Conditions: Obstructive Sleep Apnea
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 174
Healthy volunteers: no

Brief summary:
This trial is a 6-week, double-blind, placebo-controlled, randomized-withdrawal, multicenter study of safety and efficacy of JZP-110 in the treatment of excessive sleepiness in adult subjects with OSA.

Detailed description:

Arms:
arm 1: Once Daily Dosing arm 2: Once Daily Dosing

Interventions: intervention 1: JZP-110
Intervention descriptions: intervention 1: None

Protocol document:
Prot_000.pdf: 
Signature Date: 20160210
JP: Protocol 14-004 Amendment 3.pdf
Signature Date:
JP: Protocol 14-004 Amendment 3.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-004 Amendment 3 
 
 
 
 
 
CONFIDENTIAL 
CONFIDENTIAL 
 
Clinical Trial Protocol: 14-004 
Study Title: 
A Six-Week, Double-Blind, Placebo-Controlled, Randomized-Withdrawal, 
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: 
2014-005515-16 
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 
Tel: (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: 
09 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the recipient(s) that no unpublished information contained herein will be published or disclosed 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. 
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JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-004 Amendment 3 
 
  
 
 
 
CONFIDENTIAL 
CONFIDENTIAL 
 
SYNOPSIS 
SPONSOR 
Jazz Pharmaceuticals 
PRODUCT 
JZP-110 [(R)-2-amino-3-phenylpropylcarbamate hydrochloride] 
TITLE 
A Six-Week, Double-Blind, Placebo-Controlled, Randomized-
Withdrawal, 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 
14-004 
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 
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 6 weeks in doses of 75, 150, and 300 mg 
compared to placebo in the treatment of excessive sleepiness in 
adult subjects with OSA. 
DESIGN 
 
 
 
 
 
 
 
 
 
This trial is a 6-week, double-blind, placebo-controlled, 
randomized-withdrawal, multicenter study of safety and 
efficacy of JZP-110 in the treatment of excessive sleepiness in 
adult subjects with OSA. Following the completion of a 
Screening Phase, subjects will enter a 2-week, open-label 
Titration Phase. 
During the 2-week Titration Phase, subjects will be titrated to 
the maximal dose that is tolerated. Subjects will start at a 
once-daily dose of 75 mg JZP-110 and will be able to titrate up 
one dose level (to 150 mg/day or a maximum dose of 
300 mg/day) once every 3 days following a telephone 
consultation with investigative site staff. Subjects will also be 
able to titrate down to 75 mg or 150 mg at any time following a 
telephone consultation with investigative site staff. Following 
completion of the Titration Phase, subjects who have been 
titrated to an efficacious and tolerable dose will remain on that 
dose for the subsequent 2 weeks during an open-label Stable 
Dose Phase. During the 2-week Stable Dose Phase, subjects 
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JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-004 Amendment 3 
 
  
 
 
 
CONFIDENTIAL 
CONFIDENTIAL 
 
 
 
 
 
 
will receive a once daily dose of JZP-110 equal to the dose that 
they received at the end of the Titration Phase. 
At the end of the Stable Dose Phase (Week 4), subjects who 
report much or very much improvement on the Patient Global 
Impression of Change (PGIc) scale as compared to the 
beginning of the Titration Phase (after discontinuation of prior 
medications and before receiving JZP-110) will undergo 
additional assessments, which will include an overnight stay at 
the investigational site for nocturnal polysomnography (PSG) 
followed by a Maintenance of Wakefulness Test (MWT) as 
well as safety assessments. Subjects who complete the Week 4 
Visit and who report much or very much improvement on the 
PGIc scale and whose mean sleep latency on the MWT and 
Epworth Sleepiness Scale (ESS) scores also improve will be 
randomized in the Double-blind Withdrawal Phase. 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 ratio to continue to receive JZP-110 at 
the dose that was received in the Stable Dose Phase or to 
receive placebo for 2 weeks in the Double-blind Withdrawal 
Phase. Subjects who do not report being much or very much 
improved on the PGIc scale or who do not improve on the 
MWT and ESS from the beginning of the Titration Phase to 
Week 4 will be discontinued from the study. 
At the conclusion of the 2-week Double-blind Withdrawal 
Phase (end of Week 6), subjects will return to the investigative 
site for a nocturnal PSG and MWT in addition to other efficacy 
and safety assessments. The final dose of study medication will 
be taken prior to the initiation of the Week 6 MWT. 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 ESS score from Week 4 to Week 6 as co-primary 
endpoints, percentage of patients who report a worsening of 
their condition on the PGIc from Week 4 to Week 6 as a key 
secondary endpoint, and Clinical Global Impression of Change 
(CGIc) and Functional Outcomes of Sleep Questionnaire Short 
Version (FOSQ-10) from Week 4 to Week 6 as additional 
secondary endpoints. 
Subjects will return at the end of Week 8, 2 weeks after the 
final dose of study medication, 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 8 visit. 
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Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-004 Amendment 3 
 
  
 
 
 
