 
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 repeated doses administered once or 
twice daily, JZP-110 exposure was dose proportional, absorption (tmax: 1.3 to 2.5 hours) and 
elimination (t½: 6 to 7.6 hours) were rapid, and steady state was reached in 3 days. 
Pharmacokinetics were linear over the multiple-dose (14 day) range of 200 to 1000 mg/day. 
Limited accumulation and no enzyme induction were evident.  
Doses of JZP-110 previously studied in human subjects have ranged from 50 to 1200 mg per 
day in healthy subjects, from 200 to 900 mg per day in subjects with MDD, and have 
included 150 and 300 mg in subjects with narcolepsy. 
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1.3.2 
Efficacy of JZP-110 in Clinical Studies of Narcolepsy 
Two randomized, double-blind, placebo-controlled studies were conducted in 126 adult 
subjects with narcolepsy. In these studies, once daily doses included 150 and 300 mg/day 
JZP-110; the doses were based on the free base of the molecule. 
Study ADX-N05 201 was a 4-week, double-blind, placebo-controlled, crossover study of 
JZP-110 150 and 300 mg given once daily in adult subjects with narcolepsy (N=33). The 
primary efficacy endpoint was the change from Baseline in the mean sleep latency time (in 
minutes) averaged across the first four trials of the MWT at the end of 2 weeks of treatment. 
At the end of 2 weeks of treatment, the mean sleep latency on the MWT increased by 
12.7 minutes for the JZP-110 300 mg/day treatment period versus 0.9 minutes for the placebo 
period. The difference in mean change from Baseline was both statistically and clinically 
significant in favor of the active treatment period (mixed model analysis of variance; 
p=0.0002). All secondary endpoints in this study were also positive including the mean 
change in the ESS. 
Study ADX-N05 202 was a 12-week, double-blind, placebo-controlled, parallel-group study 
of JZP-110 150 and 300 mg given once daily in adult subjects with narcolepsy (N=93). The 
primary efficacy endpoints were the change from Baseline in the mean sleep latency time (in 
minutes) averaged across the first four trials of the MWT and the Clinical Global Impression 
of Change (CGIc) scores for JZP-110 versus placebo at the last (Week 12) assessment at the 
300 mg dose. At Week 12/Last Assessment, the mean sleep latency increased by 
12.8 minutes for the JZP-110 group (300 mg/day) versus 2.1 minutes for the placebo group. 
The difference in mean change from Baseline was both statistically and clinically significant 
in favor of the active treatment group (two-sample t-test; p<0.0001). All secondary endpoints 
in this study were also positive. 
1.3.3 
Safety of JZP-110 in Clinical Studies of Narcolepsy 
In Study ADX-N05 201, 1 week of treatment with JZP-110 150 mg/day followed by an 
increase to 300 mg/day for a second week was safe and well tolerated. The most common 
treatment-emergent adverse events (TEAEs) with JZP-110 treatment included nausea (12%), 
chest discomfort (9%), headache (9%), anxiety (6%), decreased appetite (6%), initial 
insomnia (6%), insomnia (6%), and muscle tightness (6%). None of these events were 
reported during placebo treatment. There were no deaths, treatment-emergent serious AEs 
(SAEs), or discontinuations due to AEs. Severe TEAEs were limited to two subjects (one 
with intermittent nausea and one with insomnia). JZP-110 treatment was associated with a 
modest effect on heart rate and blood pressure, and TEAEs suggested a profile of effects 
consistent with those of a wake-promoting drug (decreased appetite, headache, anxiety, 
insomnias, and gastrointestinal complaints). Palpitations were reported by one subject (3%) 
and chest pain was reported by 3 subjects (9%; all reported as non-cardiac pain) while on 
JZP-110. There were no reports of palpitations or chest pain while subjects were on placebo. 
 
In Study ADX-N05 202, the JZP-110 dose regimen of 150 mg/day for 4 weeks followed by 
300 mg/day for 8 weeks appeared to be safe and well tolerated. The most common TEAEs 
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with JZP-110 treatment included headache (16%), nausea (14%), insomnia (14%), decreased 
appetite (14%), diarrhea (11%), and anxiety (11%); all of these events were more common in 
the combined JZP-110 group than in the placebo group. There were no deaths in this study. 
Treatment-emergent SAEs occurred in two subjects (both in the JZP-110 group): one subject 
had conversion disorder and one had acute cholecystitis. Three subjects (6.8%) in the 
JZP-110 group and two subjects (4.1%) in the placebo group had TEAEs that led to study 
discontinuation. It appears likely that JZP-110 is causally associated with insomnia, 
decreased appetite, anxiety, irritability, palpitations, and perhaps nausea and diarrhea.  
In the ADX-N05 202 study, JZP-110 treatment was associated with small effects on placebo-
corrected changes in heart rate (both measured and from ECGs), blood pressure, and 
quantitative ECG parameters (mean heart rate increased from Baseline at 2 hours after dosing 
by 3 to 5 beats per minute [bpm] with little or no change at 9 to 10 hours after dosing; mean 
PR, QRS, QT, QTcB and QTcF demonstrated no significant changes). There were no 
clinically significant effects on the ECG parameters of PR, QRS, QTcF or QTcB in any 
subject. Palpitations were reported by 4 subjects (9%) and chest pain was reported by 
2 subjects (both appeared to be non-cardiac pain) while on JZP-110. There was one report of 
palpitations and one report of chest pain from subjects who were on placebo in the ADX-N05 
202 study. There were two subjects who had TEAEs that were related to vital signs: mildly 
elevated blood pressure beginning on Day 17 in one subject on JZP-110 and elevated blood 
pressure at the Week 4 visit and intermittent elevated systolic and diastolic pressures 
beginning at the Week 6 visit in one subject on placebo. There were two subjects who had 
TEAEs related to ECG findings: one subject had a TEAE of “heart rate increased” on 
JZP-110 that may have been related to ECG-derived measurements, and another subject on 
placebo was reported to have a TEAE of “occasional ventricular premature complexes.” 
1.3.4 
Safety of JZP-110 in Clinical Studies of Major Depression and in Healthy 
Subjects 
Three randomized, double-blind, placebo-controlled studies (SKUP- 9801, R228060-USA-
10, and R228060-MDD-201) have been conducted in a total of 600 adult subjects with MDD. 
In these studies, doses ranged from 100 to 900 mg/day JZP-110 with the dose based on the 
hydrochloride salt of the drug. These studies did not demonstrate efficacy for JZP-110 in 
treating MDD.  
• 
Study SKUP-9801 was an 8-week, double-blind, placebo-controlled, parallel-group pilot 
study in adults with MDD of low (100 to 300 mg/day; N=8), intermediate (400 to 
600 mg/day; N=9), and high (700 to 900 mg/day; N=10) doses (given twice daily) of 
JZP-110 versus placebo (N=8) (total N=35) (EDMS-PSDB-2275504).  
• 
Study R228060-USA-10 was a 3-week, double-blind, placebo-controlled, parallel-group 
study to assess the tolerability of JZP-110 200 mg/day (100 mg morning, 100 mg 
evening) and 500 mg/day (300 mg morning, 200 mg evening) in adult subjects with 
MDD (N=77), with efficacy as an exploratory objective (R228060-USA-10). 
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• 
Study R228060-MDD-201 was a large-scale (27 centers, N=488), 6-week, double-blind, 
active- (paroxetine) and placebo-controlled, parallel-group study of JZP-110 100 and 200 
mg given twice daily in adult subjects with MDD (N=488) (EDMS-PSDB-3696001). 
Most of the 219 healthy subjects and 600 subjects with MDD reported adverse events (AEs), 
the majority of which were mild or moderate. The AEs from these 219 healthy subjects do 
not include data from a recently completed Phase 1 human abuse liability study in 
43  subjects because data analysis from that study is ongoing (preliminary data will be 
included in the JZP-110 Investigators Brochure). The most common TEAEs that occurred 
≥5% and more often with JZP-110 than placebo across doses of 200 to 1200 mg/day 
included: insomnia (34%), headache (23%), dizziness (16%), anorexia (16%), dry mouth 
(16%), nervousness (15%), nausea (14%), palpitation (11%), agitation (10%), abdominal 
pain (10%), anxiety (9%), fatigue (9%), concentration impaired (8%), and diarrhea (6%). 
There were no deaths. One healthy JZP-110-treated subject (1000 mg/day) reported a serious 
adverse event (SAE, confusion) that was considered unrelated to study drug. Four JZP-110-
treated subjects with MDD reported SAEs: cellulitis (100 to 300 mg/day), aggravated 
depression (200 mg/day), aggravated depression and suicidal ideation (400 mg/day), and 
myocardial infarction (200 mg). The myocardial infarction was the only SAE that was 
classified as possibly related to study drug (see the JZP-110 Investigators Brochure for 
additional information on this SAE). 
In addition, there were reports of mostly mild cardiovascular AEs in other studies (see the 
JZP-110 Investigators Brochure for additional information). Palpitations were reported by 
one subject in each of the YUKIC 9603-01 and SKUP-9801 studies and by seven subjects in 
the MDD-201 study. Chest pain was reported by one subject in the YUKIC 9603-01 study 
and by four subjects in the MDD-201 study. T-wave inversions were observed in one subject 
in each of the YUKIC-9603 and YUKIC-9702-01 studies and in three subjects in the 
MDD-201 study (which includes the myocardial infarction described above). Ventricular 
ectopy (seen on 12-lead ECG) was reported in one patient in YUKIC-9702-01 and one 
patient in MDD-201. One patient reported orthostatic hypotension and two patients reported 
hypertension in MDD-201, all three on JZP-110. There were occasional ECG reports of 
intermittent fascicular blocks, intraventricular conduction defects, and 1st degree AV block, 
about equally common in JZP-110 and controls, and rarely new and sustained. These were 
usually considered not clinically significant findings or adverse events.  
Three healthy subjects (two on 200 mg and one on 800 mg JZP-110) and two subjects with 
MDD (both on 500 mg JZP-110) had treatment-emergent reversible elevations of liver 
enzymes (alanine aminotransferase and/or aspartate aminotransferase) of 1.1 to 4.1 × the 
upper limit of normal (ULN). Two placebo-treated subjects also developed mild elevations in 
liver enzymes. There were no other findings in laboratory safety tests. 
1.4 
Summary of Potential Benefits and Risks 
JZP-110 has not been studied in OSA. Based on two clinical studies in narcolepsy the 
potential benefits of JZP-110 to subjects randomized to the 150 mg or 300 mg treatment arms 
in this study are expected to be a clinically significant increase in the ability to stay awake 
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and a clinically significant decrease in subjective sleepiness. These benefits are anticipated 
from the MWT and ESS data, respectively, from previous studies of JZP-110 in narcolepsy 
patients. However, the therapeutic benefit of JZP-110 in OSA patients is not known, and in 
the case of a mean positive benefit, not every subject in the 150 or 300 mg treatment arms 
would be anticipated to benefit. It is not known if the 37.5 or 75 mg doses will provide a 
clinical benefit. Placebo is not anticipated to provide any benefit; however, some patients 
receiving placebo might benefit from their participation in the study. 
The risks to subjects in this study who are randomized to the 150 mg or 300 mg treatment 
arms are expected to be similar to those seen in prior clinical studies that evaluated the 
effects of 150 mg and 300 mg JZP-110 in narcolepsy patients (Section 1.3.3). However, 
JZP-110 has not been studied in patients with OSA previously and the risks associated with 
JZP-110 in the OSA patient population might differ from those in the narcolepsy patient 
population. It is not known if the 37.5 or 75 mg doses will be associated with the same type 
or magnitude of AEs that were associated with the higher doses that were previously studied 
in patients with narcolepsy. Risks for subjects who are randomized to the placebo treatment 
arm may include those associated with untreated symptoms of sleepiness in OSA. 
Subjects treated with JZP-110 might also experience small increases in blood pressure and 
heart rate in the first 8 hours after dosing. To date mean increases have been on the order of 
up to 5 beats per minute, up to 6 mmHg in systolic blood pressure, and up to 3 mmHg in 
diastolic blood pressure. In a recently completed thorough QT study, JZP-110 did not cause 
QT interval prolongation above the threshold of regulatory concern when given at either the 
300 mg or 900 mg dose (International Conference on Harmonisation [ICH] E14 Clinical 
Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-
Antiarrhythmic Drugs, 2005). 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective  
To evaluate the efficacy of JZP-110 administered once daily for up to 12 weeks in doses of 
37.5, 75, 150, and 300 mg compared to placebo in the treatment of excessive sleepiness in 
adult subjects with OSA. 
2.2 
Secondary Objective(s)  
To evaluate the safety and tolerability of JZP-110 administered once daily for up to 12 weeks 
in doses of 37.5, 75, 150, and 300 mg compared to placebo in the treatment of excessive 
sleepiness in adult subjects with OSA. 
To characterize the pharmacokinetics (PK) of JZP-110 in subjects with OSA using sparse 
sampling methods. 
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3 
STUDY DESIGN 
3.1 
Overall Study Design and Plan 
The Schedule of Events is presented in Appendix 1, and the Study Schema in Figure 1. 
This trial is a 12-week, randomized, double-blind, placebo-controlled, multicenter, 5-arm 
parallel group study of safety and efficacy of JZP-110 in the treatment of excessive 
sleepiness in adult subjects with OSA. Following the successful completion of Screening and 
Baseline visits, stratified randomization on the basis of subjects’ compliant or non-compliant 
use of their primary OSA therapy will be used to assign subjects in a 1:1:2:2:2 ratio to 
JZP-110 37.5, 75, 150, or 300 mg, or placebo. Treatment will be administered once daily 
over a Treatment Phase of 12 weeks. Subjects randomized to the 150 mg dose will initially 
receive 75 mg from Day 1 through Day 3 of the first week of the Treatment Phase and will 
receive 150 mg starting on Day 4. Subjects randomized to the 300 mg dose will initially 
receive 150 mg from Day 1 through Day 3 of the first week of the Treatment Phase and will 
receive 300 mg starting on Day 4. Subjects randomized to the other treatment groups will not 
require titration. 
During the Treatment Phase, subjects will return to the investigative site to complete efficacy 
and safety assessments at the end of Weeks 1, 4, 8, and 12; the 4 and 12 Week Visits will 
also include an overnight stay at the investigational site for nocturnal polysomnography 
(PSG) followed by a Maintenance of Wakefulness Test (MWT), and the Week 8 Visit will 
include 24-hour ambulatory blood pressure monitoring. Subjects will take their final dose of 
study drug at the Week 12 visit prior to the Week 12 visit assessments. Subjects will return at 
the end of Week 14 for follow-up assessments. Unless there are any outstanding safety issues 
that require follow-up, subjects will be discharged from the study at the Week 14 visit. 
Efficacy will be assessed by changes in the mean sleep latency on the first 4 trials of a 5-trial, 
40-minute MWT and by changes in the mean Epworth Sleepiness Scale (ESS) score as 
co-primary endpoints, percentage of patients improved on the Patient Global Impression of 
Change (PGIc) as a key secondary endpoint, and CGIc, Functional Outcomes of Sleep 
Questionnaire Short Version (FOSQ-10), 36-Item Short Form Health Survey (SF-36v2), 
EuroQoL EQ-5D-5L, and the Work Productivity and Activity Impairment Questionnaire: 
Specific Health Problem V2.0 (WPAI:SHP) as other endpoints. 
Four blood samples will be collected from each subject for PK evaluations; one sample 
during the Week 1 visit, one sample during the Week 4 visit, and two samples during the 
Week 8 visit. The samples collected at the Week 1 and Week 8 visits will be within 1-8 hours 
of dosing. The sample collected at the Week 4 visit will be within 8-12 hours of dosing. 
Safety will be assessed by the incidence of observed and reported adverse events (AEs), and 
changes in physical examination findings, electrocardiograms (ECGs), clinical laboratory 
tests, vital signs, 24-hour ambulatory blood pressure monitoring, and the Columbia-Suicide 
Severity Rating Scale (C-SSRS). Safety will be assessed throughout the study.
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Figure 1 
Study Schema 
 
 
 
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3.1.1 
Rationale for Study Design and Control Group 
This study was designed to be consistent with the United States (US) Food and Drug 
Administration (FDA) Guidance for Industry on Providing Clinical Evidence of 
Effectiveness for Human Drug and Biological Products, with The International Conference 
on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human 
Use (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 control group in this study is necessary to determine the 
efficacy and safety of this new investigational medicinal product. 
 
3.2 
Study Duration and Dates 
Each subject will participate for up to 31 days for Screening and Baseline evaluations, for 
12 weeks in the Treatment Phase, and for 2 weeks in the Safety Follow-up Phase (the 2 week 
Safety Follow-up visit is not required for subjects who enter the Open-label Safety Study 
[14-005] at the Final Clinic Visit). It is estimated that enrollment across all sites will be 
completed in 12 months. 
3.3 
End of Trial 
The end of the trial will be the date of the last visit of the last subject enrolled in the trial. 
4 
STUDY POPULATION SELECTION 
4.1 
Selection of Study Population 
Subjects must have a documented diagnosis of OSA according to ICSD-3 criteria. Subjects 
must also have sleepiness and an inability to stay awake as demonstrated by the objective and 
subjective criteria as defined below. In addition, subjects must currently use or have a history 
of an attempt to use an accepted therapy for the primary treatment of OSA. 
4.2 
Inclusion Criteria 
Each subject must meet the following criteria to be enrolled in the study. 
1. Male or female between 18 and 75 years of age, inclusive. 
2. Diagnosis of OSA according to ICSD-3 criteria (Appendix 15). 
3. Subject report (with clinician concurrence) of at least minimal use of a primary 
therapy for OSA or an attempt to use a primary therapy for OSA as follows: 
a. Use of a primary therapy for OSA (i.e., positive airway pressure, oral pressure 
therapy, oral appliance, or upper airway stimulator) on at least 1 night/week, 
or 
b. History of at least 1 month of an attempt to use one or more primary OSA 
therapies with at least one documented adjustment that was made in an 
attempt to optimize the primary OSA therapy, or 
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c. History of a surgical intervention intended to treat OSA symptoms. 
4. Subject report (with clinician concurrence) of a stable level of compliance with a 
primary OSA therapy for at least 1 month prior to Baseline as follows: 
a. A stable level of use of a primary OSA therapy, or 
b. A lack of use of a primary OSA therapy following a history of attempted use, 
or 
c. A history of a surgical intervention intended to treat OSA symptoms. 
5. Baseline Epworth Sleepiness Scale (ESS) score ≥10. 
6. Baseline mean sleep latency <30 minutes as documented by the mean of the first four 
trials of the MWT. 
7. Usual nightly total sleep time of at least 6 hours. 
8. Body mass index from 18 to <45 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. 
10. Willing and able to comply with the study design schedule and other requirements. 
11. Willing and able to provide written informed consent. 
4.3 
Exclusion Criteria 
Subjects who demonstrate any of the following will be excluded from the study. 
 