CONFIDENTIAL 
CONFIDENTIAL 
 
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 sign measurements, 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 28 days for the 
Screening procedures, 6 weeks for the Titration, Stable Dose, 
and Double-blind Withdrawal Phases, and 2 weeks for the 
Safety Follow-up Phase. 
It is estimated that the enrollment across all sites will be 
completed in 10 months. 
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 200 subjects are planned for enrollment to 
ensure that 122 subjects are randomized in the Double-blind 
Withdrawal Phase with 61 subjects per treatment group. These 
sample sizes will provide at least 90% power to detect 
differences of 6 minutes in the mean sleep latency time as 
determined from the MWT (mean of the first four trials) and 
3.5 points in ESS changes from the beginning to the end of the 
2-week Double-blind Withdrawal Phase. This calculation 
assumes common standard deviations of 9.5 minutes for the 
MWT and 5 points for the ESS changes during the Double-
blind Withdrawal Phase and a two-sided significance level of 
0.05 using a t-test. 
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 
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Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-004 Amendment 3 
 
  
 
 
 
CONFIDENTIAL 
CONFIDENTIAL 
 
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 the Titration Phase 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. Epworth Sleepiness Scale (ESS) score ≥10 at the beginning 
of the Titration Phase. 
6. Mean sleep latency <30 minutes as documented by the 
mean of the first four trials of the MWT at the beginning of 
the Titration Phase. 
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 
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Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-004 Amendment 3 
 
  
 
 
 
CONFIDENTIAL 
CONFIDENTIAL 
 
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 or safety 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 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 pressure 
≥155 mmHg or diastolic blood pressure ≥95 mmHg (at 
screening, or consistently across measures at Visit 2 
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 the Titration 
Phase 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 Titration Phase 
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 Titration Phase, in 
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Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-004 Amendment 3 
 
  
 
 
 
CONFIDENTIAL 
CONFIDENTIAL 
 
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) before the 
Titration Phase, 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) before the Titration 
Phase assessments, 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 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 for each subject will be approximately 
6 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 the end of the Stable Dose Phase 
(Week 4) to the end of the Double-blind Withdrawal 
Phase (Week 6) 
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Clinical Trial Protocol: 14-004 Amendment 3 
 
  
 
 
 
CONFIDENTIAL 
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• ESS: Change in ESS score from the end of the Stable 
Dose Phase (Week 4) to the end of the Double-blind 
Withdrawal Phase (Week 6) 
Key Secondary Efficacy Endpoint: 
• PGIc: Percentage of subjects reported as worse 
(minimally, much, or very much) on the PGIc at the end 
of the Double-blind Withdrawal Phase (Week 6) 
PHARMACOKINETIC 
ASSESSMENTS 
None 
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, 12-lead ECGs, physical exams, and C-SSRS assessments. 
STATISTICAL 
ANALYSIS 
For comparisons between JZP-110 and placebo, subjects who 
were randomized to continue JZP-110 in the Double-Blind 
Withdrawal Phase will be treated as a single group regardless of 
the dose of JZP-110 that they received. Thus, there will be no 
multiplicity issues with respect to multiple doses in the 
hypotheses testing. A fixed sequential testing strategy will be 
employed to address the multiplicity issues in testing multiple 
endpoints (co-primary and key secondary endpoints). 
For the analysis of the co-primary efficacy endpoints, an 
analysis of covariance (ANCOVA) model will be used. This 
model will include treatment group, the measurement at the end 
of the Stable Dose Phase (Week 4), and randomization 
stratification factor as fixed effects. SAS procedure PROC 
GLM will be used to carry out this analysis. The estimates of 
treatment difference versus placebo and their 95% confidence 
intervals will be presented. The last-observation carried forward 
(LOCF) approach will be used for subjects who discontinued 
early in the Double-Blind Withdrawal Phase. 
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 
09 February 2016 
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Clinical Trial Protocol: 14-004 Amendment 3 
 
  
 
 
 
CONFIDENTIAL 
CONFIDENTIAL 
 
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 ..............................................................................................24 
3 
STUDY DESIGN.............................................................................................................24 
3.1 
Overall Study Design and Plan ..............................................................................24 
3.1.1 
Rationale for Study Design and Control Group ...........................................28 
3.2 
Study Duration and Dates ......................................................................................28 
3.3 
End of Trial ............................................................................................................28 
4 
STUDY POPULATION SELECTION ...........................................................................28 
4.1 
Selection of Study Population ................................................................................28 
4.2 
Inclusion Criteria ...................................................................................................28 
4.3 
Exclusion Criteria ..................................................................................................29 
4.4 
Screening and Randomization Eligibility ..............................................................31 
5 
STUDY TREATMENT(S) ..............................................................................................31 
5.1 
Description of Treatment(s) ...................................................................................31 
5.1.1 
JZP-110 ........................................................................................................31 
5.1.2 
Placebo .........................................................................................................32 
5.2 
Treatments Administered .......................................................................................32 
5.3 
Selection and Timing of Dose for Each Subject ....................................................32 
5.4 
Method of Assigning Subjects to Treatment Groups .............................................33 
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Clinical Trial Protocol: 14-004 Amendment 3 
 
  
 
 
 
CONFIDENTIAL 
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5.5 
Randomization .......................................................................................................33 
5.6 
Blinding..................................................................................................................33 
5.7 
Prior and Concomitant Therapy .............................................................................34 
5.8 
Restrictions ............................................................................................................34 
5.8.1 
Prior Therapy ...............................................................................................34 
5.8.2 
Fluid and Food Intake ..................................................................................34 
5.8.3 
Other Restrictions ........................................................................................34 
5.9 
Investigational Medicinal Product Treatment Compliance ...................................35 
5.10 
Packaging and Labeling .........................................................................................35 
5.11 
Storage and Accountability ....................................................................................35 
5.12 
Investigational Medicinal Product Retention at Study Site ...................................36 
6 
STUDY PROCEDURES .................................................................................................36 
6.1 
Informed Consent...................................................................................................36 
6.2 
Demographics ........................................................................................................36 
6.3 
Medical History .....................................................................................................36 
6.4 
Physical Examination.............................................................................................36 
6.5 
Vital Signs ..............................................................................................................37 
6.6 
Electrocardiography ...............................................................................................37 
6.7 
Polysomnography (PSG) .......................................................................................37 
6.8 
Columbia-Suicide Severity Rating Scale (C-SSRS) ..............................................38 
6.9 
Clinical Laboratory Tests .......................................................................................38 
6.9.1 
Laboratory Parameters .................................................................................38 
6.9.2 
Sample Collection, Storage, and Shipping ..................................................41 
6.10 
Dispensing Study Drug ..........................................................................................42 
6.11 
Efficacy Assessments.............................................................................................42 
6.11.1 
Maintenance of Wakefulness Test (MWT) ..................................................42 
6.11.2 
Epworth Sleepiness Scale (ESS) ..................................................................42 
6.11.3 
Clinician Global Impression of Severity (CGIs) .........................................43 
6.11.4 
Clinician Global Impression of Change (CGIc) ..........................................43 
6.11.5 
Patient Global Impression of Change (PGIc) ..............................................43 
6.11.6 
Functional Outcomes of Sleep Questionnaire (FOSQ-10) ..........................43 
6.11.7 
Primary OSA Therapy Use ..........................................................................43 
6.12 
Adverse Event Reporting .......................................................................................44 
6.12.1 
Adverse Events (AEs) ..................................................................................44 
6.12.1.1 
Severity Assessment ..........................................................................45 
6.12.1.2 
Serious Adverse Events and Seriousness Assessment .......................45 
6.12.1.3 
Causal Relationship to Study Drug or Procedure ..............................46 
6.12.1.4 
Other Immediately Reportable Experiences ......................................47 
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Clinical Trial Protocol: 14-004 Amendment 3 
 
  
 
 
 
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6.12.1.5 
Adverse Events Recording and Reporting .........................................48 
6.12.1.6 
Follow-up of Adverse Events and Serious Adverse Events ..............48 
6.12.2 
Post-Study Reporting Requirements ............................................................48 
6.12.3 
Pregnancy .....................................................................................................48 
6.12.4 
Emergency Unblinding ................................................................................49 
6.13 
Removal of Subjects from the Trial or Study Drug ...............................................49 
6.13.1 
Handling of Early Terminations ..................................................................50 
6.13.2 
Jazz Pharmaceuticals’ Termination of Study ...............................................50 
6.14 
Appropriateness of Measurements .........................................................................50 
7 
STUDY ACTIVITIES .....................................................................................................51 
7.1 
Screening Clinic Visit(s) ........................................................................................51 
7.1.1 
Screening Visit 1, Days -31 to -3 .................................................................51 
7.1.2 
Rescreening ..................................................................................................52 
7.2 
Titration Phase .......................................................................................................52 
7.2.1 
Beginning of Titration Phase Clinic Visit ....................................................52 
7.2.2 
Titration Phase Phone Contacts ...................................................................54 
7.2.3 
Week 2 – End Titration Phase Clinic Visit ..................................................55 
7.3 
Stable Dose Phase ..................................................................................................56 
7.3.1 
Week 3 – Stable Dose Phase Phone Contact ...............................................56 
7.3.2 
Week 4 – End of Stable Dose Phase Clinic Visit ........................................56 
7.4 
Double-blind Withdrawal Phase ............................................................................58 
7.4.1 
Week 5 – Double-blind Withdrawal Phase Phone Contact .........................58 
7.4.2 
Week 6 – End of Double-Blind Withdrawal Phase Clinic Visit ..................58 
7.5 
Follow-up Period ...................................................................................................60 
7.5.1 
Week 8 – Safety Follow-up Clinic Visit ......................................................60 
7.6 
Early Termination Clinic Visit ...............................................................................60 
7.7 
Discontinuations ....................................................................................................61 
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 ...............................................................................62 
9.4 
Analysis Populations ..............................................................................................62 
9.5 
Demographics and Baseline Characteristics ..........................................................63 
9.6 
Handling of Dropouts and Missing Data ...............................................................63 
9.7 
Pooling of Investigation Centers ............................................................................63 
9.8 
Efficacy Endpoints .................................................................................................63 
9.8.1 
Co-primary Efficacy Endpoint .....................................................................63 
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Clinical Trial Protocol: 14-004 Amendment 3 
 
  
 
 
 