1. Unwilling to attempt to use one or more primary OSA therapies. 
2. Female subjects who are pregnant, nursing, or lactating. 
3. Usual bedtime later than 1 AM (0100 hours). 
4. Occupation requiring nighttime shift work or variable shift work.  
5. Any other clinically relevant medical, behavioral, or psychiatric disorder other than 
OSA that is associated with excessive sleepiness. 
6. History or presence of bipolar disorder, bipolar related disorders, schizophrenia, 
schizophrenia spectrum disorders, or other psychotic disorders according to DSM-5 
criteria. 
7. History or presence of any acutely unstable medical condition, behavioral or 
psychiatric disorder (including active suicidal ideation), or surgical history that could 
affect the safety of the subject or interfere with study efficacy, safety, PK 
assessments, or the ability of the subject to complete the trial per the judgment of the 
Investigator. 
8. History of bariatric surgery within the past year or a history of any gastric bypass 
procedure. 
9. Presence of renal impairment or calculated creatinine clearance <60 mL/min. 
10. Clinically significant ECG abnormality in the opinion of the Investigator.  
11. This criterion has been removed.  
12. Presence of significant cardiovascular disease including but not limited to: myocardial 
infarction within the past year, unstable angina pectoris, symptomatic congestive 
heart failure (ACC/AHA stage C or D), revascularization procedures within the past 
year, ventricular cardiac arrhythmias requiring an automatic implantable cardioverter 
defibrillator (AICD) or medication therapy, uncontrolled hypertension, systolic blood 
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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. 
13. Laboratory value(s) outside the laboratory reference range that are considered to be 
clinically significant by the Investigator (clinical chemistry, hematology, and 
urinalysis); NOTE: Screening labs may be repeated once. 
14. Excessive caffeine use one week prior to Baseline assessments or anticipated 
excessive use during the study defined as >600 mg/day of caffeine. 
15. Use of any over-the-counter (OTC) or prescription medications that could affect the 
evaluation of excessive sleepiness within a time period prior to the Baseline Visit 
corresponding to at least five half-lives of the drug(s) or planned use of such drug(s) 
at some point throughout the duration of the study. Examples of excluded 
medications include OTC sleep aids or stimulants (e.g., pseudoephedrine), 
methylphenidate, amphetamines, modafinil, armodafinil, sodium oxybate, pemoline, 
trazodone, hypnotics, benzodiazepines, barbiturates, and opioids. Medications should 
be discontinued such that the subject has returned to his/her baseline level of daytime 
sleepiness at least 7 days prior to the Baseline visit, in the opinion of the Investigator. 
16. Use of a monoamine oxidase inhibitor (MAOI) in the past 14 days or five half-lives 
(whichever is longer) prior to the Baseline Visit, or plans to use an MAOI during the 
study. 
17. Received an investigational drug in the past 30 days or five half-lives (whichever is 
longer) prior to the Baseline Visit, or plans to use an investigational drug (other than 
the study drug) during the study. 
18. Previous exposure to or participation in a clinical trial of JZP-110 (ADX-N05, 
R228060, or YKP10A). 
19. Current or past (within the past 2 years) diagnosis of a moderate or severe substance 
use disorder according to DSM-5 criteria. 
20. Nicotine dependence that has an effect on sleep (e.g., a subject who routinely 
awakens at night to smoke). 
21. Current, past (within the past 2 years), or seeking treatment for a substance related 
disorder. 
22. Urine drug screen positive for an illicit drug of abuse (including cannabinoids) at 
screening or at any point throughout the duration of the study, except for a prescribed 
drug (e.g., amphetamine) at screening. 
23. History of phenylketonuria (PKU) or history of hypersensitivity to phenylalanine-
derived products. 
 
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 
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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 screening if they meet the inclusion criteria and do 
not meet any exclusion criteria. 
Subjects who do not meet all eligibility criteria at screening will not be randomized. 
5 
STUDY TREATMENT(S) 
5.1 
Description of Treatment(s) 
5.1.1 
JZP-110 
The Investigational Medicinal Product JZP-110 [(R)-2-amino-3-phenylpropylcarbamate 
hydrochloride] will be supplied as 37.5, 75 mg, 150 mg, 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). 
JZP-110 is not a controlled substance under the United States Controlled Substances Act or 
under the United Nations Convention on Psychotropic Substances. 
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 the same opaque gelatin 
capsules that will be used for the active JZP-110 treatments. MCC will be used as the capsule 
backfill. 
5.2 
Treatments Administered 
Subjects will receive JZP-110 37.5, 75, 150, or 300 mg or placebo once daily as a single 
gelatin capsule over a Treatment Phase of 12 weeks. 
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 mg and 300 mg JZP-110 increased the mean sleep 
latency on the first four 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 two lower doses of 37.5 and 75 mg JZP-110 given once a day in the morning. 
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In this study, subjects will be randomized 1:1:2:2:2 to receive either JZP-110 37.5, 75, 150, 
300 mg, or placebo, respectively, as described in Section 5.5. Subjects will be instructed to 
take a single daily dose of study drug in the morning, on an empty stomach within one hour 
of awakening. Subjects will also be instructed to abstain from eating or drinking (except for 
water) for 30 minutes after taking the study drug. 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. 
The titration schedule in this protocol is based on the pharmacokinetics of the JZP-110 as 
well as the titration experience in clinical trials to date. Steady state levels of JZP-110 are 
reached within 3 days (Section 1.3.1). In the previous ADX-N05 201 and ADX-N05 202 
studies in narcolepsy patients, subjects received 150 mg JZP-110 for 1 or 4 weeks, 
respectively, prior to receiving 300 mg JZP-110. In this study, subjects randomized to receive 
the 300 mg dose will initially receive 150 mg from Day 1 through Day 3 of the first week of 
the Treatment Phase and will receive 300 mg starting on Day 4. This titration schedule is 
similar to those that were used in previous studies of JZP-110 in MDD (Section 1.3.4). 
Although previous studies in patients with narcolepsy have shown that the 150 mg dose is 
tolerated as a starting dose, subjects randomized to receive the 150 mg dose in this study will 
initially receive 75 mg from Day 1 through Day 3 of the first week of the Treatment Phase 
and will receive 150 mg starting on Day 4 to evaluate whether titration to the 150 mg dose in 
this study will result in fewer AEs as compared to a starting dose of 150 mg without titration. 
Subjects randomized to the 37.5 mg, 75 mg, or placebo groups will not require titration. 
 
5.4 
Method of Assigning Subjects to Treatment Groups 
Following the successful completion of Screening and Baseline visits, stratified 
randomization on the basis of subjects’ compliant or non-compliant use of their primary OSA 
therapy will be used to assign subjects in a 1:1:2:2:2 ratio to JZP-110 37.5, 75, 150, or 
300 mg, or placebo. Compliant use of a primary OSA therapy will be defined as use of 
≥4 hours per night on ≥70% of nights (≥5 of 7 nights/week) for subjects who use a device 
from which hourly usage data can be extracted. Compliant use of a primary OSA therapy will 
be defined as ≥70% of nights (≥5 of 7 nights/week) by historical report (with investigator 
concurrence) for subjects who use a device for which usage data cannot be retrieved. Receipt 
of a surgical intervention for OSA symptoms that is deemed to be effective will also be 
considered compliant use of a primary OSA therapy. Non-compliant use of a primary OSA 
therapy will be defined as use at a frequency or duration less than that described above, or 
receipt of a surgical intervention that is no longer effective in the absence of compliant use of 
another primary OSA therapy. 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 drugs will be 
prepared in identical opaque gelatin capsules to ensure adequate blinding. All study 
personnel will be blinded to the study treatments. 
5.7 
Prior and Concomitant Therapy 
During the Screening Phase, prior (30 days) and concomitant medication use and any 
medications or devices used for the treatment of OSA since diagnosis will be recorded on the 
case report form (CRF). 
Any medications that are included under the exclusion criteria for entry into the study must 
be discontinued prior to the Baseline visit as specified in Section 4.3 and are prohibited for 
use throughout the study as well. 
Subjects may continue to take their usual medications during the study other than the 
excluded medications described under Section 4.3. All drugs other than study drugs that are 
taken during the course of study (approved or unapproved; prescription, over-the-counter 
[including health and dietary supplements], or illicit drugs) will be documented in the 
concomitant medications CRF. The 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 excluded 
medications described in Section 4.3.  
5.8.2 
Fluid and Food Intake  
Subjects will be instructed to take a single oral daily dose of study drug in the morning, on an 
empty stomach within one hour of awakening. Subjects will also be instructed to abstain 
from eating or drinking (except for water) for 30 minutes after taking the study drug. 
Subjects will be encouraged not to increase caffeine use during the study. 
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The day after the overnight stay at Weeks 4 and 12, study drug will be administered at the 
investigative site with approximately 240 mL water (subjects may receive an additional 
240 mL of water if necessary). 
Subjects will also be given a light breakfast and light lunch at approximate times indicated in 
Appendix 2 and Sections 7.2, 7.4, and 7.7). On days when blood samples for clinical 
laboratory tests are drawn, the blood samples will be drawn prior to breakfast (i.e., fasting). 
On Visits for Weeks 4 and 12, the light breakfast should be served approximately 30 minutes 
after dosing and should be consumed within 15-20 minutes. Caffeine consumption will not 
be allowed during the Baseline and Week 4 and 12 visits.  
5.8.3 
Other Restrictions 
On the nights that PSGs are being conducted, subjects will remain in bed and if they need to 
go to the toilet during the night they will be assisted by the lab tech or other study staff 
member. On the day following the PSG, subjects should be seated in bed in a darkened room 
during the MWT trials (Section 6.12.1). In between the MWT trials subjects will be free to 
move about while staying at the sleep lab. At other times during the study there are no 
restrictions on activity. Cigarette smokers will be allowed to smoke one cigarette in the 
evening prior to initiation of the PSG, one cigarette in the morning at least 1 hour prior to the 
first trial of the MWT, and one cigarette during the day immediately following the end of an 
MWT trial. 
5.9 
Investigational Medicinal Product Treatment Compliance 
Study drug 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. Treatment compliance 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. PK data may 
be used to interpret findings of non-compliance. 
5.10 Packaging and Labeling 
Jazz Pharmaceuticals will provide the clinical sites with a supply of clinical trial material 
(study drug) as described in Section 5.1. Clinical trial material will consist of tablets that will 
be 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 and 
regulations. 
5.11 Storage and Accountability 
The drug product should be stored in the supplied packaging according to the label. 
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The Investigator or qualified designee will maintain accurate records of the receipt of all 
study drugs from Jazz Pharmaceuticals, including the date(s) of receipt. Study drug must be 
kept in a secure area and dispensed as described in Section 6.11. Unused (or partially used) 
supplies must be accounted for on the drug inventory record. The receipt and dispensing of 
new study drug and the collection of used study drug from subjects 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 JZP-110 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 the drug inventory record at the clinical site at study completion, 
one copy of the drug inventory record will be retained by the Investigator/site and the other 
will be retained by Jazz Pharmaceuticals. 
5.12 Investigational Medicinal Product Retention at Study Site 
Investigational medicinal product (JZP-110) does not need to be retained at the study site for 
FDA testing purposes.  
6 
STUDY PROCEDURES 
6.1 
Informed Consent 
All subjects will provide their written informed consent before the performance of any study 
related procedures. Each subject will be given a copy of his or her signed informed consent 
form (ICF). 
Each subject’s chart will have his or her signed ICF for study participation attached to it. 
When the study treatment is completed and the CRF 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 Screening (Visit 1) 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, month and year of birth, year of 
birth, or age at screening), sex, ethnicity, and race. 
6.3 
Medical History  
A complete medical history will be collected for each subject during the Screening Phase. 
The information will include, but is not limited to, concomitant medication use, including 
any medications or devices used for the treatment of OSA since diagnosis; any prior reaction 
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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 OSA, any surgical intervention that was conducted in an attempt to treat OSA, 
and the frequency of use of a primary therapy for OSA (positive airway pressure, oral 
pressure therapy, oral appliance, or upper airway stimulator) or at least 1 month of an attempt 
to use a primary OSA therapy with at least one documented adjustment that was made in an 
attempt to optimize the primary OSA therapy. Any updates to the medical history will be 
assessed at the Baseline Visit (Day -2). 
6.4 
Physical Examination 
A full review of body systems should be obtained for each subject during the Screening 
Phase and at the Final visit (Week 12) or early termination. Physical examinations will 
include a full 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, pulse, 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 encircle at least 80% of the arm circumference. 
Neither the subject nor the observer should talk during the measurement. 
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 measurement should be taken (Pickering et al. 2005). Vital signs will 
be recorded on the CRF. 
The mean of the two or three blood pressure assessments taken at the Screening visit will be 
used to meet entrance criteria to the study. Body temperature, respiratory rate, and blood 
pressure and pulse will be obtained on admission to the site the evenings before the PSG 
nights at Baseline and the end of Weeks 4 and 12; at Week 8; and at the Follow-up visit or at 
Early Termination. 
On the Baseline MWT day, body temperature, respiratory rate, blood pressure and pulse will 
be taken approximately 30 minutes after awakening (prior to the start of the MWT). Blood 
pressure and pulse will also be taken approximately 2, 3, 5, 7, 9 and 11 hours after 
awakening. 
On MWT days at the end of Weeks 4 and 12 (or Early Termination if PSG/MWT is 
performed), body temperature, respiratory rate, blood pressure and pulse will be taken 
approximately 1 hour before dosing (shortly before the first MWT trial). Blood pressure and 
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pulse will be taken at approximately 1, 2, 4, 6, 8 and 10 hours (approximately 10 minutes 
after completion of the last MWT trial) after dosing. The schedule of assessment for vital 
signs during PSG/MWT visits is described in Section 7 and Appendix 2. 
6.6 
24-Hour Ambulatory Blood Pressure Monitoring 
Ambulatory blood pressure monitoring is a non-invasive method of obtaining blood pressure 
readings over a 24-hour period while the subject is in his/her own environment. Subjects will 
undergo 24-hour blood pressure monitoring after discontinuation of excluded medications 
during the Screening Period and at Week 8. Blood pressure and pulse readings taken at 
30 minute intervals will be recorded over a period of 24 hours. A manual with instructions 
for ambulatory blood pressure monitoring will be provided separately. 
6.7 
Electrocardiography 
Standard 12-lead ECGs will be recorded with the subject resting supine for at least 5 minutes. 
ECGs will be performed at Screening, Baseline, and at every clinic visit. The schedule of 
ECG assessment is described in Section 7 and Appendix 2. 
6.8 
Polysomnography (PSG) 
A PSG followed by an MWT will be performed at Baseline and at Weeks 4 and 12 (or Early 
Termination if the subject is willing and able to take study drug for the assessments). If a 
subject is allowed to be rescreened, a repeat PSG and MWT will not be required if the results 
of the previous PSG and MWT in the study meet the current inclusion/exclusion criteria and 
there have been no changes to the medical history, concomitant medications, or primary OSA 
therapy that would likely affect the MWT. 
The PSG and MWT procedures will be performed according to standard protocols, which 
will be provided in a manual to each site. The manual will include all parameters to be 
recorded, methods, and a scoring appendix. Oxygen saturation will be monitored according 
to the study center’s standard procedures. Standard PSG parameters will be recorded. All 
polysomnographic data will be read by a central reader. 
For the purposes of this study, primary OSA therapy includes use of PAP, oral pressure 
therapy, an oral appliance, or an upper airway stimulator. Subjects who are compliant with a 
primary OSA therapy (see Section 5.4) should use their primary OSA therapy during each 
PSG assessment. Subjects who use a primary OSA therapy at a frequency or duration less 
than the compliant definition in Section 5.4 should decide with the clinician/investigator 
whether they will use their primary OSA therapy during all or none of the PSG assessments.  
Subjects who do not have a documented diagnosis of OSA according to ICSD-3 criteria may 
undergo diagnostic testing for OSA during the Screening period if approved by the Medical 
Monitor. 
An experienced sleep technologist must be present to monitor the PSG during PSG nights. 
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6.9 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
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 9). 
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 every clinic visit after their 
Screening visit including the Baseline and Follow-up visits (Appendix 11). 
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 one time. Clinical laboratory tests to be conducted are listed in Table 1. 
The clinical laboratory tests will be performed 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). In addition, any laboratory parameter that is out of range and considered 
clinically significant (as determined by the investigator) at the end of treatment must be re-
evaluated. The investigator will provide an explanation of all clinically significant 
observations. These findings will be reported as adverse events. 
At Screening, the investigator will calculate the estimated creatinine clearance rate 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) 
 
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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Clinical laboratory tests will include the following: 
 
Table 1 List of Laboratory Tests  
Hematology: 
- 
Complete blood count (CBC), 
including platelet count and white 
blood cell count (WBC) with 
differential 
- 
Hemoglobin 
- 
Hematocrit 
 
Urinalysis:  
- 
Appearance 
- 
Bilirubin 
- 
Color 
- 
Glucose 
- 
Ketones 
- 
Nitrite  
- 
Occult blood 
- 
pH 
- 
Protein 
- 
Specific gravity 
- 
Urobilinogen 
- 
 
 
Urine Drug Screen  
- 
Amphetamines 
- 
Barbiturates 
- 
Benzodiazepines 
- 
Cannabinoids 
- 
Cocaine metabolites 
- 
Opiates 
- 
Phencyclidine-PCP 
- 
Methadone 
 
Serum Chemistry: 
- 
Albumin (ALB) 
- 
Alkaline phosphatase (ALK-P) 
- 
Alanine aminotransferase (ALT; 
SGPT) 
- 
Aspartate aminotransferase (AST; 
SGOT) 
- 
Blood urea nitrogen (BUN) 
- 
Calcium (Ca) 
- 
Chloride (Cl) 
- 
Creatinine 
- 
Creatine kinase  
- 
Glucose 
- 
Phosphorus 
- 
Potassium (K) 
- 
Sodium (Na) 
- 
Total bilirubin 
- 
Direct bilirubin 
- 
Total cholesterol 
- 
Total protein 
- 
Triglycerides 
- 
Uric acid 
 
Pregnancy Screen:* 
- 
Serum (at Screening [or 
Rescreening] and following a 
positive urine test) 
- 
Urine (at Baseline and Week 12 or 
Early Termination) 
 
*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 follicle-stimulating hormone [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: 
Screening  
Baseline* and Week 12 
 
3 × 6 mL 
 
 
18 mL 
 
Hematology: 
Screening, Baseline*, Week 12 
 
3 × 4 mL 
 
12 mL 
Serum pregnancy test (for females of 
childbearing potential) 
Screening 
 
1 × 1 mL 
 
1 mL 
Pharmacokinetics: 
1 sample Week 1 
1 sample Week 4 
2 samples Week 8 
 
1 × 4 mL 
1 × 4 mL 
2 × 4 mL 
 
 
4 mL 
4 mL 
8 mL 
 
Approximate total blood volume per 
subject: 
females of childbearing potential 
males and females who are not of 
childbearing potential 
 
 
 
47 mL 
46 mL 
*Required if Baseline Visit occurs outside of the screening window (i.e., >29 days after the 
Screening Visit). Repeat Screening labs may be fasting or nonfasting. 
 
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. 
Blood samples for hematology and serum chemistry tests will be collected while the subject 
is fasting at Screening (or Rescreening) and Week 12 or Early Termination. If the Baseline 
visit occurs outside the of the screening window (i.e., >29 days after the Screening Visit), 
hematology and chemistry tests should be collected at the Baseline visit and may be drawn 
with the subject fasting or nonfasting. Table 2 shows the schedule for collection of blood and 
the total estimated blood volume to be collected during the study.  
Urine samples for urinalysis will be collected at Screening (or Rescreening) and Week 12 or 
Early Termination. A repeat urinalysis should be obtained if the Baseline visit occurs outside 
of the screening window (i.e., >29 days after the Screening Visit).  
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A urine sample for urine drug screen will be obtained at every clinic visit except at the 
Follow-up Visit. Samples collected at Screening (or Rescreening), Baseline, and Week 12 or 
Early Termination will be analyzed. Samples collected at other visits may be analyzed at the 
investigator’s discretion. 
A serum pregnancy test for females of childbearing potential will be performed at Screening 
(or Rescreening), and urine pregnancy tests will be performed at Baseline and Week 12 or 
Early Termination (Table 1). 
6.10.2.2 
Blood Samples for Pharmacokinetic Analysis 
Blood samples to measure plasma JZP-110 concentrations will be collected at four time 
points per subject as described in Table 2 and Section 6.13.1. These blood samples will be 
drawn within the time windows indicated in Section 6.13.1 and dispensed into labeled 
K2EDTA tubes. The actual time of blood collection for all samples will be recorded on the 
CRF. The blood samples will be collected and processed according to the PK lab manual 
provided to the sites and the plasma samples will be shipped to the bioanalytical laboratory 
on dry ice as directed by Jazz Pharmaceuticals. 
The bioanalysis will be performed by a central bioanalytical laboratory: 
6.11 Dispensing Study Drug 
Study drug will be dispensed to subjects at the end of the Baseline visit and at the end of the 
Week 1, 4, and 8 visits 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 the Baseline, Week 1, Week 4, and Week 8 visits. 
Subjects will also be provided with dosing instructions consistent with the restrictions 
described in Section 5.8. On the day after the overnight PSG and on the morning of the 
MWT at Weeks 4 and 12 (or Early Termination if PSG/MWT is performed), study drug will 
be administered by qualified study site personnel as described in Section 7 and Appendix 2. 
6.12 Efficacy Assessments 
6.12.1 
Maintenance of Wakefulness Test (MWT) 
The MWT is the standard objective measure of an individual’s ability to remain awake 
during the daytime in a darkened, quiet environment and is commonly used to assess 
response to treatment (Doghramji et al. 1997, Mitler et al. 1982, AASM 2014). A 5-trial, 
40-minute MWT will be performed at Baseline and at the Week 4 and 12 visits (or Early 
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Termination if the subject is willing and able to take study drug for the assessments) on the 
morning after an overnight PSG according to a standard protocol, which will be provided in a 
manual to each site.  
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 5 40-minute trials separated by 2-hour 
intervals. Following a light breakfast, the subject will be allowed to relax prior to initiating 
the first MWT trial. The first MWT trial should occur approximately 2 hours after “lights on” 
at the Baseline visit and approximately 1 hour after dosing with study drug at all other 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. 
6.12.2 
Epworth Sleepiness Scale (ESS) 
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 5). Subjects will be asked to 
complete the ESS with regard to the level of sleepiness they experienced over the past 7 days 
at the Baseline and Week 1, 4, 8, and 12 visits (or Early Termination). It provides a measure 
of a person’s general level of daytime sleepiness, or their average sleep propensity in daily 
life. The ESS is a validated measure with high specificity and sensitivity for assessing 
subjective sleepiness (Johns 1991, 2000; Broderick et al. 2013).  
6.12.3 
Clinician Global Impression of Severity (CGIs)  
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 12). 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 at Baseline.  
6.12.4 
Clinician Global Impression of Change (CGIc)  
The CGIc is a 7-point Likert-type rating scale and a widely used assessment to assess 
efficacy in clinical drug trials. Investigators will rate their impression of any change in the 
subject’s condition from baseline (before the subject started treatment) on a 7-point scale 
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ranging from 1 = very much improved to 7 = very much worse at the Week 1, 4, 8, and 12 
visits (or Early Termination) (Appendix 13). 
6.12.5 
Patient Global Impression of Change (PGIc)  
The PGIc is a 7-point Likert-type rating scale and a widely used measure to assess efficacy in 
clinical drug trials. Subjects will rate the change in their condition since they started 
treatment on a 7-point scale ranging from 1 = very much improved to 7 = very much worse at 
the Week 1, 4, 8, and 12 visits (or Early Termination) (Appendix 14). 
6.12.6 
Functional Outcomes of Sleep Questionnaire (FOSQ-10) 
The FOSQ is a 30-item disease specific quality of life questionnaire to determine functional 
status in adults; measures are designed to assess the impact of disorders of excessive 
sleepiness on multiple activities of everyday living and the extent to which these activities 
are improved by effective treatment (Weaver et al. 1997). The FOSQ-10 is a short version of 
the original 30-item FOSQ that has been shown to perform similarly to the longer version 
(Chasens et al. 2009). The FOSQ-10 has been shown to exhibit high internal consistency, and 
effect sizes and pre- and post-treatment differences that are highly correlated with the longer 
version (Chasens et al. 2009). Subjects will complete the FOSQ-10 at the Baseline and Week 
1, 4, 8, and 12 visits (or Early Termination) (Appendix 6). 
6.12.7 
36-Item Short Form Health Survey Version 2 (SF-36v2)  
The SF-36v2 is a multi-purpose, short-form health survey with 36 questions. It yields an 8-
scale profile of functional health and well-being scores as well as psychometrically-based 
physical and mental health summary measures and a preference-based health utility index 
(Hays & Stewart 1992, Ware & Sherbourne 1992) (Appendix 7). Subjects will complete the 
SF-36v2 at the Baseline and Week 4, 8, and 12 visits (or Early Termination) 
6.12.8 
 EuroQoL EQ-5D-5L 
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome that 
includes a descriptive system consisting of 5 dimensions (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression) and an EQ visual analogue scale (VAS) (EuroQol 
Group, 2013). It is applicable to a wide range of health conditions and treatments, it provides 
a simple descriptive profile and a single index value for health status. The EQ-5D-5L 
includes five levels of severity for each of the 5 dimensions of the descriptive system and 
was developed to improve the instrument’s reliability and sensitivity and to reduce ceiling 
effects. Subjects will complete the EQ-5D-5L at the Baseline and Week 1, 4, 8, and 12 visits 
(or Early Termination) (Appendix 8). 
6.12.9 
Work Productivity and Activity Impairment Questionnaire: Specific Health 
Problem V2.0 (WPAI:SHP) 
The WPAI:SHP questionnaire is a 6-item self-administered questionnaire that measures work 
time missed and work and activity impairment because of a specified health problem during 
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the past 7 days. The WPAI:SHP will be used with “OSA” as the specified health problem. 
The validity of the WPAI has been established in a number of diseases (Reilly et al. 1993). 
Subjects will complete the WPAI:SHP at the Baseline and Week 1, 4, 8, and 12 visits (or 
Early Termination) (Appendix 10). 
6.12.10 Primary OSA Therapy Use  
For the purposes of this study, primary OSA therapy is defined as use of PAP, oral pressure 
therapy, an oral appliance, or an upper airway stimulator. Subjects who report using a 
primary OSA therapy will have information regarding whether they used their device each 
night and the duration of nightly use extracted from the data download from their device or 
memory card at each clinic visit from Screening and through the Final Visit at Week 12. 
Subjects who report using a device for which usage data cannot be retrieved will record their 
primary OSA therapy usage and the estimated duration of use (more than half of the night, 
less than half of the night, or don’t know) on a daily basis from Screening and through the 
Final Visit at Week 12. Subjects who report not using a primary OSA therapy at Screening 
will be asked to confirm that they have continued to not use a primary OSA therapy. The 
study staff will review the information that each subject provides regarding their primary 
OSA therapy use at each study visit and will discuss it with the subject at each phone contact. 
A stable level of use of a primary OSA therapy is defined as a change of <30% of the number 
of nights used per week. 
Subjects will be encouraged to stay on their current primary OSA therapy at the same level of 
use throughout the study. 
6.13 Pharmacokinetic Assessments 
6.13.1 
Blood Samples 
Four blood samples will be collected from each subject for PK evaluations. One sample will 
be collected at Week 1 and two samples will be collected at Week 8 (one sample at the 
beginning of the visit and one sample at the end of the visit before the subject leaves the 
clinic) within 1-8 hours after dosing to characterize the absorption phase of the PK curve. 
One sample will be collected at Week 4 within 8-12 hours after dosing on the day that 
subjects check in for the overnight PSG to characterize the trough of the PK curve. PK 
samples should be taken within the windows indicated. The actual time of blood collection 
for all samples and the exact time that the subject dosed on each morning that samples are 
collected will be recorded. To the extent possible, investigators should schedule the Week 8 
clinic visit in the morning to facilitate characterization of the absorption phase of the PK 
curve. 
6.13.2 
Pharmacokinetic Parameters  
Four blood samples will be collected from each subject for an assessment of population PK 
parameters using sparse sampling. These data may be pooled with PK data from other 
JZP-110 studies to establish a population PK model. This approach is expected to permit 
characterization of the JZP-110 PK profile, specifically in the OSA patient population 
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6.14 Adverse Event Reporting 
6.14.1 
Adverse Events (AEs) 
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) abnormal clinically 
significant laboratory values. 
• Symptoms of the underlying medical condition of OSA are not considered as adverse 
events unless there is an exacerbation of the symptoms from baseline. 
• During the study, clinically significant adverse changes in ECGs, routine laboratory 
tests, and physical examinations are considered AEs. Any subject complaint 
associated with such an abnormal finding will also be reported as an AE.  
All AEs, whether observed by the investigator, reported by the subject, determined from 
laboratory findings, or other means, will be recorded on the AE CRF, with each individual 
AE to be listed as a separate entry on the AE CRF. 
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, and on the 
AE CRF. Each AE is to be evaluated for duration, severity, seriousness, and causal 
relationship to the study drug or procedure.  
6.14.1.1 
Severity Assessment 
Adverse events will be classified by the investigator as mild, moderate, or severe as defined 
below. When the severity of the AE changes over time, the change in severity will be 
recorded on the AE CRF as a new AE, and the original AE will stop when the new AE starts. 
Mild 
Symptom(s) barely noticeable to subject or does not make subject 
uncomfortable; does not influence performance or functioning; prescription 
drug not ordinarily needed for relief of symptom(s) but may be given. 
Moderate 
Symptom(s) of a sufficient severity to make subject uncomfortable; 
performance of daily activities is influenced; treatment for symptom(s) may 
be needed. 
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Severe 
Symptom(s) causes severe discomfort; symptom(s) incapacitate or 
significantly affect subject’s daily life; treatment for symptom(s) may be 
given and/or subject hospitalized.  
 
6.14.1.2 
Serious Adverse Events and Seriousness Assessment 
An SAE is an AE that fulfills any of the following criteria, as per Title 21 CFR 312.32 and 
ICH E2A.II.B. Events meeting the following seriousness criteria must be reported to Jazz 
Pharmaceuticals or its designee using the SAE Report form within 24 hours of the site being 
notified of the event. The event must also be entered on the AE CRF. 
• 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 medically significant or requires intervention to prevent one of the outcomes listed 
above   
− 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. 
• Suspected transmission of an infectious agent via a medicinal product [for EU sites only; 
EMA Guideline on Good Pharmacovigilance Practices (GVP) Module VI] 
 
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. 
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Overdose, medication errors, and drug misuse of the study drug are SAEs only if any of the 
seriousness criteria are met. Details of signs and symptoms, clinical management, and 
outcome should be reported. 
6.14.1.3 
Causal Relationship to Study Drug or Procedure 
The investigator’s assessment of an AE’s relationship to study drug or 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 
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 AE follows a reasonable temporal sequence from administration 
of the study drug or procedure and at least one of the following 
instances of clinical evidence: 
• Follows a known or suspected response pattern to the 
study drug or procedure. 
• Is confirmed by improvement upon stopping the study 
drug or procedure or decreasing the dose (dechallenge). 
• Reappears upon repeated exposure (rechallenge) if 
medically appropriate. 
There is a reasonable possibility that the study drug or procedure 
caused the event—i.e., there is evidence to suggest a causal 
relationship. In such case, the AE is considered an adverse reaction 
(AR). A suspected AR has a lesser degree of certainty about causality 
than an AR. 
Not 
Related 
to Study 
Drug or 
Procedure 
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. 
A reasonable possibility or clinical evidence that the study drug or 
procedure caused the event is lacking. 
 
6.14.1.4 
Other Immediately Reportable Experiences 
The following immediately reportable experiences may occur during participation in this 
clinical trial and must be entered on the AE CRF and SAE Report form and reported within 
24 hours of first knowledge of the event by study personnel to the appropriate Jazz 
Pharmaceuticals contact or designee: 
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• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) with a 3-fold or 
greater elevation above the upper limit of normal (ULN) in addition to an elevation of 
serum total bilirubin greater than two times the ULN, with no other identifiable etiology 
• Liver enzyme (AST, ALT) value greater than or equal to 5 times the ULN 
 
As with other SAEs (Section 6.14.1.2), immediately reportable experiences must be reported 
on the SAE report form, which should be completed as thoroughly as possible and signed by 
the investigator or his/her designee before transmittal to the contact provided on the form. 
The investigator must provide his/her assessment of causality to study drug or 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.” If 
the investigator’s assessment of causality changes, then a follow-up SAE form must be 
submitted. 
The source document to determine expectedness of an SAE is the JZP-110 Investigator’s 
Brochure. 
6.14.1.5 
Adverse Events Recording and Reporting 
The investigator must report to Jazz Pharmaceuticals or its designee all AEs 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. 
6.14.1.6 
Follow-up of Adverse Events and Serious Adverse Events 
Adverse events 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. 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 stabilizes, or the subject is lost to follow up. If resolved, a resolution 
date should be provided, and for SAEs, a follow-up SAE Report form must be submitted 
indicating 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 
Post-Study Reporting Requirements 
If an investigator becomes aware of an SAE within 30 days after the last dose of study 
medication, the event must be documented and reported as described in Section 6.14.1.2. 
Any AE or SAE assessed as related to study drug or procedure by the investigator must be 
reported regardless of time after study termination. 
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6.14.3 
Pregnancy   
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 should be used to report the pregnancy to Jazz Pharmaceuticals or its designee. 
Pregnancy of a subject or a male subject’s partner is an immediately reportable event and 
should be reported within 24 hours of first knowledge of the event by study personnel to the 
appropriate Jazz Pharmaceuticals contact or 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 
should 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 the immediate medical management of the subject or to ensure subject safety 
in the trial. 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. 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 Director/Medical Monitor will discuss with the 
Investigator the rationale for the request. If the treatment assignment is unblinded, then any 
broken blinding code must be clearly justified and explained by a comment in the source 
documentation, along with the date on which the code was broken and the identity of the 
person authorizing the unblinding. In addition, the study biostatistician will document the 
occurrence of investigator-initiated unblinding in the section of “Documentation of Statistical 
Method” in the final study report. 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). The blinded SAE will be reviewed by 
Jazz Pharmaceuticals Drug Safety to assess the expectedness and relationship to the study 
drugs and to assess whether there is a potential safety concern for the individual subject or 
the other subjects in the study. 
6.15 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 discontinued from the study. 
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• Suicide risk reported or assessed by C-SSRS 
• 3-fold or greater elevation above the upper limit of normal (ULN) of alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) accompanied by an 
elevation of serum total bilirubin greater than two times the ULN 
• Liver enzyme (AST, ALT) value greater than or equal to 5 times the ULN 
• Creatinine ≥2 mg/dL 
• Positive urine drug screen 
• Positive pregnancy test 
• Subject demonstrates a QTc value above 500 msec (determinations should be based on at 
least two ECG recordings performed on drug in close proximity) 
• 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 (same assessments as those performed at the final study visit). 
Subjects should be asked to return 2 weeks later for a safety follow-up visit.  
The specific reason for the discontinuation should be carefully documented on the 
termination CRF. 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 CRF. 
6.15.1 
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 CRF 
page and notify the Jazz Pharmaceuticals immediately. All subjects who terminate from the 
study early should undergo all final study visit assessments as indicated in Section 7.9. 
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. 
6.15.2 
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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6.16 Appropriateness of Measurements 
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 (Doghramji et al. 
1997, Mitler et al. 1982). The ESS is a validated measure with high specificity and sensitivity 
for assessing subjective sleepiness (Johns 1991, 2000; Broderick et al. 2013). Additionally, 
the CGIc, PCIc, SF-36v2, FOSQ-10, EQ-5D-5L and the WPAI:SHP have been used 
extensively in clinical trials to assess efficacy and quality of life. 
Sparse samples (4 samples per subject) are being drawn at various time points following drug 
administration to use a population approach to characterize the PK profile of JZP-110 in the 
OSA patient population.  
The use of vital signs, including 24-hour ambulatory monitoring, 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). 
7 
STUDY ACTIVITIES 
Visit windows and approximate times for assessments are provided below and in Appendix 1 
and Appendix 2. 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 (Section 6.1). 
7.1 
Screening Clinic Visit(s) 
7.1.1 
Screening Visit 1, Days -31 to -3 
Subjects may be screened over a maximum period of 29 days.  
• Review the inclusion (Section 4.2) and exclusion (Section 4.3) criteria. 
• Obtain demographics (Section 6.2) and a medical history, including details of OSA 
symptoms, diagnosis, and any past and current primary and adjunctive therapies for 
OSA (Section 6.3). 
• Record all prior and concomitant medications, including OTC medications, health, 
and dietary supplements taken during the 30 days before Screening; also record any 
medications or devices used for the treatment of OSA since diagnosis (Sections 4.3 
and 5.7). 
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• 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) (Section 6.4). 
• Obtain vital signs (systolic and diastolic blood pressure, pulse and respiratory rate, 
and body temperature), including at least two sets of blood pressure and pulse rate 
measurements in the seated position, as described in Section 6.5. 
• Obtain a 12-lead ECG after the subject has been resting supine for at least 5 minutes 
(Section 6.7). 
• Administer the Columbia-Suicide Severity Rating Scale (C-SSRS) 
Baseline/Screening version and record results (Section 6.9). 
• Complete clinical laboratory tests (Section 6.10.2.1 and Table 1). 
o Obtain fasting blood samples for serum chemistry and hematology tests including 
a serum pregnancy test for all females of childbearing potential (Table 1 see 
footnote for definitions of childbearing potential). 
o Obtain a urine sample for urinalysis and urine drug screens  
• Provide a light breakfast after blood samples are collected. 
• After screening procedures have been completed and eligibility criteria have been 
confirmed, provide eligible subjects with instructions on how to discontinue any 
excluded medications (Section 4.3).  
• If the subject uses a primary OSA therapy, instruct the subject to bring the device or 
memory card to the next clinic visit for review of his or her primary OSA therapy use. 
If the subject does not use a primary OSA therapy, from which the usage data can be 
extracted or does not use a primary OSA therapy, instruct the subject on reporting 
daily use (or lack of use) as appropriate. Remind the subject to continue to use his or 
her primary OSA therapy and to maintain the same level of use during the study 
(Section 6.12.10). 
• Dispense the 24-hour ambulatory blood pressure monitoring equipment after 
demonstrating how it should be used. Provide instructions for use, guidance for when 
and how the subject should record 24-hour ambulatory blood pressure following 
medication washout, and instructions for returning the equipment. 
• Schedule a Baseline visit after the Investigator has thoroughly reviewed results of all 
screening procedures and has confirmed all eligibility criteria. 
7.1.2 
Rescreening  
Subjects may be allowed to rescreen if approved by the Medical Monitor. 
Subjects who are approved for rescreening must be re-consented and must repeat all 
screening procedures in Section 7.1.1. For subjects who are being rescreened, a repeat PSG 
and MWT are not required at Visit 2 if the results of the previous PSG and MWT meet the 
current inclusion/exclusion criteria and there have been no changes to the medical history, 
concomitant medications, or primary OSA therapy that would likely affect the MWT results. 
 
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7.2 
Baseline Clinic Visit  
Visit 2, Days -2 and -1 
After a subject has successfully completed the screening procedures he or she will return to 
the investigative site for an overnight stay to complete his or her baseline procedures. If the 
subject is being rescreened and does not require a repeat PSG and MWT, perform all other Visit 
2 procedures listed below (with the exception of the repeated vital signs during the MWT 
conduct and the provision of meals) during a single visit on one day. If a subject is being 
rescreened and does require a repeat PSG and MWT, perform all procedures for Visit 2 as listed 
below. 
 