CONFIDENTIAL 
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9.8.2 
Key Secondary Efficacy Endpoint ...............................................................64 
9.8.3 
Additional Secondary Endpoints .................................................................64 
9.8.4 
Exploratory Endpoints .................................................................................64 
9.9 
Safety Endpoints ....................................................................................................64 
9.10 
Efficacy Analyses ..................................................................................................64 
9.11 
Safety Analyses ......................................................................................................65 
9.11.1 
Adverse Event ..............................................................................................65 
9.11.2 
Vital Signs ....................................................................................................66 
9.11.3 
Laboratory Evaluation .................................................................................66 
9.11.4 
12-Lead Electrocardiograms ........................................................................66 
9.11.5 
Physical Examinations .................................................................................66 
9.11.6 
Columbia-Suicide Severity Rating Scale (C-SSRS) ....................................66 
9.12 
Subgroup Analyses ................................................................................................66 
9.13 
Interim Analysis and Data Monitoring ..................................................................67 
10 DATA QUALITY ASSURANCE ...................................................................................67 
10.1 
Data Management ..................................................................................................67 
10.2 
Case Report Forms .................................................................................................67 
10.3 
Retention of Data ...................................................................................................67 
10.4 
Data Safety Monitoring Board ...............................................................................68 
11 ADMINISTRATIVE CONSIDERATIONS ....................................................................68 
11.1 
Investigators and Study Administrative Structure .................................................68 
11.1.1 
Contract Research Organization ..................................................................68 
11.1.2 
Jazz Pharmaceuticals Medical Monitors ......................................................68 
11.1.3 
EU Medical Monitor ....................................................................................68 
11.1.4 
Investigator ..................................................................................................68 
11.2 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval ................................................................................................................68 
11.3 
Ethical/Legal Conduct of the Study .......................................................................69 
11.4 
Subject Information and Consent...........................................................................69 
11.5 
Subject Confidentiality ..........................................................................................70 
11.6 
Protocol Adherence – Amendments ......................................................................70 
11.7 
Required Documents ..............................................................................................70 
11.8 
Study Monitoring ...................................................................................................70 
11.9 
Protocol Violations/Deviations ..............................................................................71 
11.10 Access to Source Documentation ..........................................................................71 
11.11 Publication and Disclosure Policy .........................................................................71 
12 REFERENCE LIST .........................................................................................................73 
13 LIST OF UNPUBLISHED STUDY REPORTS .............................................................76 
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LIST OF IN-TEXT TABLES 
Table 1 
List of Laboratory Tests ...............................................................................40 
Table 2 
Schedule of Clinical Laboratory Samples and Estimated Blood Volume ...41 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Study Schema...............................................................................................27 
 
LIST OF APPENDIXES 
Appendix 1 
Schedule of Events .............................................................................77 
Appendix 2 
Example Schedule of Times for Procedures During MWT Visits ....80 
Appendix 3 
DSM-5 Criteria for Psychiatric Disorders .........................................81 
Appendix 4 
DSM-5 Substance Use Disorder Diagnostic Criteria .........................88 
Appendix 5 
Epworth Sleepiness Scale (ESS) ........................................................89 
Appendix 6 
Functional Outcomes of Sleep Questionnaire Short Version 
                        (FOSQ-10)..........................................................................................91 
Appendix 7 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
                         Baseline/Screening Version ..............................................................94 
Appendix 8 
Columbia-Suicide Severity Rating Scale (C-SSRS) Since Last Visit 
                        Version.................................................................................................98 
Appendix 9 
Clinical Global Impression of Severity (CGIs) ................................102 
Appendix 10 
Clinical Global Impression of Change (CGIc) - Week 4 ..................103 
Appendix 11 
Clinical Global Impression of Change (CGIc) - Week 6 ..................104 
Appendix 12 
Patient Global Impression of Change (PGIc) – Week 4 ...................105 
Appendix 13 
Patient Global Impression of Change (PGIc) - Week 6 ....................106 
Appendix 14 
ICSD-3 Diagnostic Criteria for OSA ................................................107 
Appendix 15 
Signatures of Agreement for Protocol ..............................................108 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AASM 
American Academy of Sleep Medicine 
ACC 
ACC American College of Cardiology 
AE 
Adverse event 
AHA 
AHA American Heart Association 
AHI 
Apnea hypopnea index 
AICD 
Automatic Implantable Cardioverter Defibrilator 
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 
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 
Good Manufacturing Practices 
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 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
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ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EMA 
European Medicines Agency 
EU 
European Union 
ESS 
Epworth Sleepiness Scale 
FDA 
Food and Drug Administration 
FSH 
Follicle stimulating hormone 
FOSQ-10 
Functional Outcomes of Sleep Questionnaire Short Version 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization  
ICSD-3 
International Classification of Sleep Disorders, 3rd Edition 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug  
IRB 
Institutional Review Board 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
K 
Potassium 
LOCF 
Last Observation Carried Forward 
MCC 
Microcrystalline cellulose 
MDD 
Major depressive disorder 
MAOI 
Monoamine Oxidase Inhibitor 
mITT 
Modified Intent-to-treat 
MSLT 
Multiple Sleep Latency Test 
MWT 
Maintenance of Wakefulness Test 
OSA 
Obstructive Sleep Apnea 
OCST 
Out of center sleep test 
OTC 
Over the counter 
PAP 
Positive airway pressure 
PGIc 
Patient Global Impression of change 
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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 
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 
WASO 
Wake after sleep onset 
WBC 
White blood cell (count) 
 
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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 
(see ICSD-3 criteria in Appendix 14). 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 
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estimated that 46-83% of patients with OSA are non-compliant with their prescribed 
continuous positive airway pressure (CPAP) therapy (Weaver & Grunstein 2008). 
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 
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latency using a 20-minute MWT with maximal differences in the means between drug and 
placebo groups ranging from 2.3 to 4.5 minutes (US Modafinil in Narcolepsy Multicenter 
Study Group 1998, US Modafinil in Narcolepsy Multicenter Study Group 2000, Harsh et al. 
2006). 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. Importantly, these studies found no unexpected drug-
related toxicities and concluded that JZP-110 appeared to be safe and well tolerated under the 
parameters tested. Taken together, these data suggest that JZP-110 may offer an important 
advance in the treatment of excessive sleepiness in OSA by increasing patients’ ability to 
stay awake throughout the day. 
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 (ADX-N05 202) 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 
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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 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, and 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 the 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, 
555received 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.  
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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.  
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. 
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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 
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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JZP-110 
 