On admission to the investigative site in the evening (Day -2), complete the following: 
• Obtain weight in ordinary indoor clothes (without shoes). 
• Obtain a urine sample for a pregnancy test for all females of childbearing potential 
(see footnote of Table 1 for definitions of childbearing potential). 
• Obtain a urine sample for a urine drug screen (Section 6.10.2.1 and Table 1). 
• Obtain vital signs (systolic and diastolic blood pressure, pulse and respiratory rate, 
and body temperature), including at least two sets of blood pressure and pulse rate 
measurements in the seated position, as described in Section 6.5. 
• Administer the C-SSRS Since Last Visit version and record the results (Section 6.9). 
• 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 tests and 
a urine sample for urinalysis (Section 6.10.2.1 and Table 1). Record if the samples 
were collected with the subject fasted or nonfasted. 
• Review and record primary OSA therapy use frequency from the subject’s device or 
memory card, or frequency of use (or lack of use) as reported by the subject. Remind 
the subject to continue to use his or her primary OSA therapy and to maintain the 
same level of use during the study. If the subject uses a primary OSA therapy from 
which the usage data can be extracted, instruct the subject to bring the device or 
memory card to the next clinic visit for review of primary OSA therapy use (Section 
6.12.10) If the subject does not use a primary OSA therapy from which usage data 
can be extracted or does not use a primary OSA therapy, instruct the subject on 
reporting use as appropriate. 
• Record the date(s) that excluded medications were discontinued (Sections 4.3 and 
5.7) and any other changes to concomitant medications since screening on the 
concomitant medication CRF. 
• Assess if there are any updates to the subject’s medical history (Section 6.3). 
• Prepare subject for the overnight PSG. 
• At “lights out” initiate the overnight PSG (Section 6.8). 
On the morning of the following day (Day -1), complete the following procedures. The time 
for these procedures should occur relative to “lights on” (see Appendix 2 for an example 
schedule). 
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• “Lights on” (waking). 
• Approximately 30 minutes after “lights on,” obtain vital signs (systolic and diastolic 
blood pressure, pulse and respiratory rate, and body temperature), including at least 
two sets of blood pressure and pulse rate measurements in the seated position, as 
described in Section 6.5. 
• Approximately 1.5 hours after “lights on,” subjects should be served a light breakfast. 
Breakfast should be completed within 15 to 20 minutes (Section 5.8.2). 
• Approximately 1 hour and 50 minutes after “lights on,” obtain at least two sets of 
blood pressure and pulse rate measurements in the seated position, as described in 
Section 6.5. 
• Approximately 2 hours after “lights on,” initiate the first trial of the MWT 
(Section 6.12.1). 
• Approximately 2 hours and 50 minutes after “lights on,” obtain at least two sets of 
blood pressure and pulse rate measurements in the seated position, as described in 
Section 6.5. 
• Approximately 3 hours after “lights on,” obtain a 12-lead ECG after the subject has 
been resting supine for at least 5 minutes (Section 6.7). 
• Administer the following questionnaires to the subject in the order specified below: 
− ESS (Section 6.12.2) 
− FOSQ-10 (Section 6.12.6) 
− SF-36v2 (Section 6.12.7) 
− EQ-5D-5L (Section 6.12.8) 
− WPAI:SHP questionnaire (Section 6.12.9) 
• Complete the CGIs (Section 6.12.3). 
• Approximately 4 hours after “lights on,” initiate the second trial of the MWT.  
• Subjects should be served a light lunch immediately after the second or third trial of 
the MWT. 
• Approximately 5 hours after “lights on,” obtain at least two sets of blood pressure and 
pulse rate measurements in the seated position, as described in Section 6.5. 
• Approximately 6 hours after “lights on,” initiate the third trial of the MWT. 
• Approximately 7 hours after “lights on,” obtain at least two sets of blood pressure and 
pulse rate measurements in the seated position, as described in Section 6.5. 
• Approximately 8 hours after “lights on,” initiate the fourth trial of the MWT. 
• Approximately 9 hours after “lights on,” obtain two sets of blood pressure and pulse 
rate measurements in the seated position, as described in Section 6.5. 
• Approximately 10 hours after “lights on,” initiate the fifth trial of the MWT. 
• Approximately 11 hours after “lights on,” obtain at least two sets of blood pressure 
and pulse rate measurements in the seated position, as described in Section 6.5. 
• Record all AEs on the AE CRF that occurred after the ICF was signed (Section 6.14).  
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• Record all concomitant medications on the concomitant medications CRF that were 
taken after the ICF was signed (Section 5.7). 
• Review the inclusion (Section 4.2) and exclusion (Section 4.3) criteria, including 
MWT and ESS results and medical history to determine the subject’s eligibility to 
continue participating in the study. 
• Randomize to study treatment (access IVRS/IWRS). 
• Dispense study drug and instruct subject on the daily dose administration to begin on 
the following morning (Day 1) (Section 6.11). 
• Schedule the next return clinic visit.  
 
7.3 
End of Week 1 Visit 
Visit 3, Day 7 (-1 and +2 days) 
• Obtain weight in ordinary indoor clothes (without shoes). 
• Obtain a urine sample for a urine drug screen (Section 6.10.2.1 and Table 1). 
• Obtain vital signs (systolic and diastolic blood pressure, pulse and respiratory 
rate, and body temperature), including at least two sets of blood pressure and 
pulse rate measurements in the seated position, as described in Section 6.5. 
• Obtain a 12-lead ECG after the subject has been resting supine for at least 5 
minutes. (Section 6.7) 
• Administer the C-SSRS Since Last Visit version and record the results (Section 
6.9). 
• Obtain a single PK sample (1-8 hours postdose) and record the exact time of 
collection and record the exact time that the subject dosed that morning 
(Section 6.13.1). 
• Collect study drug and assess compliance (Section 5.9). 
• Review and record primary OSA therapy use from the subject’s device or 
memory card or frequency of use (or lack of use) as reported by the subject. 
Remind the subject to continue to use their primary OSA therapy and to maintain 
the same level of use during the study. If the subject uses a primary OSA therapy, 
instruct the subject to bring the device or memory card to the next clinic visit for 
review of primary OSA therapy use. If the subject does not use a primary OSA 
therapy from which usage data can be extracted or does not use a primary OSA 
therapy, instruct the subject on reporting use as appropriate (Section 6.12.10). 
• Administer the following questionnaires to the subject in the order specified below: 
• ESS (Section 6.12.2) 
• PGIc (Section 6.12.5) 
• FOSQ-10 (Section 6.12.6) 
• EQ-5D-5L (Section 6.12.8) 
• WPAI:SHP questionnaire (Section 6.12.9) 
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• Record all AEs on the AE CRF that occurred since the last visit or phone contact 
(Section 6.14). 
• Record all concomitant medications on the concomitant medications CRF that 
were taken after the last visit or phone contact (Section 5.7). 
• Complete the CGIc (Section 6.12.4). 
• Dispense study drug and instruct subject on the daily dose administration to begin 
on the following morning (Section 6.11). 
• Schedule the next Phone Contact times and return clinic visit.  
7.4 
End of Week 4 Clinic Visit 
Visit 6, Days 27 & 28 (±3 days) 
On admission to the investigative site in the evening on Day 27 (±3), complete the following: 
• Obtain weight in ordinary indoor clothes (without shoes). 
• Obtain a urine sample for a urine drug screen (Section 6.10.2.1 and Table 1). 
• Obtain vital signs (systolic and diastolic blood pressure, pulse and respiratory rate, 
and body temperature), including at least two sets of blood pressure and pulse rate 
measurements in the seated position, as described in Section 6.5. 
• Administer the C-SSRS Since Last Visit version and record the results (Section 6.9). 
• Obtain a single PK sample (8-12 hours postdose) and record the exact time of 
collection and record the exact time that the subject dosed that morning 
(Section 6.13.1). 
• Collect study drug and assess compliance (Section 5.9). 
• Review and record primary OSA therapy use from the subject’s device or memory 
card or frequency of use (or lack of use) as reported by the subject. Remind the 
subject to continue to use their primary OSA therapy and to maintain the same level 
of use during the study. If the subject uses a primary OSA therapy, instruct the 
subject to bring the device or memory card to the next clinic visit for review of 
primary OSA therapy use. If the subject does not use a primary OSA therapy from 
which usage data can be extracted or does not use a primary OSA therapy, instruct the 
subject on reporting use as appropriate (Section 6.12.10). (This assessment may be 
performed on either day of this visit.) 
• Prepare the subject for the PSG. 
• “Lights out” and initiate the overnight PSG (Section 6.8). 
On the morning of the following day, complete the following procedures. The time for these 
procedures should occur relative to dosing (see Appendix 2 for an example schedule). 
• “Lights on” (waking) should occur approximately 1 hour before dosing. 
• Approximately 30 minutes before dosing, obtain vital signs (systolic and diastolic 
blood pressure, pulse and respiratory rate, and body temperature), including at least 
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two sets of blood pressure and pulse rate measurements in the seated position, as 
described in Section 6.5. 
• Administer study drug to the subject (dosing) on an empty stomach at least 1 hour 
after waking (Section 5.8.2). 
• Approximately 30 minutes after dosing, subjects should be served a light breakfast. 
Breakfast should be completed within 15 to 20 minutes (Section 5.8.2). 
• Approximately 50 minutes after dosing, obtain at least two sets of blood pressure and 
pulse rate measurements in the seated position, as described in Section 6.5. 
• Approximately 1 hour after dosing, initiate the first trial of the MWT 
(Section 6.12.1). 
• Approximately 1 hour and 50 minutes after dosing, obtain at least two sets of blood 
pressure and pulse rate measurements in the seated position, as described in 
Section 6.5. 
• Approximately 2 hours after dosing, obtain a 12-lead ECG after the subject has been 
resting supine for at least 5 minutes. (Section 6.7) 
• Administer the following questionnaires to the subject in the order specified below: 
• ESS (Section 6.12.2) 
• PGIc (Section 6.12.5) 
• FOSQ-10 (Section 6.12.6) 
• SF-36v2 (Section 6.12.7)  
• EQ-5D-5L (Section 6.12.8) 
• WPAI:SHP questionnaire (Section 6.12.9) 
• Approximately 3 hours after dosing, initiate the second trial of the MWT. 
• Subjects should be served a light lunch immediately after the second or third trial of 
the MWT. 
• Approximately 4 hours after dosing, obtain at least two sets of blood pressure and 
pulse rate measurements in the seated position, as described in Section 6.5. 
• Approximately 5 hours after dosing, initiate the third trial of the MWT. 
• Approximately 6 hours after dosing, obtain at least two sets of blood pressure and 
pulse rate measurements in the seated position, as described in Section 6.5. 
• Approximately 7 hours after dosing, initiate the fourth trial of the MWT. 
• Approximately 8 hours after dosing, obtain at least two sets of blood pressure and 
pulse rate measurements in the seated position, as described in Section 6.5. 
• Approximately 9 hours after dosing, initiate the fifth trial of the MWT. 
• Approximately 10 hours after dosing, obtain at least two sets of blood pressure and 
pulse rate measurements in the seated position, as described in Section 6.5. 
• Record all AEs on the AE CRF that occurred since the last visit or phone contact 
(Section 6.14). 
• Record all concomitant medications on the concomitant medications CRF that were 
taken after the last visit or phone contact (Section 5.7). 
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• Complete the CGIc (Section 6.12.4). 
• Dispense study drug and instruct subject on the daily dose administration to begin on 
the following morning (Section 6.11). 
• Schedule the next Phone Contact times and return clinic visit. To the extent possible, 
the Week 8 clinic visit should be scheduled in the morning to facilitate 
characterization of the absorption phase of the PK curve. 
7.5 
Phone Contact at the end of Weeks 2, 3, 5, 6, 7, 9, 10, and 11 
Visits 
4 
5 
7 
8 
9 
11 
12 
13 
Days 
14±3 
21±3 
35±3 
42±3 
49±3 
63±3 
70±3 
77±3 
Weeks 
2 
3 
5 
6 
7 
9 
10 
11 
 
• Record all AEs on the AE CRF that occurred since the last visit or phone contact 
(Section 6.14). 
• Record all concomitant medications on the concomitant medications CRF that were 
taken after the last visit or phone contact (Section 5.7). 
• If the subject uses a primary OSA therapy, from which the usage data can be 
extracted, instruct the subject to bring the device or memory card to the next clinic 
visit for review of his/her primary OSA therapy use. If the subject does not use a 
primary OSA therapy from which usage data can be extracted or does not use a 
primary OSA therapy, instruct the subject on reporting use as appropriate (Section 
6.12.10). 
• Remind the subject of the next Phone Contact time or return clinic visit. 
7.6 
End of Week 8 Clinic Visit 
Visit 10, Day 56 (±3 days) 
• Obtain weight in ordinary indoor clothes (without shoes). 
• Obtain a urine sample for a urine drug screen (Section 6.10.2.1 and Table 1). 
• Obtain vital signs (systolic and diastolic blood pressure, pulse and respiratory rate, 
and body temperature), including at least two sets of blood pressure and pulse rate 
measurements in the seated position, as described in Section 6.5. 
• Obtain a 12-lead ECG after the subject has been resting supine for at least 5 minutes 
(Section 6.7). 
• Obtain two PK samples within 1-8 hours postdose (one sample at beginning of visit 
and one sample at the end of the visit before the subject leaves the clinic) and record 
the exact time of collection and the exact time that subject dosed that morning 
(Section 6.13). 
• Collect study drug and assess compliance. 
• Review and record primary OSA therapy use from the subject’s device or memory 
card, or frequency of use (or lack of use) as reported by the subject. Remind the 
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subject to continue to use their primary OSA therapy and to maintain the same level 
of use during the study. If the subject uses a primary OSA therapy, instruct the 
subject to bring the device or memory card to the next clinic visit for review of 
primary OSA therapy use. If the subject does not use a primary OSA therapy from 
which usage data can be extracted or does not use a primary OSA therapy, instruct the 
subject on reporting use as appropriate (Section 6.12.10).  
• Administer the following questionnaires to the subject in the order specified below: 
− ESS (Section 6.12.2) 
− PGIc (Section 6.12.5) 
− FOSQ-10 (Section 6.12.6) 
− SF-36v2 (Section 6.12.7) 
− EQ-5D-5L (Section 6.12.8) 
− WPAI:SHP questionnaire (Section 6.12.9) 
• Administer the C-SSRS Since Last Visit version and record the results (Section 6.9). 
• Record all AEs on the AE CRF that occurred since the last visit or phone contact 
(Section 6.14). 
• Record all concomitant medications on the concomitant medications CRF that were 
taken after the last visit or phone contact (Section 5.7). 
• Complete the CGIc (Section 6.12.4). 
• Dispense study drug and instruct subject on the daily dose administration to begin on 
the following morning (Section 6.11). 
• Dispense the 24-hour ambulatory blood pressure monitoring equipment after 
demonstrating how it should be used. Provide instructions for use and for returning 
the equipment. 
• Schedule the next Phone Contact times and return clinic visit. 
• Assess whether the subject is interested in participating in the Open-Label Safety 
Study (14-005). If the subject is interested, the Investigator should provide the subject 
with a copy of the 14-005 ICF for their review prior to the Final Week 12 visit in this 
study. 
7.7 
Final Clinic Visit Week 12  
Visit 14, Days 83 & 84 (±3 days) 
On admission to the investigative site in the evening, complete the following: 
• Obtain weight in ordinary indoor clothes (without shoes). 
• Obtain a urine sample for a pregnancy test for all females of childbearing potential 
(Section 6.10, Table 1 see footnote for definitions of childbearing potential). 
• Obtain a urine sample for urinalysis and urine drug screens (Section 6.10.2.1 and 
Table 1). 
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• Obtain vital signs (systolic and diastolic blood pressure, pulse and respiratory rate, 
and body temperature), including at least two sets of blood pressure and pulse rate 
measurements in the seated position, as described in Section 6.5. 
• Administer the C-SSRS Since Last Visit version and record the results (Section 6.9) 
• Collect study drug and assess compliance (Section 5.9). 
• Review and record primary OSA therapy use from the subject’s device or memory 
card, or frequency of use (or lack of use) as reported by the subject (Section 6.12.10). 
(This assessment may be performed on either day of this visit.) 
• Prepare the subject for the PSG. 
• “Lights out” and initiate the overnight PSG (Section 6.8). 
On the morning of the following day, complete the following procedures. The time for these 
procedures should occur relative to dosing (see Appendix 2 for an example schedule). 
• “Lights on” (waking) should occur approximately 1 hour before dosing. 
• Approximately 30 minutes before dosing, obtain vital signs (systolic and diastolic 
blood pressure, pulse and respiratory rate, and body temperature), including at least 
two sets of blood pressure and pulse rate measurements in the seated position, as 
described in Section 6.5. 
• Obtain fasting blood samples for serum chemistry and hematology tests (see 
Section 6.10.2.1 and Table 1) 
• Administer study drug to the subject (dosing) on an empty stomach at least 1 hour 
after waking (Section 5.8.2). 
• Approximately 30 minutes after dosing subjects should be served a light breakfast. 
Breakfast should be completed within 15 to 20 minutes (Section 5.8.2). 
• Approximately 50 minutes after dosing, obtain at least two sets of blood pressure and 
pulse rate measurements in the seated position, as described in Section 6.5. 
• Approximately 1 hour after dosing, initiate the first trial of the MWT 
(Section 6.12.1). 
• Approximately 1 hour and 50 minutes after dosing, obtain at least two sets of blood 
pressure and pulse rate measurements in the seated position, as described in 
Section 6.5. 
• Approximately 2 hours after dosing, obtain a 12-lead ECG after the subject has been 
resting supine for at least 5 minutes (Section 6.7). 
• Administer the following questionnaires to the subject in the order specified below: 
− ESS (Section 6.12.2) 
− PGIc (Section 6.12.5) 
− FOSQ-10 (Section 6.12.6) 
− SF-36v2 (Section 6.12.7) 
− EQ-5D-5L (Section 6.12.8) 
− WPAI:SHP questionnaire (Section 6.12.9) 
• Approximately 3 hours after dosing, initiate the second trial of the MWT. 
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• Subjects should be served a light lunch immediately after the second or third trial of 
the MWT. 
• Approximately 4 hours after dosing, obtain at least two sets of blood pressure and 
pulse rate measurements in the seated position, as described in Section 6.5. 
• Approximately 5 hours after dosing, initiate the third trial of the MWT. 
• Approximately 6 hours after dosing, obtain  at least two sets of blood pressure and 
pulse rate measurements in the seated position, as described in Section 6.5. 
• Approximately 7 hours after dosing, initiate the fourth trial of the MWT. 
• Approximately 8 hours after dosing, obtain at least two sets of blood pressure and 
pulse rate measurements in the seated position, as described in Section 6.5. 
• Approximately 9 hours after dosing, initiate the fifth trial of the MWT. 
• Approximately 10 hours after dosing, obtain at least two sets of blood pressure and 
pulse rate measurements in the seated position, as described in Section 6.5. 
• Record all AEs on the AE CRF that occurred since the last visit or phone contact 
(Section 6.14). 
• Record all concomitant medications on the concomitant medications CRF that were 
taken after the last visit or phone contact (Section 5.7). 
• Complete the CGIc (Section 6.12.4). 
• Perform a physical examination including a full examination of body systems 
(excluding a full genitourinary exam) and a brief neurological examination 
(Section 6.4). 
• If the subject is interested in participating in the Open-Label Safety Study, the 
Investigator should follow procedures for enrollment in Study 14-005. Subjects who 
enroll in Study 14-005 will not have a Safety Follow-up Visit in this study. 
• If the subject is not interested in participating in the Open-Label Safety Study, the 
Investigator should schedule the (Week 14) Safety Follow-up Visit. 
7.8 
Follow-up Clinic Visit Week 14 
Visit 15, Day 98 (±3 days) 
The Follow-up Period is not required for subjects who agreed to enter the Open-label Safety 
Study (14-005) at the Final Clinic Visit.  
• Obtain weight in ordinary indoor clothes (without shoes). 
• Obtain vital signs (systolic and diastolic blood pressure, pulse and respiratory rate, 
and body temperature), including at least two sets of blood pressure and pulse rate 
measurements in the seated position, as described in Section 6.5.  
• Obtain a 12-lead ECG after the subject has been resting supine for at least 5 minutes 
(Section 6.7). 
• Administer the C-SSRS Since Last Visit version and record the results (Section 6.9). 
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• Record all AEs on the AE CRF that occurred since the last visit or phone contact 
(Section 6.14). 
• Record all concomitant medications on the concomitant medications CRF that were 
taken after the last visit or phone contact (Section 5.7). 
 
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. 
A subject who did not agree to enter Study 14-005 at the Final Clinic Visit of this study, may 
decide to enroll in Study 14-005 at any time prior to this Follow-up visit; however, that 
subject must first complete the Follow-up visit in this study before enrolling in Study 14-005. 
In that case, enrollment in Study 14-005 will occur concurrently with the Follow-up visit in 
this study.  
7.9 
Early Termination Clinic Visit 
If a subject intends to withdraw from the study and the subject is willing and able to safely 
take additional study drug, schedule a clinic visit and complete all final visit assessments 
indicated at the Final Visit Week 12 (Section 7.7) except for assessing whether the subject is 
interested in participating in Study 14-005. Subjects who withdraw from this study are not 
eligible for Study 14-005. 
If a subject withdraws and is unable or unwilling to take additional study drug, the following 
safety and final assessments should be conducted.  
• Obtain weight in ordinary indoor clothes (without shoes). 
• Obtain a urine sample for a pregnancy test for all females of childbearing potential 
(Section 6.10, Table 1 see footnote for definitions of childbearing potential). 
• Obtain a urine sample for urinalysis and urine drug screens (Section 6.10.2.1 and 
Table 1). 
• Obtain vital signs (systolic and diastolic blood pressure, pulse and respiratory rate, 
and body temperature), including at least two sets of blood pressure and pulse rate 
measurements in the seated position, as described in Section 6.5. 
• Obtain a 12-lead ECG after the subject has been resting supine for at least 5 minutes 
(Section 6.7). 
• Obtain fasting blood samples for serum chemistry and hematology tests (see 
Section 6.10.2.1 and Table 1).  
• Provide a light breakfast after blood samples are collected. 
• Administer the C-SSRS Since Last Visit version and record the results (Section 6.9). 
• Collect study drug and assess compliance (Section 5.9). 
• Review and record primary OSA therapy use from the subject’s device or memory 
card, or frequency of use (or lack of use) as reported by the subject (Section 6.12.10). 
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• Record all AEs on the AE CRF that occurred since the last visit or phone contact 
(Section 6.14). 
• Record all concomitant medications on the concomitant medications CRF that were 
taken after the last visit or phone contact (Section 5.7). 
• Perform a physical examination including a full examination of body systems 
(excluding a full genitourinary exam) and a brief neurological examination 
(Section 6.4). 
• Schedule a 2-week Follow-up visit (Section 7.8), if the subject is willing to continue 
with follow-up procedures. 
7.10 Discontinuations 
If a subject is withdrawn before completing the study, the reason for withdrawal will be 
entered on the appropriate CRF. The specific reason for the withdrawal should be carefully 
documented on the CRF. 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 as noted above.  
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. 
8 
QUALITY CONTROL AND ASSURANCE 
The study will be conducted according to GCP guidelines and according to national law. 
Quality Assurance audits may be performed at the discretion of Jazz Pharmaceuticals. 
9 
PLANNED STATISTICAL METHODS 
9.1 
General Considerations 
All study data will be summarized by treatment using descriptive statistics. Categorical 
variables will be reported as frequency and percent (e.g., gender, race). Continuous variables 
will be reported as number of subjects, mean, standard deviation, median, minimum, and 
maximum (e.g., age, weight). All summaries, statistical analyses, and individual subject data 
listings described below will be completed 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 
The primary objective of the study is to evaluate the efficacy of JZP-110 administered once 
daily for up to 12 weeks in doses of 37.5, 75, 150, and 300 mg compared to placebo in the 
treatment of excessive sleepiness in adult subjects with OSA. To address this objective, 
pairwise treatment difference between each of the 4 doses and placebo will be tested.  The 
family-wise error rate will be controlled at a significance level of 0.05. To address the 
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multiplicity issue due to the multiple efficacy endpoints and doses, a fixed hierarchical 
testing sequence will be employed (Section 9.10). 
9.3 
Determination of Sample Size 
Approximately 440 subjects are planned for enrollment with approximately 110 subjects per 
treatment group in the placebo, 150 mg, and 300 mg groups. A sample size of 99 subjects per 
group (placebo, 150 mg, and 300 mg groups) will provide at least 90% power to detect a 
difference of 5 minutes in the mean sleep latency time as determined from the MWT (mean 
of the first four trials) and a difference of 3.5 points on the ESS changes from Baseline to 
Week 12 between each of these JZP-110 treatment dose groups and placebo. This calculation 
assumes common standard deviations of 10 minutes for the MWT and 6 points for the ESS 
changes from Baseline and a two-sided significance level of 0.05 using a t-test. To account 
for dropouts without evaluable data, a sample size of 110 subjects per treatment group 
(placebo, 150 mg, and 300 mg groups) is planned. Approximately 55 subjects will be 
randomized to each of the JZP-110 37.5 mg and 75 mg groups. 
9.4 
Analysis Populations  
The Safety Population will consist of all subjects who received at least one dose of study 
medication. This population will be analyzed for safety evaluation and will be presented in 
the tables and listings of safety data. 
The Modified Intent-to-Treat (mITT) Population will include subjects who received at least 
one dose of study medication and have baseline and at least one post-baseline evaluation of 
MWT or ESS. This population will be evaluable for the co-primary endpoints. This 
population will also be analyzed for other efficacy endpoints. If a subject in the mITT 
Population does not have an assessment for a particular secondary efficacy endpoint, that 
subject will be excluded in the analysis of that endpoint. 
The Per-Protocol population will include subjects who completed the trial according to 
protocol specifications without a major violation. The type of protocol violations that will 
result in exclusion from the Per-Protocol Population will be identified in the statistical 
analysis plan. This population will be identified before unblinding the study, and will only be 
used in a secondary analysis of the co-primary endpoints. 
The PK Population will include subjects who have evaluable PK data for the population PK 
analysis. 
9.5 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized for the Safety Population, the 
mITT Population, and the Per-Protocol Population. The summaries of data will include 
frequencies and percentages for categorical variables and mean, standard deviation, median, 
minimum, and maximum for continuous variables. 
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9.6 
Handling of Dropouts and Missing Data 
For the analysis of the co-primary efficacy parameters of MWT and ESS, the key secondary 
efficacy parameter of PGIc, and secondary efficacy parameter of CGIc, multiple imputation 
methods will be used to impute the missing data in order to assess the sensitivity of the 
results. These methods will be described in the statistical analysis plan. 
The assumptions important to the validity of these imputation methods will be examined and 
discussed in the final study report where the sensitivity analysis is presented. 
9.7 
Pooling of Investigation Centers 
Data from all investigational centers will be pooled for primary analyses. Data may also be 
pooled by region of country as appropriate for exploratory analyses. 
9.8 
Efficacy Endpoints 
9.8.1 
Co-primary Efficacy Endpoint 
• MWT: Change in the mean sleep latency time (in minutes) as determined from the 
first four trials of a 40-minute MWT from Baseline to Week 12 
• ESS: Change in ESS score from Baseline to Week 12 
9.8.2 
Key Secondary Efficacy Endpoints 
• 
PGIc: Percentage of subjects reported as improved (minimally, much, or very 
much) at Week 12 
 
9.8.3 
Other Secondary Endpoints 
• 
Time course of efficacy on the MWT: Change in sleep latency time (in minutes) 
on each of the 5 MWT trials 
• 
CGIc: Percentage of subjects reported as improved (minimally, much, or very 
much) at Week 12 
• 
MWT: Change in the mean sleep latency time (in minutes) as determined from 
the first four trials of a 40-minute MWT from Baseline to Week 4 
• 
ESS: Change in ESS score from Baseline to Week 1, Week 4, and Week 8  
• 
PGIc: Percentage of subjects reported as improved at Week 1, Week 4, and 
Week 8 
• 
CGIc: Percentage of subjects reported as improved at Week 1, Week 4, and 
Week 8 
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9.8.4 
Functional Outcomes and Quality of Life Endpoints 
• FOSQ-10: Change in the total score from Baseline to Week 1, Week 4, Week 8, and 
Week 12 
• SF-36v2: Change in the total score and change in the 8 subscales from Baseline to 
Week 4, Week 8, and Week 12 
• EQ-5D-5L: 
o EQ-5D  Dimensions:  
 Number and percentage of subjects in each of the 5 levels (e.g., no 
problem, slight problem, moderate problem, severe problem, unable) 
for each dimension (e.g., mobility, self-care) over time  
 Number and percentage of subjects reporting any problems (levels 2-
5) for each dimension (e.g., mobility, self-care) over time  
o EQ VAS: Mean and SD or median with 25th and 75th percentiles for the VAS 
at  baseline, Week 1, Week 4, Week 8 and Week 12. Change in the mean VAS 
scores from Baseline to Week 1, Week 4, Week 8, and Week 12 
o EQ-5D-5L Index: Index value at Baseline, to Week 1, Week 4, Week 8, and 
Week 12 
• WPAI:SHP: Percent work time missed due to problem over time, percent impairment 
while working due to problem over time, percent overall work impairment due to 
problem over time, and percent activity impairment due to problem over time. 
9.8.5 
Exploratory Endpoints 
• Change in frequency of use of primary OSA therapy from Baseline to Week 12. 
• Change in PSG parameters including total sleep time (TST), time in Stages N1, N2, 
N3, wake after sleep onset (WASO), number of awakenings, AI, AHI, number of 
central apneas, SaO2 nadir, and SaO2 mean from Baseline to Week 4 and Week 12. 
9.9 
Safety Endpoints 
To evaluate the safety and tolerability evaluations as determined by the occurrence of and/or 
changes in: 
• Treatment-emergent adverse events 
• Change in clinical laboratory tests (chemistry, hematology, and urinalysis) 
• Vital signs 
• 24 hour ambulatory blood pressure monitoring 
• 12-lead electrocardiograms (ECGs) 
• Physical examination 
• C-SSRS 
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9.10 Multiplicity Issue 
To address the multiplicity issue of multiple endpoints and dose groups, the fixed 
hierarchical testing sequence in Figure 2 will be used. The testing will begin with the 
comparison of 300 mg dose versus placebo for the co-primary efficacy endpoints MWT and 
ESS. Since they are co-primary endpoints, both have to be significant at the 0.05 level before 
the test can proceed to the next level. The testing will stop when a significant level exceeds 
0.05. This gate keeping approach will control the family-wise error rate at 0.05 for the 
comparisons of the three JZP-110 doses versus placebo in MWT, ESS, and PGIc. Although 
the study is not powered for the 37.5 and 75 mg treatment arms, the testing will proceed to 
levels as outlined in Figure 2. The dose(s) that show(s) significant difference versus placebo 
in both MWT and ESS will be considered efficacious doses and additional testing to 
characterize the time course of efficacy will be performed (Section 9.11). 
Figure 2 
Multiplicity Strategy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.11 Efficacy Analyses 
Efficacy analyses will be performed for the mITT Analysis Population. The per-protocol 
analysis will only be used in a secondary analysis of the co-primary endpoints. For the 
analysis of the co-primary efficacy endpoints, a mixed-effect repeated measures (MMRM) 
MWT and ESS  
300 mg vs. placebo; proceed to next test if both are significant at α=0.05 
PGIc 
300 mg vs. placebo; proceed to next test if significant α=0.05 
PGIc 
75 mg vs. placebo; proceed to next test if significant α=0.05 
PGIc 
150 mg vs. placebo; proceed to next test if significant α=0.05 
MWT, ESS  
75 mg vs. placebo; proceed to next test if both are significant at α=0.05 
MWT, ESS  
150 mg vs. placebo; proceed to next test if both are significant at α=0.05 
PGIc 
37.5 mg vs. placebo; use α=0.05 
MWT, ESS  
37.5 mg vs. placebo; proceed to next test if both are significant at α=0.05 
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model will be used as the primary method of analysis. This model will include fixed effects 
for treatment (i.e., dose group), time (as a discrete factor), treatment-by-time interaction, 
baseline value of the efficacy endpoint, and randomization stratification factor. SAS 
procedure PROC MIXED will be used to carry out this analysis. All available data will be 
included in the model. An unstructured covariance matrix will be used to model the 
correlation among repeated measurements. The estimates of treatment difference versus 
placebo and their 95% confidence intervals will be presented. In addition to the MMRM 
model, an analysis of covariance (ANCOVA) model will be used to analyze MWT and ESS 
to provide sensitivity analyses. This ANCOVA model will include the effect for treatment as 
a fixed effect, and baseline value of the efficacy endpoint as the covariate. 
The chi-squared test will be used to test the hypotheses associated with the analysis of the 
key secondary efficacy endpoint of PGIc and the secondary efficacy endpoint of CGIc at 
Week 12. 
For the time course efficacy analysis, the dose(s) that show(s) significant difference versus 
placebo in both MWT and ESS will be considered efficacious dose(s). For each of these 
doses, additional testing to characterize the time course of efficacy using MWT will be 
performed.  The mean and standard error of the mean MWT data will be displayed 
graphically for the dose and placebo. Pairwise comparison versus placebo for each of the 
5 MWT trials will be conducted at a significance level of 0.05. Characterizing the time 
course of efficacy will begin with identifying the first trial that demonstrates significant 
difference from placebo. If such a trial is identified, the treatment difference at the next trial 
will be examined. If the treatment difference for the next trial is also significant at the 0.05 
level, the treatment will be considered efficacious at the time of the next trial. This procedure 
will continue as long as significance for each subsequent trial is observed or until trial 5 is 
examined. 
For the other MWT and ESS endpoints, FOSQ-10 endpoints, SF-36v2 endpoints, EQ VAS 
endpoints, EQ-5D-5L Index endpoints, and WPAI:SHP endpoints, a similar MMRM model 
will be used as the method of analysis;  the other PGIc and CGIc endpoints, and EQ-5D-5L: 
EQ-5D Dimensions endpoints will be analyzed using the chi-squared test. 
No sensitivity analyses and no multiplicity adjustments will be employed for these endpoints. 
9.12 Safety Analyses 
Safety analyses will be performed for the Safety Analysis Population. No formal statistical 
testing will be performed for the safety analyses. 
9.12.1 
Adverse Event 
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. Results will be presented by system 
organ class and preferred term. The overview will also report TEAEs by maximum severity. 
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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. The increase in severity will be accounted for in the maximum 
severity analysis. 
For all AE summaries, if a subject has more than one AE within a preferred term, 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. The information presented will include subject number, treatment, 
primary system organ class and preferred term, date of onset, severity, relationship to study 
drug, action taken, and stop date (if available). 
9.12.2 
Vital Signs and 24-Hour Ambulatory Blood Pressure Monitoring 
Abnormal vital signs will be counted by treatment. The number and percent of subjects with 
any post-baseline vital sign readings above and/or below specified levels will be presented 
for each treatment. In addition, summary statistics (i.e., mean, median, minimum, maximum, 
standard deviation, and number of subjects) will be presented by treatment for each vital sign 
as per protocol schedule. An additional listing will be provided of those subjects who have 
clinically significant vital sign values. 
9.12.3 
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, standard 
deviation, and number of subjects) will be presented by treatment for each laboratory 
parameter as per protocol schedule. An additional listing will be provided of those subjects 
who have clinically significant laboratory values. 
9.12.4 
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 patients 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. 
9.12.5 
Physical Examinations 
A finding identified by the investigator as abnormal on the physical examination at the 
Screening visit will be recorded on the Medical History eCRF. A clinically significant 
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adverse change (i.e., worsening) of a physical examination finding after screening will be 
recorded as an AE.  
9.12.6 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Data from the Since Last Visit Version of the C-SSRS will be summarized by treatment 
group according to the Columbia Classification Algorithm of Suicide Assessment (C-CASA) 
(Posner et al. 2007). 
9.13 Analysis of Pharmacokinetic and Pharmacodynamic Variables 
PK analyses will be performed for the PK Analysis Population. 
Concentration data for JZP-110 will be tabulated by sampling time point and will be included 
in a population PK analysis. The population PK model will be used to characterize JZP-110 
PK profile in OSA patients and to explore exposure-efficacy correlations. Available subject 
characteristics (such as demographics, labs, etc.) will be tested as potential covariates, as 
appropriate. 
9.14 Subgroup Analyses 
Exploratory analyses of the efficacy and safety endpoints will be conducted in the subgroups 
of subjects who report compliant and non-compliant use of a primary OSA therapy at 
randomization.  
9.15 Interim Analysis and Data Monitoring 
No interim analyses are planned. 
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 will be reviewed for accuracy and completeness by 
Jazz Pharmaceuticals or its representatives during and after onsite monitoring visits, and any 
discrepancies will be resolved with the investigator or designees as appropriate. 
10.1 Data Management 
The standard procedures for handling and processing records will be followed in compliance 
with 21 CFR 11, Good Clinical Practices, ICH Guidelines, and the Standard Operating 
Procedures (SOPs) of Jazz Pharmaceuticals or the Contract Research Organization (CRO). A 
comprehensive Data Management Plan (DMP) will be developed, which may include but is 
not limited to a Data Management Overview, Database Contents, annotated CRF, Query 
Contacts, and Consistency Checks. A central laboratory will review all PSG data. 
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10.2 Case Report Forms 
Jazz Pharmaceuticals or its designee will supply eCRFs (electronic case report forms) for the 
recording of all trial data, ECG or generated by laboratory report. All data recorded must be 
completed in the eCRFs. 
The principal investigator must review the eCRFs and provide his/her signature certifying 
that he/she has reviewed the data and considers the data accurate to the best of his/her 
knowledge. Regardless of who completes the forms, it is the principal investigator’s 
responsibility to ensure the accuracy of the forms. 
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. 
11 ADMINISTRATIVE CONSIDERATIONS 
11.1 Investigators and Study Administrative Structure 
11.1.1 
Contract Research Organization  
11.1.2 
Jazz Pharmaceuticals Medical Monitors 
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11.1.3 
EU Medical Monitor  
Contact information for the EU Medical Monitor will be provided separately. 
11.1.4 
Investigator 
Multicenter 
11.2 Institutional Review Board (IRB) or Independent Ethics Committee 
(IEC) Approval 
The final approved protocol and the informed consent form will be reviewed by the IRB/IEC.  
In addition, the IRB/IEC 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 IRB/IEC. 
A list of the IRB/IEC members who actually participated in the review, their respective titles 
(occupational identification), and institutional affiliations or an IRB/IEC assurance number 
must be provided to Jazz Pharmaceuticals. The approval letter or notice must be provided on 
IRB/IEC 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 by an IRB meeting federal regulations. 
The clinical study remains subject to continuing review by the IRB. Jazz Pharmaceuticals or 
its designee will supply all necessary data for the investigator to submit to the IRB/IEC. Jazz 
Pharmaceuticals will not ship clinical supplies to an investigational site until written signed 
approval from the site’s IRB/IEC has been received by Jazz Pharmaceuticals. 
The investigator is responsible for ensuring initial and continued review and approval of the 
clinical trial by the IRB/IEC at his/her site. The investigator must also ensure that he/she will 
promptly report to the IRB/IEC 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 IRB/IEC approval, 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 
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Pharmaceuticals or its designee. Within 3 months of trial completion or termination, a final 
report must be provided to the IRB/IEC by the clinical site. 
11.3 Ethical/Legal Conduct of the Study 
The study will be conducted in accordance with applicable local regulations relating to Good 
Clinical Practice (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. Subjects will be given a copy of their signed ICF. 
Each subject’s chart will have his/her signed ICF for study participation attached to it. When 
the study treatment is completed and the CRF 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. 
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 CRFs. The IRB 
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 IRB/IEC will be notified of all amendments to the protocol. Amendments to 
the protocol will not be implemented until written IRB/IEC approval has been received.  
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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. 
11.9 Protocol Violations/Deviations 
All major protocol violations must be reported to the IRB in an expedited fashion. It is the 
responsibility of the principal investigator to ensure proper reporting to the IRB. Protocol 
violations and deviations should be reported to Jazz Pharmaceuticals or designee. 
11.10 Access to Source Documentation  
Jazz Pharmaceuticals (or its designee) will be responsible for monitoring this clinical trial. 
Jazz Pharmaceuticals will monitor the study conduct, proper CRF and source documentation 
completion and retention, and accurate study drug accountability. To this end, a monitor will 
visit the study site at suitable intervals and be in frequent contact with the site through verbal 
and written communication. It is essential that the monitor have access to all documents 
(related to the study and the individual participants) at any time they are requested. In turn, 
the monitor will adhere to all requirements for subject confidentiality as outlined in the 
informed consent form. The investigator and his/her staff will be expected to cooperate with 
the monitor, to be available during a portion of the monitoring visit to answer questions, and 
to provide any missing information. 
In addition, representatives of the Clinical Quality Assurance Department of Jazz 
Pharmaceuticals (or equivalent), or appointed monitoring organization(s), and representatives 
of the FDA or other regulatory agencies may request to inspect the study documents (e.g., 
study protocol, CRFs, study drug, original medical records/files). All subject data will be 
treated confidentially. 
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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. CRFs 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 JZP-110, 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 will 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 
American Academy of Sleep Medicine (AASM). International Classification of Sleep 
Disorders-Third Edition (ICSD-3), Darien, IL. American Academy of Sleep Medicine, 2014; 
53-62, 143-155.  
American Psychiatric Association. (2013). Diagnostic and statistical manual of mental 
disorders (5th ed.). Washington, DC. 
Black J, Hirshkowitz M. Modafinil for treatment of residual excessive sleepiness in nasal 
continuous airway pressure-treated obstructive sleep apnea/hypopnea syndrome. SLEEP 
2005; 28:464-71. 
Broderick JE, Junghaenel DU, Schneider S, Pilosi JJ, Stone AA. Pittsburgh and Epworth 
sleep scale items: accuracy of ratings across different reporting periods. 2013; Behav Sleep 
Med. 11:173-88. 
Chasens E, Ratcliffe S, Weaver T. Development of the FOSQ-10: A short version of the 
Functional Outcomes of Sleep Questionnaire. 2009; SLEEP 32: 915-919. 
Doghramji K, Mitler MM, Sangal B, Shapiro C, Taylor S, Walsleben J, Belisle C, Erman M, 
Hayduk R, Hosn R, O’Malley E, Sangal J, Schutte S and Youakim J. A normative study of 
the maintenance of wakefulness test (MWT). Electroencephalogr Clin Neurophysiol 1997; 
103:554-562. 
Epstein LJ, Kristo D, Strollo PJ Jr, Friedman N, Malhotra A, Patil SP, Ramar K, Rogers R, 
Schwab RJ, Weaver EM, Weinstein MD; Adult Obstructive Sleep Apnea Task Force of the 
American Academy of Sleep Medicine. Clinical guideline for the evaluation, management 
and long-term care of obstructive sleep apnea in adults. J Clin Sleep Med. 2009 5:263-76. 
EQ-5D-5L User Guide. 2013. Available at: 
http://www.euroqol.org/fileadmin/user_upload/Documenten/PDF/Folders_Flyers/UserGuide
_EQ-5D-5L_v2.0_October_2013.pdf.   Accessed November 19, 2014. 
Fietze I, Penzel T, Alonderis A, et al. COST Action B26 Group. Management of obstructive 
sleep apnea in Europe. Sleep Med. 2011; 12:190-7. 
Gasa M, Tamisier R, Launois SH, et al. Scientific Council of the Sleep Registry of the 
French Federation of Pneumology-FFP. Residual sleepiness in sleep apnea patients treated by 
continuous positive airway pressure. J Sleep Res. 2013; 22:389-97. 
Gay P, Weaver T, Loube D, Iber C. Evaluation of positive airway pressure treatment for 
sleep related breathing disorders in adults: A review by the Positive Airway Pressure Task 
Force of the Standards of Practice Committee of the American Academy of Sleep Medicine. 
Sleep. 2006;29:381-401. 
Harsh JR, Hayduk R, Rosenberg R, Wesnes KA, Walsh JK, Arora S, Niebler GE, Roth T. 
The efficacy and safety of armodafinil as treatment for adults with excessive sleepiness 
associated with narcolepsy. Curr Med Res Opin. 2006 22:761-74. 
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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. 
Hays RD, Stewart AL. (1992b). Construct validity of MOS health measures. In A. L. Stewart 
& J. E. Ware (eds.), Measuring functioning and well-being: The Medical Outcomes Study 
approach (pp. 325-342), Durham, NC: Duke University Press. 
Johns, MW. Sensitivity and specificity of the multiple sleep latency test (MSLT), the 
maintenance of wakefulness test and the Epworth Sleepiness Scale: failure of the MSLT as a 
gold standard J Sleep Res 2000; 9 (1): 5–11. 
Johns, MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. 
Sleep. 1991 Dec;14(6):540-5. 
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. 
Mitler MM, Gujavarty KS, and Broman C. Maintenance of wakefulness test: A 
polysomnographic technique for evaluating treatment efficacy in patients with excessive 
somnolence. Electroencephalogr Clin Neurophysiol. Jun 1982; 53(6): 658–661. 
Nuvigil® (armodafinil) tablets. US Prescribing Information, North Wales, PA: Teva 
Pharmaceuticals USA, Inc; 2013. 
Pépin JL, Viot-Blanc V, Escourrou P, et al. Prevalence of residual excessive sleepiness in 
CPAP-treated sleep apnoea patients: the French multicentre study. Eur Respir J. 2009; 
33:1062-7. 
Pickering TG, Hall JE, Appel LJ, Falkner BE, Graves J, Hill MN, Jones DW, Kurtz T, Sheps 
SG, Roccella EJ; Subcommittee of Professional and Public Education of the American Heart 
Association Council on High Blood Pressure Research. Recommendations for blood pressure 
measurement in humans and experimental animals: Part 1: blood pressure measurement in 
humans: a statement for professionals from the Subcommittee of Professional and Public 
Education of the American Heart Association Council on High Blood Pressure Research. 
Hypertension. 2005; 45:142-61. 
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo M, Currier GW, Melvin 
GA, Greenhill L, Shen S, Mann JJ. 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.  
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm 
of Suicide Assessment (C-CASA): classification of suicidal events in the FDA's pediatric 
suicidal risk analysis of antidepressants. Am J Psychiatry. 2007;164:1035-1043. 
Provigil® (modafinil) tablets. US Prescribing Information, Cephalon 2010. 
Randerath WJ, Verbraecken J, Andreas S, et al. Non-CPAP therapies in obstructive sleep 
apnoea. European Respiratory Society task force on non-CPAP therapies in sleep apnoea. 
Eur Respir J. 2011; 37:1000-28. 
 