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Clinical Trial Protocol: 14-004 Amendment 3 
 
  
 
 
 
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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 who are titrated to an efficacious and tolerable dose 
in this study are expected to be a clinically significant increase in the ability to stay awake 
and a clinically significant decrease in subjective sleepiness. These benefits are anticipated 
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from the MWT and ESS data, respectively, from previous studies of doses of 150 and 300 
mg JZP-110 in narcolepsy patients. However, the therapeutic benefit of JZP-110 in OSA 
patients is not known, and not every subject is anticipated to benefit from JZP-110. It is not 
known if the 75 mg dose will provide a clinical benefit in this study, however, all subjects 
will undergo titration in an attempt to maximize the therapeutic efficacy of JZP-110 at a dose 
that is safe and tolerable. The administration of placebo during the Double-blind Withdrawal 
Phase is not anticipated to provide any benefit. 
The risks to subjects in this study who receive 150 mg or 300 mg JZP-110 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 
75 mg dose 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 during the Double-blind Withdrawal Phase 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  
The primary objective of this study is to evaluate the efficacy of JZP-110 administered once 
daily compared to placebo in the treatment of excessive sleepiness in adult subjects with 
OSA. 
2.2 
Secondary Objective  
The secondary objective of this study is to evaluate the safety and tolerability of JZP-110 
administered once daily for up to 6 weeks in doses of 75, 150, and 300 mg compared to 
placebo in the treatment of excessive sleepiness in adult subjects with OSA. 
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. 
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Clinical Trial Protocol: 14-004 Amendment 3 
 
  
 
 
 
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This trial is a 6-week, double-blind, placebo-controlled, randomized-withdrawal, multicenter 
study of safety and efficacy of JZP-110 in the treatment of excessive sleepiness in adult 
subjects with OSA. Following the completion of a Screening Phase, subjects will enter a 
2-week, open-label Titration Phase. 
During the 2-week Titration Phase, subjects will be titrated to the maximal dose that is 
tolerated. Subjects will start at a once-daily dose of 75 mg JZP-110 and will be able to titrate 
up one dose level (to 150 mg/day or a maximum dose of 300 mg/day) once every 3 days 
following a telephone consultation with investigative site staff. Subjects will also be able to 
titrate down to 75 mg or 150 mg at any time following a telephone consultation with 
investigative site staff. Following completion of the Titration Phase, subjects who have been 
titrated to an efficacious and tolerable dose will remain on that dose for the subsequent 
2 weeks during an open-label Stable Dose Phase. During the 2-week Stable Dose Phase, 
subjects will receive a once daily dose of JZP-110 equal to the dose that they received at the 
end of the Titration Phase. 
At the end of the Stable Dose Phase (Week 4), subjects who report much or very much 
improvement on the Patient Global Impression of Change (PGIc) scale as compared to the 
beginning of the Titration Phase (after discontinuation of prior medications and before 
receiving JZP-110) will undergo additional assessments, which will include an overnight stay 
at the investigational site for nocturnal polysomnography (PSG) followed by a Maintenance 
of Wakefulness Test (MWT) as well as safety assessments. Subjects who complete the 
Week 4 Visit and who report much or very much improvement on the PGIc scale and whose 
mean sleep latency on the MWT and Epworth Sleepiness Scale (ESS) scores also improve 
will be randomized in the Double-blind Withdrawal Phase. 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 ratio to continue to receive JZP-110 at the dose that was received 
in the Stable Dose Phase or to receive placebo for 2 weeks in the Double-blind Withdrawal 
Phase. Subjects who do not report being much or very much improved on the PGIc scale or 
who do not improve on the MWT and ESS from the beginning of the Titration Phase to 
Week 4 will be discontinued from the study. 
At the conclusion of the 2-week Double-blind Withdrawal Phase (end of Week 6), subjects 
will return to the investigative site for a nocturnal PSG and MWT in addition to other 
efficacy and safety assessments. The final dose of study medication will be taken prior to the 
initiation of the Week 6 MWT. 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 ESS 
score from Week 4 to Week 6 as co-primary endpoints, percentage of patients who report a 
worsening of their condition on the PGIc from Week 4 to Week 6 as a key secondary 
endpoint, and Clinical Global Impression of Change (CGIc) and Functional Outcomes of 
Sleep Questionnaire Short Version (FOSQ-10) from Week 4 to Week 6 as additional 
secondary endpoints. 
Subjects will return at the end of Week 8, 2 weeks after the final dose of study medication, 
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 8 visit. 
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Clinical Trial Protocol: 14-004 Amendment 3 
 
  
 
 
 
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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 sign measurements, 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 as a control arm in the 2-week Double-blind Withdrawal 
Phase of 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 up to 28 days for Screening procedures, 6 weeks for the 
Titration, Stable Dose, and Double-blind Withdrawal Phases, and 2 weeks in the Safety 
Follow-up Phase. It is estimated that the enrollment across all sites will be completed in 
10 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 the International 
Classification of Sleep Disorders, Third Edition (ICSD-3). 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. 
The subjects who enter the Double-blind Withdrawal Phase will be those who have 
responded positively to the study drug and who continue to meet the inclusion criteria and do 
not meet any exclusion criteria. The entrance criteria for the Double-blind Withdrawal Phase 
will include subjects who complete the Week 4 Visit and who from the beginning of the 
Titration Phase (Day -1) to Week 4: 
• report much or very much improvement on the PGIc scale, 
• have a numerical improvement in mean sleep latency on the MWT, and 
• have a numerical improvement in ESS score. 
 