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Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity 
and activity impairment instrument. PharmacoEconomics 1993; 4(5):353-65. 
Roth T, White D, Schmidt-Nowara W, Wesnes KA, Niebler G, Arora S, Black J. Effects of 
armodafinil in the treatment of residual excessive sleepiness associated with obstructive sleep 
apnea/hypopnea syndrome: a 12-week, multicenter, double-blind, randomized, placebo-
controlled study in nCPAP-adherent adults. Clin Ther. 2006 28:689-706. 
Sawyer AM, Gooneratne NS, Marcus CL, Ofer D, Richards KC, Weaver TE. A systematic 
review of CPAP adherence across age groups: clinical and empiric insights for developing 
CPAP adherence interventions. Sleep Med Rev. 2011;15:343-356. 
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. 
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. 
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. 
Veasey SC, Guilleminault C, Strohl KP, Sanders MH, Ballard RD, Magalang UJ. Medical 
therapy for obstructive sleep apnea: a review by the Medical Therapy for Obstructive Sleep 
Apnea Task Force of the Standards of Practice Committee of the American Academy of 
Sleep Medicine. Sleep. 2006;29:1036-1044. 
Ware JE, Sherbourne CD. The MOS 36-item short-form health survey (SF-36): I. Conceptual 
framework and item selection. Medical Care. 1992; 30: 473-483. 
Weaver TE, Maislin G, Dinges DF, Bloxham T, George CF, Greenberg H, Kader G, 
Mahowald M, Younger J, Pack AI. Relationship between hours of CPAP use and achieving 
normal levels of sleepiness and daily functioning. Sleep. 2007;30:711-719. 
Weaver TE, Grunstein RR. Adherence to continuous positive airway pressure therapy: the 
challenge to effective treatment. Proc Am Thorac Soc. 2008;5:173-178. 
Weaver TE, Sawyer AM. Adherence to continuous positive airway pressure treatment for 
obstructive sleep apnoea: implications for future interventions. Indian J Med Res. 
2010;131:245-258. 
Weaver TE, Laizner AM, Evans LK, et al. An instrument to measure functional status 
outcomes for disorders of excessive sleepiness. Sleep 1997;20:835-43. 
 
 
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13 LIST OF UNPUBLISHED STUDY REPORTS 
Document ID or Report No. 
Unpublished Study Report Citation 
EDMS-PSDB-4956838 
Dupuis P, Neliat G. Study of BZ-818730-000-D and BZ-
10A000-301-A in various receptor binding and cell 
biology assays (870189) (03 July 2001). 
EDMS-PSDB-5305783 
Janowsky A.  In vitro receptor, transporter, and release 
assay for NIDA medications discovery and abuse liability 
testing (Release Assays) (March 2006a). 
EDMS-PSDB-2735318 
Mailman R. Assessment of dopaminergic actions of 
YK-10A (May 2003). 
EDMS-PSDB-2275504 
Newton K. A double-blind, placebo-controlled, 
randomized, single center, parallel-design study to 
evaluate the preliminary efficacy and safety of three dose 
ranges of YKP10A in outpatients with major depressive 
disorder (Protocol SKUP-9801) PPD Development, Inc. 
Final Report (03 July 2001). 
EDMS-PSDB-3696001 
Sporn J, Ness S, Gassmann-Mayer C, Grattan J. 6-week, 
randomized, double-blind, parallel- group, active- and 
placebo-controlled study to assess the efficacy of 
R228060 in adult subjects with major depressive disorder 
(MDD) (Protocol R228060-MDD-201); J&JPRD, 
Clinical Study Report (2004). 
R228060-USA-10 
Sutherland S, Okamoto A, Boom S, Hedli C, Kusumakar 
V, Grossman F. Three-week, randomized study to assess 
the tolerability of 2 fixed doses (200 mg and 500 mg) of 
R228060 (2003). 
 
CONFIDENTIAL
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Signature Date: 20160210
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Clinical Trial Protocol: 14-003 Amendment 3 
 
  
 
 
 
 
 
 
Appendix 1 
Schedule of Events 
 
Screening 
Baseline 
Treatment Phase 
Early 
Term 
Safety 
Follow-
upa 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
 
15 
Day/ End of 
Week 
Day 
-31 to -3 
Day  
-2&-1 
Day 7 
(-1, +2) 
Wk 1 
Day 
14 
(±3) 
Wk 
2 
Day 
21 
(±3)
Wk 
3 
Day 
27&28 
(±3) 
Wk 4 
Day 
35 
(±3) 
Wk 
5 
Day 
42 
(±3) 
Wk 
6 
Day 
49 
(±3)
Wk 
7 
Day 
56 
(±3)  
Wk 
8 
Day 
63 
(±3)
Wk 
9 
Day 
70 
(±3)
Wk 
10 
Day 
77 
(±3)
Wk 
11 
Day 
83&84 
(±3) 
Wk 12 
 
Day 98 
(±3) 
Wk 
14 
Clinic visit 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
Phone Contact 
 
 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
Vital signs 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
ECG 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
Fasting serum 
chemistry, 
hematology, 
urinalysis 
X 
Xb 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Urine sample 
for possible drug 
screen  
X 
Xc 
X 
 
 
Xc 
 
 
 
Xc 
 
 
 
X 
X 
 
Serum pregnancy 
test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy 
test  
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Light breakfast 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
Light lunch 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
Xd 
 
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Clinical Trial Protocol: 14-003 Amendment 3 
 
  
 
 
 
 
 
 
 
Screening 
Baseline 
Treatment Phase 
Early 
Term 
Safety 
Follow-
upa 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
 
15 
Day/ End of 
Week 
Day 
-31 to -3 
Day  
-2&-1 
Day 7 
(-1, +2) 
Wk 1 
Day 
14 
(±3) 
Wk 
2 
Day 
21 
(±3)
Wk 
3 
Day 
27&28 
(±3) 
Wk 4 
Day 
35 
(±3) 
Wk 
5 
Day 
42 
(±3) 
Wk 
6 
Day 
49 
(±3)
Wk 
7 
Day 
56 
(±3)  
Wk 
8 
Day 
63 
(±3)
Wk 
9 
Day 
70 
(±3)
Wk 
10 
Day 
77 
(±3)
Wk 
11 
Day 
83&84 
(±3) 
Wk 12 
 
Day 98 
(±3) 
Wk 
14 
Clinic visit 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
Phone Contact 
 
 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
C-SSRS  
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
Concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review and remind 
to record primary 
OSA therapy use  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Instruct how to 
discontinue 
excluded 
medications  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense 24-hr 
ambulatory blood 
pressure monitor 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Overnight stay 
PSG/MWT  
 
Xe 
 
 
 
X 
 
 
 
 
 
 
 
X 
Xd 
 
ESS  
 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
Xd 
 
FOSQ-10  
 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
Xd 
 
SF-36v2  
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Xd 
 
EQ-5D-5L  
 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
Xd 
 
WPAI:SHP  
 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
Xd 
 
CGIs  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense study drug  
 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
Collect study drug/ 
assess compliance 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
PGIc  
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
Xd 
 
CGIc  
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
Xd 
 
CONFIDENTIAL
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Signature Date: 20160210
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Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-003 Amendment 3 
 
  
 
 
 
 
 
 
 
Screening 
Baseline 
Treatment Phase 
Early 
Term 
Safety 
Follow-
upa 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
 
15 
Day/ End of 
Week 
Day 
-31 to -3 
Day  
-2&-1 
Day 7 
(-1, +2) 
Wk 1 
Day 
14 
(±3) 
Wk 
2 
Day 
21 
(±3)
Wk 
3 
Day 
27&28 
(±3) 
Wk 4 
Day 
35 
(±3) 
Wk 
5 
Day 
42 
(±3) 
Wk 
6 
Day 
49 
(±3)
Wk 
7 
Day 
56 
(±3)  
Wk 
8 
Day 
63 
(±3)
Wk 
9 
Day 
70 
(±3)
Wk 
10 
Day 
77 
(±3)
Wk 
11 
Day 
83&84 
(±3) 
Wk 12 
 
Day 98 
(±3) 
Wk 
14 
Clinic visit 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
Phone Contact 
 
 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
Study drug 
administration prior 
to MWT 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
Xd 
 
Blood draws for PK  
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
Assess interest in 
Study 14-005 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
Adverse Events  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Schedule next clinic 
visit and/or phone 
contact 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Shaded columns indicate clinic visits. 
a. 
The 2 week Safety Follow-up is not required for subjects who enter the Open-label Safety Study (14-005) at the Final Clinic Visit. 
b. 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. Record if the subject was fasting or nonfasting at the time of the collection. 
c. 
Samples collected at Screening, Baseline, and Week 12 or Early Termination will be analyzed. Samples collected at other visits may be analyzed at the 
investigator’s discretion. 
d. These assessments are not required for subjects who are withdrawing early from the study and are unable or unwilling to take additional study drug to 
complete a final PSG/MWT. 
e. 
For subjects who are being rescreened, a repeat PSG and MWT is not required at Visit 2 if the results of the previous PSG and MWT meet the current 
inclusion/exclusion criteria and there have been no changes to the medical history, concomitant medications, or primary OSA therapy that would likely 
affect the MWT.  
 
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Clinical Trial Protocol: 14-003 Amendment 3 
 
   
 
 
 
 
CONFIDENTIAL 
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Appendix 2 
Example Schedule of Times for Procedures During 
MWT Visits 
 
Baseline Visit – Day -1 (following overnight PSG)* 
Time relative to 
“lights on” 
Approximate 
time 
Procedure/activity 
0 h 
7:00 
Lights on 
~0.5 h 
7:30 
Body temperature, respiratory rate, and at least 2 sets of blood 
pressure and pulse 
~1.5 h 
8:30 
Light breakfast 
~2 h 
8:50 
At least 2 sets of blood pressure and pulse 
~2 h 
9:00 
Start 1st MWT Trial 
~3 h 
9:50 
At least 2 sets of blood pressure and pulse 
~3 h 
10:00 
ECG 
~3-4 h 
10:00-11:00 
Administer Questionnaires 
~4 h 
11:00 
Start 2nd MWT Trial 
 
 
Light lunch served immediately after the end of the 2nd or 3rd trial 
~5 h 
12:00 
At least 2 sets of blood pressure and pulse 
~6 h 
13:00 
Start 3rd MWT Trial 
~7 h 
14:00 
At least 2 sets of blood pressure and pulse 
~8 h 
15:00 
Start 4th MWT Trial 
~9 h 
16:00 
At least 2 sets of blood pressure and pulse 
~10 h 
17:00 
Start 5th MWT Trial 
~11 h 
18:00 
At least 2 sets of blood pressure and pulse 
Week 4 and 12 Visits or Early Termination – MWT (following overnight PSG) 
Time relative to 
dosing 
Approximate 
time 
Procedure/activity 
~-1 h 
7:00 
Lights on 
~-0.5 h 
7:30 
Body temperature, respiratory rate, and at least 2 sets of blood 
pressure and pulse 
 
 
Obtain fasting blood samples (Week 12 or Early Termination only) 
0 h 
8:00 
Dosing 
~0.5 h 
8:30 
Light breakfast 
~1 h 
8:50 
At least 2 sets of blood pressure and pulse 
~1 h 
9:00 
Start 1st MWT Trial 
~2 h 
9:50 
At least 2 sets of blood pressure and pulse 
~2 h 
10:00 
ECG 
~2-3 h 
10:00-11:00 
Administer Questionnaires 
~3 h 
11:00 
Start 2nd MWT Trial 
 
 
Light lunch served immediately after the end of the 2nd or 3rd trial 
~4 h 
12:00 
At least 2 sets of blood pressure and pulse 
~5 h 
13:00 
Start 3rd MWT Trial 
~6 h 
14:00 
At least 2 sets of blood pressure and pulse 
~7 h 
15:00 
Start 4th MWT Trial 
~8 h 
16:00 
At least 2 sets of blood pressure and pulse 
~9 h 
17:00 
Start of 5th MWT Trial 
~10 h 
~18:00 
At least 2 sets of blood pressure and pulse 
*For subjects who are being rescreened, a repeat PSG and MWT are not required at Visit 2 if the results of the 
previous PSG and MWT meet the current inclusion/exclusion criteria and there have been no changes to the 
medical history, concomitant medications, or primary OSA therapy that would likely affect the MWT results. 
CONFIDENTIAL
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Clinical Trial Protocol: 14-003 Amendment 3 
 
   
 
 
 
 
CONFIDENTIAL 
Page 83 of 102 
 
Appendix 3 
DSM-5 Criteria for Psychiatric Disorders 
The following selected psychiatric DSM-5 criteria are presented as a resource, if needed 
when screening subjects. The full DSM Edition 5 (DSM-5) criteria for psychiatric conditions 
should be consulted for diagnoses not listed here. 
Bipolar and Related Disorders 
Bipolar I Disorder 
For a diagnosis of bipolar I disorder, it is necessary to meet the following criteria for a manic 
episode. The manic episode may have been preceded by and may be followed by hypomanic 
or major depressive episodes. 
Manic Episode 
A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood 
and abnormally and persistently increased goal-directed activity or energy, lasting at least 
1 week and present most of the day, nearly every day (or any duration if hospitalization is 
necessary). 
B. During the period of mood disturbance and increased energy or activity, three (or more) 
of the following symptoms (four if the mood is only irritable) are present to a significant 
degree and represent a noticeable change from usual behavior: 
1. Inflated self-esteem or grandiosity. 
2. Decreased need for sleep (e.g., feels rested after only 3 hours of sleep). 
3. More talkative than usual or pressure to keep talking. 
4. Flight of ideas or subjective experience that thoughts are racing. 
5. Distractibility (i.e., attention too easily drawn to unimportant or irrelevant external 
stimuli), as reported or observed. 
6. Increase in goal-directed activity (either socially, at work or school, or sexually) or 
psychomotor agitation (i.e., purposeless non-goal-directed activity). 
7. Excessive involvement in activities that have a high potential for painful 
consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or 
foolish business investments). 
C. The mood disturbance is sufficiently severe to cause marked impairment in social or 
occupational functioning or to necessitate hospitalization to prevent harm to self or 
others, or there are psychotic features. 
D. The episode is not attributable to the physiological effects of a substance (e.g., a drug of 
abuse, a medication, other treatment) or to another medical condition. 
 
Hypomanic Episode 
A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood 
and abnormally and persistently increased activity or energy, lasting at least 4 
consecutive days and present most of the day, nearly every day. 
B. During the period of mood disturbance and increased energy and activity, three (or more) 
of the following symptoms (four if the mood is only irritable) have persisted, represent a 
noticeable change from usual behavior, and have been present to a significant degree: 
1. Inflated self-esteem or grandiosity. 
2. Decreased need for sleep (e.g., feels rested after only 3 hours of sleep). 
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CONFIDENTIAL 
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3. More talkative than usual or pressure to keep talking. 
4. Flight of ideas or subjective experience that thoughts are racing. 
5. Distractibility (i.e., attention too easily drawn to unimportant or irrelevant external 
stimuli), as reported or observed. 
6. Increase in goal-directed activity (either socially, at work or school, or sexually) or 
psychomotor agitation. 
7. Excessive involvement in activities that have a high potential for painful 
consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or 
foolish business investments). 
C. The episode is associated with an unequivocal change in functioning that is 
uncharacteristic of the individual when not symptomatic. 
D. The disturbance in mood and the change in functioning are observable by others. 
E. The episode is not severe enough to cause marked impairment in social or occupational 
functioning or to necessitate hospitalization. If there are psychotic features, the episode 
is, by definition, manic. 
F. The episode is not attributable to the physiological effects of a substance (e.g., a drug of 
abuse, a medication, other treatment). 
 
Major Depressive Episode 
A. Five (or more) of the following symptoms have been present during the same 2-week 
period and represent a change from previous functioning; at least one of the symptoms is 
either (1) depressed mood or (2) loss of interest or pleasure. 
Note: Do not include symptoms that are clearly attributable to another medical condition. 
1. Depressed mood most of the day, nearly every day, as indicated by either subjective 
report (e.g., feels sad, empty, or hopeless) or observation made by others (e.g., 
appears tearful). (Note: In children and adolescents, can be irritable mood.) 
2. Markedly diminished interest or pleasure in all, or almost all, activities most of the 
day, nearly every day (as indicated by either subjective account or observation). 
3. Significant weight loss when not dieting or weight gain (e.g., a change of more than 
5% of body weight in a month), or decrease or increase in appetite nearly every day. 
(Note: In children, consider failure to make expected weight gain.) 
4. Insomnia or hypersomnia nearly every day. 
5. Psychomotor agitation or retardation nearly every day (observable by others; not 
merely subjective feelings of restlessness or being slowed down). 
6. Fatigue or loss of energy nearly every day. 
7. Feelings of worthlessness or excessive or inappropriate guilt (which may be 
delusional) nearly every day (not merely self-reproach or guilt about being sick). 
8. Diminished ability to think or concentrate, or indecisiveness, nearly every day (either 
by subjective account or as observed by others). 
9. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation 
without a specific plan, or a suicide attempt or a specific plan for committing suicide. 
B. The symptoms cause clinically significant distress or impairment in social, occupational, 
or other important areas of functioning. 
C. The episode is not attributable to the physiological effects of a substance or another 
medical condition.  
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Bipolar I Disorder 
A. Criteria have been met for at least one manic episode (Criteria A–D under “Manic 
Episode” above). 
B. The occurrence of the manic and major depressive episode(s) is not better explained 
by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional 
disorder, or other specified or unspecified schizophrenia spectrum and other 
psychotic disorder. 
Bipolar II Disorder 
Diagnostic Criteria 
For a diagnosis of bipolar II disorder, it is necessary to meet the following criteria for a 
current or past hypomanic episode and the following criteria for a current or past major 
depressive episode: 
Hypomanic Episode 
A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood 
and abnormally and persistently increased activity or energy, lasting at least 4 
consecutive days and present most of the day, nearly every day. 
B. During the period of mood disturbance and increased energy and activity, three (or more) 
of the following symptoms have persisted (four if the mood is only irritable), represent a 
noticeable change from usual behavior, and have been present to a significant degree: 
1. Inflated self-esteem or grandiosity. 
2. Decreased need for sleep (e.g., feels rested after only 3 hours of sleep). 
3. More talkative than usual or pressure to keep talking. 
4. Flight of ideas or subjective experience that thoughts are racing. 
5. Distractibility (i.e., attention too easily drawn to unimportant or irrelevant external 
stimuli), as reported or observed. 
6. Increase in goal-directed activity (either socially, at work or school, or sexually) or 
psychomotor agitation. 
7. Excessive involvement in activities that have a high potential for painful 
consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or 
foolish business investments). 
C. The episode is associated with an unequivocal change in functioning that is 
uncharacteristic of the individual when not symptomatic.  
D. The disturbance in mood and the change in functioning are observable by others. 
E. The episode is not severe enough to cause marked impairment in social or occupational 
functioning or to necessitate hospitalization. If there are psychotic features, the episode 
is, by definition, manic. 
F. The episode is not attributable to the physiological effects of a substance (e.g., a drug of 
abuse, a medication or other treatment). 
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CONFIDENTIAL 
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Major Depressive Episode 
A. Five (or more) of the following symptoms have been present during the same 2-week 
period and represent a change from previous functioning; at least one of the symptoms is 
either (1) depressed mood or (2) loss of interest or pleasure. 
1. Depressed mood most of the day, nearly every day, as indicated by either subjective 
report (e.g., feels sad, empty, or hopeless) or observation made by others (e.g., 
appears tearful). (Note: In children and adolescents, can be irritable mood.) 
2. Markedly diminished interest or pleasure in all, or almost all, activities most of the 
day, nearly every day (as indicated by either subjective account or observation). 
3. Significant weight loss when not dieting or weight gain (e.g., a change of more than 
5% of body weight in a month), or decrease or increase in appetite nearly every day. 
(Note: In children, consider failure to make expected weight gain.) 
4. Insomnia or hypersomnia nearly every day. 
5. Psychomotor agitation or retardation nearly every day (observable by others; not 
merely subjective feelings of restlessness or being slowed down). 
6. Fatigue or loss of energy nearly every day. 
7. Feelings of worthlessness or excessive or inappropriate guilt (which may be 
delusional) nearly every day (not merely self-reproach or guilt about being sick). 
8. Diminished ability to think or concentrate, or indecisiveness, nearly every day (either 
by subjective account or as observed by others). 
9. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation 
without a specific plan, a suicide attempt, or a specific plan for committing suicide. 
B. The symptoms cause clinically significant distress or impairment in social, occupational, 
or other important areas of functioning. 
C. The episode is not attributable to the physiological effects of a substance or another 
medical condition. 
 
Bipolar II Disorder 
A. Criteria have been met for at least one hypomanic episode (Criteria A–F under 
“Hypomanic Episode” above) and at least one major depressive episode (Criteria A–C 
under “Major Depressive Episode” above). 
B. There has never been a manic episode. 
C. The occurrence of the hypomanic episode(s) and major depressive episode(s) is not better 
explained by schizoaffective disorder, schizophrenia, schizophreniform disorder, 
delusional disorder, or other specified or unspecified schizophrenia spectrum and other 
psychotic disorder. 
D. The symptoms of depression or the unpredictability caused by frequent alternation 
between periods of depression and hypomania causes clinically significant distress or 
impairment in social, occupational, or other important areas of functioning. 
Schizophrenia Spectrum and Other Psychotic Disorders 
Delusional Disorder 
Diagnostic Criteria 
A. The presence of one (or more) delusions with a duration of 1 month or longer. 
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CONFIDENTIAL 
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B. Criterion A for schizophrenia has never been met.  
Note: Hallucinations, if present, are not prominent and are related to the 
delusional theme (e.g., the sensation of being infested with insects associated 
with delusions of infestation). 
C. Apart from the impact of the delusion(s) or its ramifications, functioning is not 
markedly impaired, and behavior is not obviously bizarre or odd. 
D. If manic or major depressive episodes have occurred, these have been brief relative to 
the duration of the delusional periods. 
E. The disturbance is not attributable to the physiological effects of a substance or 
another medical condition and is not better explained by another mental disorder, 
such as body dysmorphic disorder or obsessive-compulsive disorder. 
 
Brief Psychotic Disorder 
Diagnostic Criteria 
A. Presence of one (or more) of the following symptoms. At least one of these must be 
(1), (2), or (3): 
1. Delusions. 
2. Hallucinations. 
3. Disorganized speech (e.g., frequent derailment or incoherence). 
4. Grossly disorganized or catatonic behavior. 
o Note: Do not include a symptom if it is a culturally sanctioned response.  
B. Duration of an episode of the disturbance is at least 1 day but less than 1 month, with 
eventual full return to premorbid level of functioning. 
C. The disturbance is not better explained by major depressive or bipolar disorder with 
psychotic features or another psychotic disorder such as schizophrenia or catatonia, 
and is not attributable to the physiological effects of a substance (e.g., a drug of 
abuse, a medication) or another medical condition. 
 
Schizophreniform Disorder 
Diagnostic Criteria 
A. Two (or more) of the following, each present for a significant portion of time during a 
1-month period (or less if successfully treated). At least one of these must be (1), (2), 
or (3): 
1. Delusions. 
2. Hallucinations. 
3. Disorganized speech (e.g., frequent derailment or incoherence). 
4. Grossly disorganized or catatonic behavior. 
5. Negative symptoms (i.e., diminished emotional expression or avolition). 
B. An episode of the disorder lasts at least 1 month but less than 6 months. When the 
diagnosis must be made without waiting for recovery, it should be qualified as 
“provisional.” 
C. Schizoaffective disorder and depressive or bipolar disorder with psychotic features 
have been ruled out because either 1) no major depressive or manic episodes have 
occurred concurrently with the active-phase symptoms, or 2) if mood episodes have 
occurred during active-phase symptoms, they have been present for a minority of the 
total duration of the active and residual periods of the illness.  
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D. The disturbance is not attributable to the physiological effects of a substance (e.g., a 
drug of abuse, a medication) or another medical condition. 
Schizophrenia 
Diagnostic Criteria 
A. Two (or more) of the following, each present for a significant portion of time during a 
1-month period (or less if successfully treated). At least one of these must be (1), (2), 
or (3): 
1. Delusions. 
2. Hallucinations. 
3. Disorganized speech (e.g., frequent derailment or incoherence). 
4. Grossly disorganized or catatonic behavior. 
5. Negative symptoms (i.e., diminished emotional expression or avolition). 
B. For a significant portion of the time since the onset of the disturbance, level of 
functioning in one or more major areas, such as work, interpersonal relations, or self-
care, is markedly below the level achieved prior to the onset (or when the onset is in 
childhood or adolescence, there is failure to achieve expected level of interpersonal, 
academic, or occupational functioning). 
C. Continuous signs of the disturbance persist for at least 6 months. This 6-month period 
must include at least 1 month of symptoms (or less if successfully treated) that meet 
Criterion A (i.e., active-phase symptoms) and may include periods of prodromal or 
residual symptoms. During these prodromal or residual periods, the signs of the 
disturbance may be manifested by only negative symptoms or by two or more 
symptoms listed in Criterion A present in an attenuated form (e.g., odd beliefs, 
unusual perceptual experiences). 
D. Schizoaffective disorder and depressive or bipolar disorder with psychotic features 
have been ruled out because either 1) no major depressive or manic episodes have 
occurred concurrently with the active-phase symptoms, or 2) if mood episodes have 
occurred during active-phase symptoms, they have been present for a minority of the 
total duration of the active and residual periods of the illness. 
E. The disturbance is not attributable to the physiological effects of a substance (e.g., a 
drug of abuse, a medication) or another medical condition. 
F. If there is a history of autism spectrum disorder or a communication disorder of 
childhood onset, the additional diagnosis of schizophrenia is made only if prominent 
delusions or hallucinations, in addition to the other required symptoms of 
schizophrenia, are also present for at least 1 month (or less if successfully treated). 
Schizoaffective Disorder 
Diagnostic Criteria 
A. An uninterrupted period of illness during which there is a major mood episode (major 
depressive or manic) concurrent with Criterion A of schizophrenia. 
Note: The major depressive episode must include Criterion A1: Depressed mood. 
B. Delusions or hallucinations for 2 or more weeks in the absence of a major mood 
episode (depressive or manic) during the lifetime duration of the illness.  
C. Symptoms that meet criteria for a major mood episode are present for the majority of 
the total duration of the active and residual portions of the illness. 
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CONFIDENTIAL 
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D. The disturbance is not attributable to the effects of a substance (e.g., a drug of abuse, 
a medication) or another medical condition. 
 
American Psychiatric Association. (2013). Diagnostic and statistical manual of mental 
disorders (5th ed.). Washington, DC. 
 
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CONFIDENTIAL 
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Appendix 4 
DSM-5 Substance Use Disorder Diagnostic Criteria 
The following criteria are adapted from the DSM-5 criteria for substance use disorders and 
are presented as a resource, if needed for screening subjects. The full DSM Edition 5 
(DSM-5) criteria for substance use disorders should be consulted for further information. 
 
A. A pattern of ________use leading to clinically significant impairment or distress, as 
manifested by at least two of the following, occurring within a 12-month period: 
1. The _______ is often taken in larger amounts or over a longer period than was 
intended. 
2. There is a persistent desire or unsuccessful efforts to cut down or control _______ 
use. 
3. A great deal of time is spent in activities necessary to obtain the _______ use the 
_______, or recover from its effects. 
4. Craving, or a strong desire or urge to use the _______. 
5. Recurrent _______ use resulting in a failure to fulfill major role obligations at work, 
school, or home. 
6. Continued _______ use despite having persistent or recurrent social or interpersonal 
problems caused or exacerbated by the effects of the _______. 
7. Important social, occupational, or recreational activities are given up or reduced 
because of _______  use. 
8. Recurrent _______ use in situations in which it is physically hazardous. 
9. _______ use is continued despite knowledge of having a persistent or recurrent 
physical or psychological problem that is likely to have been caused or exacerbated 
by the _______. 
10. Tolerance, as defined by either of the following: 
a. A need for markedly increased amounts of the _______ to achieve intoxication or 
desired effect. 
b. A markedly diminished effect with continued use of the same amount of the 
_______. 
Note: This criterion is not considered to be met for those taking _______ medications under 
appropriate medical supervision.  
11. Withdrawal, as manifested by either of the following:  
a. The characteristic withdrawal syndrome for the _______ (refer to Criteria A and 
B of the criteria set for _______withdrawal – see full DSM-5 criteria). 
b. The _______ (or a closely related substance) is taken to relieve or avoid 
withdrawal symptoms. 
Severity: 
 
Mild: Presence of 2–3 symptoms. 
 
Moderate: Presence of 4–5 symptoms. 
 
Severe: Presence of 6 or more symptoms. 
 
American Psychiatric Association. (2013). Diagnostic and statistical manual of mental 
disorders (5th ed.). Washington, DC. 
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CONFIDENTIAL 
Page 91 of 102 
 
 
Appendix 5 
Epworth Sleepiness Scale (ESS) 
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Epworth Sleepiness Scale 
 
 
 
Name:   
 Today’s date:   
 
 
Your age (Yrs):   
 Your  sex (Male = M, Female = F):   
 
 
 
 
How likely are you to doze off or fall asleep in the following situations, in contrast to feeling just 
tired? 
 
This refers to your usual way of life in the past week. 
 
Even if you haven’t done some of these things recently try to work out how they would have affected 
you. 
 
Use the following scale to choose the most appropriate number for each situation: 
 
0  =  would never doze 
1  =  slight chance of dozing 
2  =  moderate chance of dozing 
3  =  high chance of dozing 
 
It is important that you answer each question as best you can. 
 
Situation  
Chance of Dozing (0-3) 
 
 
 
Sitting and reading 
  
 
 
Watching TV 
  
 
 
Sitting, inactive in a public place (e.g. a theatre or a meeting) 
  
 
 
As a passenger in a car for an hour without a break 
  
 
 
Lying down to rest in the afternoon when circumstances permit     
 
 
Sitting and talking to someone     
 
 
Sitting quietly after a lunch without alcohol     
 
 
In a car, while stopped for a few minutes in the traffic    
 
 
 
 
 
THANK YOU FOR YOUR COOPERATION 
 
 M.W. Johns 1990-
97 
CONFIDENTIAL
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Clinical Trial Protocol: 14-003 Amendment 3 
 
   
 
 
 
 
CONFIDENTIAL 
Page 92 of 102 
 
 
Appendix 6 
Functional Outcomes of Sleep Questionnaire Short 
Version (FOSQ-10) 
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©Weaver, June, 2004 
fosq.97 updated 6/04 
Functional Outcomes of Sleep Questionnaire (FOSQ ) short 
Page 1 
FUNCTIONAL OUTCOMES OF SLEEP QUESTIONNAIRE 
(FOSQ) 
Some people have difficulty performing everyday activities when they feel tired or sleepy.  The 
purpose of this questionnaire is to find out if you generally have difficulty carrying out certain 
activities because you are too sleepy or tired.  In this questionnaire, when the words “sleepy” or 
“tired” are used, it means the feeling that you can’t keep your eyes open, your head is droopy, 
that you want to “nod off”, or that you feel the urge to take a nap.  These words do not refer to 
the tired or fatigued feeling you may have after you have exercised. 
DIRECTIONS: Please put an (X) in the box for your answer to each question.  Select only one 
answer for each question.  Please try to be as accurate as possible.  All information will be kept 
confidential.  
(0) 
I don’t do 
this 
activity 
for other 
reasons 
(4) 
No 
difficulty 
 (3) 
Yes, 
a little 
difficulty 
(2) 
Yes, 
moderate 
difficulty 
(1) 
Yes, 
extreme 
difficulty 
1. Do you have difficulty concentrating on the
things you do because you are sleepy or tired? 
! 
! 
! 
!
2. Do you generally have difficulty
remembering things, because you are sleepy or 
tired? 
! 
! 
! 
!
3. Do you have difficulty operating a motor
vehicle for short distances (less than 100 miles) 
because you become sleepy or tired? 
! 
! 
! 
! 
!
4. Do you have difficulty operating a motor
vehicle for long distances (greater than 100  
miles) because you become sleepy or tired? 
! 
! 
! 
! 
!
CONFIDENTIAL
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Signature Date: 20160210
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©Weaver, June, 2004 
fosq.97 updated 6/04 
Functional Outcomes of Sleep Questionnaire (FOSQ ) short 
Page 2 
(0) 
I don’t do this 
activity for 
other reasons 
(4) 
No 
difficulty 
 (3) 
Yes, 
a little 
difficulty 
(2) 
Yes, 
moderate 
difficulty 
(1) 
Yes, 
extreme 
difficulty 
5. Do you have difficulty visiting with your
family or friends in their home because you 
become sleepy or tired? 
! 
! 
! 
! 
!
6. Has your relationship with family, friends
or work colleagues been affected because you 
are sleepy or tired?
! 
! 
! 
!
!
7. Do you have difficulty watching a movie
or videotape because you become sleepy or 
tired? 
! 
! 
! 
! 
!
8. Do you have difficulty being as active as
you want to be in the evening because you are 
sleepy or tired? 
! 
! 
! 
!
9. Do you have difficulty being as
active as you want to be in the morning 
because you are sleepy or tired? 
! 
! 
! 
!
(0) 
I don’t 
engage in 
sexual 
activity for 
other reasons 
(4) 
No 
(3) 
Yes, 
a 
little 
(2) 
Yes, 
moderately 
(1) 
Yes, 
extremely 
10. Has your desire for intimacy or sex
been affected because you are sleepy or tired? 
!
! 
! 
! 
!
Thank you for completing this questionnaire.
CONFIDENTIAL
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Signature Date: 20160210
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JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-003 Amendment 3 
 
   
 
 
 
 
CONFIDENTIAL 
Page 93 of 102 
 
 
Appendix 7 
36-Item Short Form Health Survey Version 2 (SF-36v2) 
CONFIDENTIAL
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Signature Date: 20160210
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SF-36v2™ Health Survey  1996, 2000 by QualityMetric Incorporated and Medical Outcomes Trust.  All Rights Reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
 
(SF-36v2 Standard, US Version 2.0) 
 
Your Health and Well-Being 
 
 
This survey asks for your views about your health.  This information will help 
keep track of how you feel and how well you are able to do your usual 
activities.  Thank you for completing this survey! 
For each of the following questions, please mark an 
 in the one box that best 
describes your answer. 
1. In general, would you say your health is: 
 
Excellent 
Very good 
Good 
Fair 
Poor 
 
 
 
 
 
  
1 
 
2 
 
3 
 
4 
 
5 
 
2. Compared to one year ago, how would you rate your health in general 
 
now? 
 
Much better 
now than one 
year ago 
Somewhat 
better now 
than one year 
ago 
About the 
same as one 
year ago 
Somewhat 
worse now 
than one year 
ago 
Much worse 
now than one 
year ago 
 
 
 
 
 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
CONFIDENTIAL
Page 97 of 122

Signature Date: 20160210
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SF-36v2™ Health Survey  1996, 2000 by QualityMetric Incorporated and Medical Outcomes Trust.  All Rights Reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
 
(SF-36v2 Standard, US Version 2.0) 
 
 
 
3. The following questions are about activities you might do during a typical 
day.  Does your health now limit you in these activities?  If so, how much? 
 