4.2 
Inclusion Criteria 
Each subject must meet the following criteria to be enrolled in the study. 
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1. Male or female between 18 and 75 years of age, inclusive. 
2. Diagnosis of OSA according to ICSD-3 criteria (Appendix 14). 
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 the Titration Phase 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. Epworth Sleepiness Scale (ESS) score ≥10 at the beginning of the Titration Phase. 
6. Mean sleep latency <30 minutes as documented by the mean of the first four trials of 
the MWT at the beginning of the Titration Phase. 
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 or safety assessments 
or the ability of the subject to complete the trial per the judgment of the Investigator. 
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8. History of bariatric surgery within the past year or a history of any gastric bypass 
procedure. 
9. Presence of renal impairment or 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 pressure ≥155 mmHg or diastolic blood pressure 
≥95 mmHg (at screening, or consistently across measures at Visit 2 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 the Titration Phase 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 Titration Phase 
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 Titration Phase, 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) before the Titration Phase, 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) before the Titration Phase assessments, 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. 
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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 
postmenopausal range and a negative serum or urine βHCG); vasectomy (>6 months prior to 
dosing with the study drug) 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 will not 
receive study drug. 
Subjects who will be eligible for randomization in the Double-blind Withdrawal Phase will 
be those who have responded positively to the study drug and who continue to meet the 
inclusion criteria and do not meet any exclusion criteria. The entrance criteria for the Double-
blind Withdrawal Phase will include subjects who complete the Week 4 Visit and who from 
the beginning of the Titration Phase (Day -1) to Week 4: 
• report much or very much improvement on the PGIc scale, 
• have a numerical improvement in mean sleep latency on the MWT, and 
• have a numerical improvement in ESS score. 
 
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 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. 
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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 75, 150, or 300 mg once daily as a single gelatin capsule 
during the Titration and Stable Dose Phases of the study. Subjects will receive one of the 
doses of JZP-110 listed above or placebo once daily as a single gelatin capsule during the 
Double-blind Withdrawal Phase of the study. 
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 the lower dose of 75 mg JZP-110 given once a day in the morning. 
In this study, subjects will be titrated to an effective and tolerated dose over 2 weeks in the 
Titration Phase, will continue to receive that dose for 2 weeks in the Stable Dose Phase, and 
will be randomized 1:1 as described in Section 5.5 to either continue to receive JZP-110 at 
the dose that was received in the Stable Dose Phase or to receive placebo for 2 weeks in the 
Double-blind Withdrawal Phase. In each phase of the study, 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 will initially receive 
75 mg from Day 1 through Day 3 of the Titration Phase and will be able to titrate up one 
dose level (to 150 mg/day or a maximum dose of 300 mg/day) once every 3 days following a 
telephone consultation with investigative site staff. Subjects will also be able to titrate down 
to any dose at any time following a telephone consultation with investigative site staff to 
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achieve optimal efficacy and tolerability. Although previous studies have shown that the 
150 mg dose is tolerated as a starting dose in patients with narcolepsy, subjects in this study 
initially receive 75 mg from Day 1 through Day 3 of the first week of the Titration Phase 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. 
 
5.4 
Method of Assigning Subjects to Treatment Groups 
Subjects who complete the Week 4 Visit at the end of the Stable Dose Phase, who report 
much or very much improvement on the PGIc scale, and who also show a numerical 
improvement in mean sleep latency on the MWT and ESS score from the beginning of the 
Titration Phase (Day -1) to Week 4 will be randomized in the Double-blind Withdrawal 
Phase. Stratified randomization on the basis of subjects’ compliant or non-compliant use of 
their primary OSA therapy at the end of the Stable Dose Phase will be used to assign subjects 
in a 1:1 ratio to continue to receive JZP-110 at the dose that was received in the Stable Dose 
Phase or to receive placebo for 2 weeks in the Double-blind Withdrawal Phase. 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. 
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 
The Titration and Stable Dose Phases of this study will not be blinded to the subjects or the 
investigators. A double-blind approach will be used during the Double-blind Withdrawal 
Phase with subjects and all study personnel blinded to treatment. All study drug throughout 
the study will be prepared in identical opaque gelatin capsules to ensure adequate blinding in 
the Double-blind Withdrawal Phase. 
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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 Visit 2 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 in 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 section of the CRF. 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. 
The day after the overnight stay at Weeks 4 and 6, 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 times indicated in the Schedule 
of Events (Appendix 1) and Section 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 
Day -1 and Weeks 4 and 6, the light breakfast will be served approximately 30 minutes after 
dosing and should be consumed within 15-20 minutes. Caffeine consumption will not be 
allowed during the Day -1 and the Weeks 4 and 6 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 
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during the MWT trials (Section 6.11.1). In between the MWT trials subjects will be free to 
move about while staying at the sleep lab.  
Cigarette smokers will be allowed to smoke 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. 
At other times during the study there are no restrictions on activity. 
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.  
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. 
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 6.10. 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 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.  
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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/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; any 
medications or devices used for the treatment of OSA since diagnosis; any prior reaction to 
drugs; history and treatment (if any) of cardiovascular, pulmonary, gastrointestinal, hepatic, 
renal, immunologic, neurologic, or psychiatric disease; reproductive status; and confirmation 
of relevant inclusion criteria. Medical history should include documenting the diagnosis of 
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 Day -2 visit. 
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 6) 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. 
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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 Day -1 and the end of Weeks 4 and 6; at Week 2; and at the Follow-up visit or at 
Early Termination. 
On the MWT day at the start of the Titration Period (Day -1), 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 6 (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 
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 
Electrocardiography 
Standard 12-lead ECGs will be recorded with the subject resting supine for at least 5 minutes. 
ECGs will be performed at every clinic visit. The schedule of ECG assessment is described 
in Section 7 and Appendix 2. 
6.7 
Polysomnography (PSG) 
A PSG followed by an MWT will be performed at the beginning of the Titration Phase 
(Day -2) and at Weeks 4 and 6 (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 results. 
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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. 
6.8 
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 7). 
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 Follow-up visit (Appendix 8). 
6.9 
Clinical Laboratory Tests 
6.9.1 
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 
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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. 
Clinical laboratory tests will include the following: 
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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 Day -1, Week 6, and 
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  
Visit 2* and Week 6 
 