Yes, 
limited 
a lot 
Yes, 
limited 
a little 
No, not 
limited 
at all 
 
 
 
 
a  Vigorous activities, such as running, lifting  
 heavy objects, participating in strenuous  
 sports ....................................................................
1...................
2 ..................
3 
 
b   Moderate activities, such as moving a table,  
  pushing a vacuum cleaner, bowling, or  
 playing golf ...........................................................
1...................
2 ..................
3 
 
c   Lifting or carrying groceries ..................................
1...................
2 ..................
3 
 
d  Climbing several flights of stairs............................
1...................
2 ..................
3 
 
e  Climbing one flight of stairs...................................
1...................
2 ..................
3 
 
f  Bending, kneeling, or stooping...............................
1...................
2 ..................
3 
 
g Walking more than a mile ......................................
1...................
2 ..................
3
 
h Walking several hundred yards..............................
1...................
2 ..................
3
 
i Walking one hundred yards ....................................
1...................
2 ..................
3
 
j  Bathing or dressing yourself...................................
1...................
2 ..................
3
 
CONFIDENTIAL
Page 98 of 122

Signature Date: 20160210
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Signature Date:
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SF-36v2™ Health Survey  1996, 2000 by QualityMetric Incorporated and Medical Outcomes Trust.  All Rights Reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
 
(SF-36v2 Standard, US Version 2.0) 
 
4. During the past 4 weeks, how much of the time have you had any of the 
following problems with your work or other regular daily activities as a 
result of your physical health? 
 
 
All of 
the time
Most of 
the time
Some of 
the time 
A little 
of the 
time 
None of 
the time
 
 
 
 
 
a  Cut down on the amount of time you spent  
on work or other activities.......................................
1.........
2........
3.........
4.........
5 
b  Accomplished less than you would like .................
1.........
2........
3.........
4.........
5 
 
c  Were limited in the kind of work or other  
    activities.................................................................
1.........
2........
3.........
4.........
5 
d  Had difficulty performing the work or other  
  activities (for example, it took extra effort) ...........
1.........
2........
3.........
4.........
5 
 
5. During the past 4 weeks, how much of the time have you had any of the 
following problems with your work or other regular daily activities as a 
result of any emotional problems (such as feeling depressed or anxious)? 
 
All of 
the time
Most of 
the time
Some of 
the time 
A little 
of the 
time 
None of 
the time
 
 
 
 
 
 
a  Cut down on the amount of time you spent  
 on work or other activities ....................................
1 .........
2 ........
3..........
4.........
5 
b  Accomplished less than you would like................
1 .........
2 ........
3..........
4.........
5 
 
c  Did work or other activities less carefully  
 than usual...............................................................
1 .........
2 ........
3..........
4.........
5 
 
CONFIDENTIAL
Page 99 of 122

Signature Date: 20160210
JP: Protocol 14-003 Amendment 3.pdf
Signature Date:
JP: Protocol 14-003 Amendment 3.pdf
 
SF-36v2™ Health Survey  1996, 2000 by QualityMetric Incorporated and Medical Outcomes Trust.  All Rights Reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
 
(SF-36v2 Standard, US Version 2.0) 
6. During the past 4 weeks, to what extent has your physical health or 
emotional problems interfered with your normal social activities with 
family, friends, neighbors, or groups? 
Not at all 
Slightly 
Moderately 
Quite a bit 
Extremely 
 
 
 
 
 
 
1 
 
2 
 
3 
  
4 
 
5 
 
7. How much bodily pain have you had during the past 4 weeks? 
None 
Very mild 
Mild 
Moderate 
Severe 
Very Severe 
 
 
 
 
 
 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
8. During the past 4 weeks, how much did pain interfere with your normal 
work (including both work outside the home and housework)? 
Not at all 
A little bit 
Moderately 
Quite a bit 
Extremely 
 
 
 
 
 
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
 
CONFIDENTIAL
Page 100 of 122

Signature Date: 20160210
JP: Protocol 14-003 Amendment 3.pdf
Signature Date:
JP: Protocol 14-003 Amendment 3.pdf
 
SF-36v2™ Health Survey  1996, 2000 by QualityMetric Incorporated and Medical Outcomes Trust.  All Rights Reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
 
(SF-36v2 Standard, US Version 2.0) 
 
9. These questions are about how you feel and how things have been with you 
during the past 4 weeks.  For each question, please give the one answer that 
comes closest to the way you have been feeling.  How much of the time 
during the past 4 weeks... 
 
All of 
the time
Most of 
the time
Some of 
the time 
A little 
of the 
time 
None of 
the time
 
 
 
 
 
 
 
a   Did you feel full of life? ......................................
1..........
2 ..........
3..........
4 ..........
5
b  Have you been very nervous?..............................
1..........
2 ..........
3..........
4 ..........
5
 
c  Have you felt so down in the dumps  
 that nothing could cheer you up? .........................
1..........
2 ..........
3..........
4 ..........
5
d  Have you felt calm and peaceful?........................
1..........
2 ..........
3..........
4 ..........
5
 
e  Did you have a lot of energy?..............................
1..........
2 ..........
3..........
4 ..........
5
 
f  Have you felt downhearted and  
 depressed?............................................................
1..........
2 ..........
3..........
4 ..........
5
 
g  Did you feel worn out? ........................................
1..........
2 ..........
3..........
4 ..........
5
 
h  Have you been happy?.........................................
1..........
2 ..........
3..........
4 ..........
5
 
i  Did you feel tired?................................................
1..........
2 ..........
3..........
4 ..........
5
 
 
10.  During the past 4 weeks, how much of the time has your physical health  
or emotional problems interfered with your social activities (like visiting 
friends, relatives, etc.)? 
All of the 
time 
Most of the 
time 
Some of the 
time 
A little of the 
time 
None of the 
time 
 
 
 
 
 
 
1 
 
2 
 
3 
  
4 
 
5 
 
CONFIDENTIAL
Page 101 of 122

Signature Date: 20160210
JP: Protocol 14-003 Amendment 3.pdf
Signature Date:
JP: Protocol 14-003 Amendment 3.pdf
 
SF-36v2™ Health Survey  1996, 2000 by QualityMetric Incorporated and Medical Outcomes Trust.  All Rights Reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
 
(SF-36v2 Standard, US Version 2.0) 
11.   How TRUE or FALSE is each of the following statements for you? 
 
Definitely 
true 
Mostly 
true 
Don't 
know 
Mostly 
false 
Definitely 
false 
 
 
 
 
 
 
a  I seem to get sick a little easier  
 than other people....................................
1............
2 ...........
3 ...........
4 ...........
5 
b  I am as healthy as anybody I know........
1............
2 ...........
3 ...........
4 ...........
5 
c  I expect my health to get worse .............
1............
2 ...........
3 ...........
4 ...........
5 
d  My health is excellent............................
1............
2 ...........
3 ...........
4 ...........
5
 
 
THANK YOU FOR COMPLETING THESE QUESTIONS! 
 
CONFIDENTIAL
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Signature Date: 20160210
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Signature Date:
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JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-003 Amendment 3 
 
   
 
 
 
 
CONFIDENTIAL 
Page 94 of 102 
 
 
Appendix 8 
EuroQoL EQ-5D-5L 
The version attached is an example. The US English language version will be used in the US. 
CONFIDENTIAL
Page 103 of 122

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Signature Date: 20160210
JP: Protocol 14-003 Amendment 3.pdf
Signature Date:
JP: Protocol 14-003 Amendment 3.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-003 Amendment 3 
 
   
 
 
 
 
CONFIDENTIAL 
Page 95 of 102 
 
 
Appendix 9 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Baseline/Screening Version 
CONFIDENTIAL
Page 107 of 122

Signature Date: 20160210
JP: Protocol 14-003 Amendment 3.pdf
Signature Date:
JP: Protocol 14-003 Amendment 3.pdf
 
 
 
 
 
 
 
 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS)  
Baseline/Screening Version 
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 108 of 122

Signature Date: 20160210
JP: Protocol 14-003 Amendment 3.pdf
Signature Date:
JP: Protocol 14-003 Amendment 3.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. 
Lifetime: Time 
He/She Felt 
Most Suicidal 
Past __ 
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 
□    □ 
 
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 
   □    □ 
 
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 
 □    □ 
 
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 
□    □ 
 
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 
 □    □ 
 
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.  
                                   
Lifetime -           Most Severe Ideation:  _______                  ________________________________________ 
                                                                       Type # (1-5)                                                 Description of  Ideation 
 
Past X Months - Most Severe Ideation:  _______                   ________________________________________ 
                                                                      Type # (1-5)                                                 Description of  Ideation 
Most  
Severe 
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—Baseline/Screening (Version 1/14/09)    
 
 
                             Page 1 of 2     
CONFIDENTIAL
Page 109 of 122

Signature Date: 20160210
JP: Protocol 14-003 Amendment 3.pdf
Signature Date:
JP: Protocol 14-003 Amendment 3.pdf
SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
 
Lifetime 
Past __ 
Years 
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 
□   □ 
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 
 
______ 
 
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 
 
______ 
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 
□   □ 
 
 
Yes     No 
□   □ 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes      No 
□   □ 
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—Baseline/Screening (Version 1/14/09)    
 
 
                             Page 2 of 2     
CONFIDENTIAL
Page 110 of 122

Signature Date: 20160210
JP: Protocol 14-003 Amendment 3.pdf
Signature Date:
JP: Protocol 14-003 Amendment 3.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-003 Amendment 3 
 
   
 
 
 
 
CONFIDENTIAL 
Page 96 of 102 
 
 
Appendix 10 
Work Productivity and Activity Impairment 
Questionnaire: Specific Health Problem V2.0 
(WPAI:SHP) 
CONFIDENTIAL
Page 111 of 122

Signature Date: 20160210
JP: Protocol 14-003 Amendment 3.pdf
Signature Date:
JP: Protocol 14-003 Amendment 3.pdf
Work Productivity and Activity Impairment Questionnaire: 
Specific Health Problem V2.0 (WPAI:SHP) 
 
 
 
The following questions ask about the effect of your OSA on your ability to work and 
perform regular activities.  Please fill in the blanks or circle a number, as indicated. 
 
1. 
 Are you currently employed (working for pay)?  _____ NO ___ YES 
  If NO, check “NO” and skip to question 6. 
The next questions are about the past seven days, not including today. 
 
 
2. During the past seven days, how many hours did you miss from work because of 
problems associated with your OSA?  Include hours you missed on sick days, times 
you went in late, left early, etc., because of your OSA.  Do not include time you 
missed to participate in this study. 
 
_____ HOURS 
 
 
3. During the past seven days, how many hours did you miss from work because of 
any other reason, such as vacation, holidays, time off to participate in this study? 
 
_____HOURS 
 
 
4. During the past seven days, how many hours did you actually work? 
 
_____HOURS  (If “0”, skip to question 6.) 
 
 
 
 
 
 
 
 
 
 
Page 112 of 122
CONFIDENTIAL
Page 112 of 122

Signature Date: 20160210
JP: Protocol 14-003 Amendment 3.pdf
Signature Date:
JP: Protocol 14-003 Amendment 3.pdf
Reilly MC, Zbrozek AS, Dukes E: The validity and reproducibility of a work productivity and activity impairment measure.  
PharmacoEconomics 1993; 4(5):353-365. 
 
2
 
 
 
5. During the past seven days, how much did your OSA affect your productivity while 
you were working?   
 
Think about days you were limited in the amount or kind of work you could do, days 
you accomplished less than you would like, or days you could not do your work as 
carefully as usual.  If OSA affected your work only a little, choose a low number.  
Choose a high number if OSA affected your work a great deal.   
Consider only how much OSA affected  
productivity while you were working. 
OSA had no 
effect on my 
work 
 
 
 
 
 
 
 
 
 
 
 
OSA completely 
prevented me 
from working 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
CIRCLE A NUMBER 
 
6. During the past seven days, how much did your OSA affect your ability to do your 
regular daily activities, other than work at a job?   
 
By regular activities, we mean the usual activities you do, such as work around the 
house, shopping, childcare, exercising, studying, etc.  Think about times you were 
limited in the amount or kind of activities you could do and times you accomplished 
less than you would like.  If OSA affected your activities only a little, choose a low 
number.  Choose a high number if OSA affected your activities a great deal.   
 
Consider only how much OSA affected your ability  
to do your regular daily activities, other than work at a job. 
OSA had no 
effect on my 
daily activities 
 
 
 
 
 
 
 
 
 
 
 
OSA completely 
prevented me 
from doing my 
daily activities 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
                           
CIRCLE A NUMBER 
 
WPAI:SHP  V2.0 (US English)      
Page 113 of 122
CONFIDENTIAL
Page 113 of 122

Signature Date: 20160210
JP: Protocol 14-003 Amendment 3.pdf
Signature Date:
JP: Protocol 14-003 Amendment 3.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-003 Amendment 3 
 
   
 
 
 
 
CONFIDENTIAL 
Page 97 of 102 
 
 
Appendix 11 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Since Last Visit Version 
CONFIDENTIAL
Page 114 of 122

Signature Date: 20160210
JP: Protocol 14-003 Amendment 3.pdf
Signature Date:
JP: Protocol 14-003 Amendment 3.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 115 of 122

Signature Date: 20160210
JP: Protocol 14-003 Amendment 3.pdf
Signature Date:
JP: Protocol 14-003 Amendment 3.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 116 of 122

Signature Date: 20160210
JP: Protocol 14-003 Amendment 3.pdf
Signature Date:
JP: Protocol 14-003 Amendment 3.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)    
 
 
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Signature Date: 20160210
JP: Protocol 14-003 Amendment 3.pdf
Signature Date:
JP: Protocol 14-003 Amendment 3.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-003 Amendment 3 
 
   
 
 
 
 
CONFIDENTIAL 
Page 98 of 102 
 
 
Appendix 12 
Clinical Global Impression of Severity (CGIs) 
Check if Not Done □ 
 
CGI – SEVERITY 
(Choose only one) 
 
Considering your total clinical experience with this patient population, how ill is the patient at this 
time?  
 
□ 
1. Normal, not at all ill 
□ 
2. Borderline ill 
□ 
3. Mildly ill 
□ 
4. Moderately ill 
□ 
5. Markedly ill 
□ 
6. Severely ill 
□ 
7. Among the most extremely ill patients 
 
 
CONFIDENTIAL
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Signature Date: 20160210
JP: Protocol 14-003 Amendment 3.pdf
Signature Date:
JP: Protocol 14-003 Amendment 3.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-003 Amendment 3 
 
   
 
 
 
 
CONFIDENTIAL 
Page 99 of 102 
 
 
Appendix 13 
Clinical Global Impression of Change (CGIc) 
Check if Not Done □ 
 
CGI – CHANGE 
Compared to the subject’s condition at BASELINE, 
how much has he/she changed?  
(Choose only one) 
 
□  1. Very much improved 
□  2. Much improved 
□  3. Minimally improved 
□  4. No change 
□  5. Minimally worse 
□  6. Much worse 
□  7. Very much worse 
CONFIDENTIAL
Page 119 of 122

Signature Date: 20160210
JP: Protocol 14-003 Amendment 3.pdf
Signature Date:
JP: Protocol 14-003 Amendment 3.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-003 Amendment 3 
 
   
 
 
 
 
CONFIDENTIAL 
Page 100 of 102 
 
 
Appendix 14 
Patient Global Impression of Change (PGIc) 
Check if Not Done □ 
 
PGI – CHANGE 
(Choose only one) 
 
Since you STARTED study treatment, your OVERALL condition is:  
 
□  1. Very much improved 
□  2. Much improved 
□  3. Minimally improved 
□  4. No change 
□  5. Minimally worse 
□  6. Much worse 
□  7. Very much worse 
 
CONFIDENTIAL
Page 120 of 122

Signature Date: 20160210
JP: Protocol 14-003 Amendment 3.pdf
Signature Date:
JP: Protocol 14-003 Amendment 3.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-003 Amendment 3 
 
   
 
 
 
 
CONFIDENTIAL 
Page 101 of 102 
 
 
Appendix 15 
ICSD-3 Diagnostic Criteria for OSA  
ICSD-3 Diagnostic Criteria for Obstructive Sleep Apnea, Adult 
ICD-9-CM code: 327.23 
ICD-10-CM code: G47.33 
Alternate Names 
OSA syndrome, sleep apnea, sleep apnea syndrome, obstructive apnea, sleep disordered 
breathing, obstructive sleep apnea hypopnea syndrome. 
The term upper airway resistance syndrome (UARS) is subsumed under this diagnosis 
because the pathophysiology does not significantly differ from that of obstructive sleep 
apnea. Use of the term Pickwickian syndrome is discouraged because not only has it been 
applied to those with OSA, but also indiscriminately used to describe persons who are only 
obese and those with obesity hypoventilation syndrome. 
Diagnostic Criteria 
(A and B) or C satisfy the criteria 
A. The presence of one or more of the following: 
1. The patient complains of sleepiness, nonrestorative sleep, fatigue, or insomnia 
symptoms. 
2. The patient wakes with breath holding, gasping, or choking. 
3. The bed partner or other observer reports habitual snoring, breathing interruptions, or 
both during the patient’s sleep. 
4. The patient has been diagnosed with hypertension, a mood disorder, cognitive 
dysfunction, coronary artery disease, stroke, congestive heart failure, atrial 
fibrillation, or type 2 diabetes mellitus. 
B. Polysomnography (PSG) or OCST1 demonstrates: 
1. Five or more predominantly obstructive respiratory events2 (obstructive and mixed 
apneas, hypopneas, or respiratory effort related arousals [RERAs])3 per hour of sleep 
during a PSG or per hour of monitoring (OCST).1 
OR 
C. PSG or OCST1 demonstrates: 
1. Fifteen or more predominantly obstructive respiratory events (apneas, hypopneas, or 
RERAs)3 per hour of sleep during a PSG or per hour of monitoring (OCST).1 
Notes 
1. OCST commonly underestimates the number of obstructive respiratory events per hour as 
compared to PSG because actual sleep time, as determined primarily by EEG, is often not 
recorded. The term respiratory event index (REI) may be used to denote event frequency 
based on monitoring time rather than total sleep time. 
2. Respiratory events defined according the latest version of the AASM Manual for the 
Scoring of Sleep and Associated Events. 
3. RERAs and hypopnea events based on arousals from sleep cannot be scored using OCST 
because arousals by EEG criteria cannot be identified.  
American Academy of Sleep Medicine (AASM). Obstructive Sleep Apnea Disorders. In: 
International Classification of Sleep Disorders-Third Edition (ICSD-3), Darien, IL. 
American Academy of Sleep Medicine, 2014, 53-54. 
CONFIDENTIAL
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Signature Date: 20160210
JP: Protocol 14-003 Amendment 3.pdf
Signature Date:
JP: Protocol 14-003 Amendment 3.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-003 Amendment 3 
 
   
 
 
 
 
CONFIDENTIAL 
Page 102 of 102 
 
 
Appendix 16 
Signatures of Agreement for Protocol 
Study Title: 
A Twelve-Week, Double-Blind, Placebo-Controlled, Randomized, 
Parallel-Group, Multicenter Study of the Safety and Efficacy of 
JZP-110 [(R)-2-amino-3-phenylpropylcarbamate hydrochloride] in 
the Treatment of Excessive Sleepiness in Subjects with Obstructive 
Sleep Apnea (OSA) 
Study Number: 
14-003 
Original Protocol: 
17 December 2014 
Amendment 1: 
18 February 2015 
Amendment 2: 
10 September 2015 
Amendment 3: 
08 February 2016 
 
This clinical study protocol was subject to critical review and has been approved by Jazz 
Pharmaceuticals.  
 
Signed:  {Please see appended electronic signature page}  
Date: 
 
 
 
Signed:  {Please see appended electronic signature page}  
Date: 
 
 
 
Signed:  {Please see appended electronic signature page}  
Date: 
 
 
 
 
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Signature Date: 20160210
JP: Protocol 14-003 Amendment 3.pdf
 
 
 
Signature Manifestation