3 × 6 mL 
 
 
18 mL 
 
Hematology: 
Screening, Visit 2*, Week 6 
 
3 × 4 mL 
 
12 mL 
Serum pregnancy test (for females of 
childbearing potential) 
Screening 
 
1 × 1 mL 
 
1 mL 
Approximate total blood volume per 
subject: 
females of childbearing potential 
males and females who are not of 
childbearing potential 
 
 
 
31 mL 
30 mL 
*Required if Visit 2 occurs outside of the screening window (i.e., >29 days after the 
Screening Visit). Repeat Screening labs at Visit 2 may be fasting or nonfasting. 
 
6.9.2 
Sample Collection, Storage, and Shipping 
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 6 or Early Termination. If Visit 2 occurs 
outside of the screening window (i.e., >29 days after the Screening Visit), hematology and 
chemistry tests should be collected at Visit 2 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. 
A urine sample for urinalysis will be collected at Screening (or Rescreening) and Week 6 or 
Early Termination. A repeat urinalysis should be obtained if Visit 2 occurs outside of the 
screening window (i.e., >29 days after the Screening Visit). 
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), beginning of the Titration 
Phase, and Week 6 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). Urine pregnancy tests will be performed at the beginning of the Titration 
Phase and at Week 6 or Early Termination (Table 1). 
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6.10  Dispensing Study Drug 
Study drug will be dispensed to subjects at the beginning of the Titration Phase and at the 
end of Weeks 2 and 4 or at alternative intervals if necessary to comply with State and local 
laws and regulations. Subjects will be instructed to begin daily dosing with the new supply of 
study drug the day after the completion of visits at the beginning of the Titration Phase and at 
the end of Weeks 2 and 4. Subjects will also be provided with dosing instructions consistent 
with the restrictions described in Section 5.8. On the day after the overnight PSG, on the 
morning of the MWT at Weeks 4 and 6, and at Early Termination if a PSG/MWT is 
performed, study drug will be administered by qualified study site personnel as described in 
Section 7 and Appendix 2. 
6.11 Efficacy Assessments 
6.11.1 
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 five-trial, 
40-minute MWT will be performed at the beginning of the Titration Phase (Day -1) and at 
the Week 4 and 6 visits (or Early 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 beginning of the Titration Phase (Day -1) 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. 
6.11.2 
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 
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complete the ESS with regard to the level of sleepiness they experienced over the past 7 days 
at the beginning of the Titration Phase (Day -1) and at Weeks 2, 4, and 6 (or Early 
Termination). The ESS provides a measure of a person’s general level of daytime sleepiness, 
or their average sleep propensity in daily life. It is a validated measure with high specificity 
and sensitivity for assessing subjective sleepiness (Johns 1991, 2000; Broderick et al. 2013).  
6.11.3 
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 9). 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 condition at the beginning of the Titration Phase relative to his/her experience with 
this patient population. 
6.11.4 
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 on a 7-point scale ranging from 1 = very much improved to 7 = very 
much worse at Week 4 (Appendix 10) and at Week 6 (or Early Termination) (Appendix 11). 
6.11.5 
Patient Global Impression of Change (PGIc) 
The PGIc is a 7-point Likert-type rating scale and a widely used assessment to assess 
efficacy in clinical drug trials. Subjects will rate the change in their condition on a 7-point 
scale ranging from 1 = very much improved to 7 = very much worse at Week 4  
(Appendix 12) and Week 6 (or Early Termination) (Appendix 13). 
6.11.6 
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 abilities 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 beginning of the 
Titration Phase (Day -1) and at Week 4 and 6 (or Early Termination) (Appendix 6). 
6.11.7 
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 
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memory card at each clinic visit from Screening and through the Double-blind Withdrawal 
Phase (Week 6). 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 Double-blind Withdrawal Phase (Week 6). 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. 
6.12 Adverse Event Reporting 
6.12.1 
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.  
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6.12.1.1 
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. 
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.  
 
6.12.1.2 
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] 
 
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Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-004 Amendment 3 
 
  
 
 
 
CONFIDENTIAL 
CONFIDENTIAL 
 
Hospitalization is NOT considered an SAE if: 
• It is planned prior to subject entering trial 
• It is for social reasons and respite care in the absence of any deterioration in the subject’s 
general condition 
• It is elective in nature and not related to worsening of an underlying condition 
 
Complications that occur during hospitalizations are AEs. If a complication prolongs the 
hospitalization, it is an SAE. 
“In-patient hospitalization” means the subject has been formally admitted to a hospital for 
medical reasons, for any length of time. Emergency room care without admission to a 
hospital is considered outpatient care. 
Overdose, 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. 
6.12.1.3 
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:  
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Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-004 Amendment 3 
 
  
 
 
 
CONFIDENTIAL 
CONFIDENTIAL 
 
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. 
 
6.12.1.4 
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: 
• 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 6.12.1.2), 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 
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JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-004 Amendment 3 
 
  
 
 
 
CONFIDENTIAL 
CONFIDENTIAL 
 
the investigator’s assessment of causality changes, then a follow-up SAE Report form must 
be submitted. 
The source document to determine expectedness of an SAE, is the JZP-110 Investigator’s 
Brochure. 
6.12.1.5 
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. 
6.12.1.6 
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. 
6.12.2 
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 6.12.1.2. 
Any AE or SAE assessed as related to study drug or procedure by the investigator must be 
reported regardless of time after study termination. 
6.12.3 
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. 
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Signature Date:
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JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-004 Amendment 3 
 
  
 
 
 
CONFIDENTIAL 
CONFIDENTIAL 
 
6.12.4 
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 6.12.1.2). 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.  
6.13 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. 
• 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) 
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Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-004 Amendment 3 
 
  
 
 
 
CONFIDENTIAL 
CONFIDENTIAL 
 
• Subject experiences a serious adverse event that is considered related to study drug or 
procedure  
 
For all subjects who prematurely discontinue, an attempt should be made to perform all early 
termination assessments as indicated in Section 7.6. Subjects should be asked to return 
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 appropriate CRF. 
6.13.1 
Handling of Early Terminations 
If a subject terminates early from the study, either at his/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 Jazz Pharmaceuticals immediately. All subjects who terminate from the 
study early should undergo all final study visit assessments as indicated in Section 7.6. 
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. 
6.13.2 
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. 
6.14 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, and FOSQ-10 have been used extensively in clinical trials to assess efficacy 
and quality of life. 
The use of vital signs, clinical laboratory tests, standard AE reporting, and the questionnaires 
that have been selected to assess the safety of the study drug are appropriate since they are 
routinely used to assess the safety profile of drugs in clinical studies and pertinent to known 
risks of JZP-110. The C-SSRS is able to determine clinically meaningful points at which a 
person may be at risk for an impending suicide attempt (Posner et al. 2011). 
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JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-004 Amendment 3 
 
  
 
 
 
CONFIDENTIAL 
CONFIDENTIAL 
 
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 or 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). 
• 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 6.6). 
• Administer the Columbia-Suicide Severity Rating Scale (C-SSRS) 
Baseline/Screening version and record results (Section 6.8).  
• Complete clinical laboratory tests (Section 6.9 and Table 1). 
o Obtain fasting blood samples for serum chemistry and hematology 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. 
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Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-004 Amendment 3 
 
  
 
 
 
CONFIDENTIAL 
CONFIDENTIAL 
 
• 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 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 6.11.7). 
• Schedule Visit 2 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 will not be 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. 
7.2 
Titration Phase 
7.2.1 
Beginning of Titration Phase Clinic Visit 
Visit 2, Days -2 and -1 
 
After a subject has successfully completed the screening procedures, they will return to the 
investigative site after washout of any excluded medications for an overnight nocturnal PSG 
and MWT, to confirm stable use of primary OSA therapy, and to complete safety and efficacy 
assessments. 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 6.9 and Table 1). 
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Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-004 Amendment 3 
 
  
 
 
 
CONFIDENTIAL 
CONFIDENTIAL 
 
• 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 6.8). 
• If Visit 2 (Day -2) 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 6.9.1 and Table 1). Record if the samples were 
collected with the subject fasted or nonfasted. 
• Record the date(s) that excluded medications were discontinued (Sections 4.3 and 
5.7) on the concomitant medication CRF. 
• Assess if there are any updates to the subject’s medical history (Section 6.3).  
• 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 6.11.7). 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.  
• Review inclusion and exclusion criteria (Section 4.2 and Section 4.3). 
• Prepare subject for the overnight PSG. 
• At “lights out” initiate the overnight PSG (Section 6.7). 
 
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). 
• “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 6.11.1). 
• 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. 
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Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-004 Amendment 3 
 
  
 
 
 
CONFIDENTIAL 
CONFIDENTIAL 
 
• Approximately 3 hours after “lights on,” obtain a 12-lead ECG after the subject has 
been resting supine for at least 5 minutes (Section 6.6). 
• Administer the following questionnaires to the subject in the order specified below: 
− ESS (Section 6.11.2) 
− FOSQ-10 (Section 6.11.6) 
• Complete the CGIs (Section 6.11.3). 
• 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 at least 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 6.12). 
• Record all concomitant medications on the concomitant medications CRF that were 
taken after the ICF was signed (Section 5.7). 
• Dispense study drug, provide instruction for how the subject should begin taking 
study drug on the following morning (Day 1) (Section 6.10), and review the 
instructions associated with the different blister cards and how they will be used for 
titration (Section 5.3). 
• Schedule the Phone Contacts for Days 3, 6, 9, and 12 and explain how the clinical 
titration to the maximal dose that is tolerated will be conducted over the next 2 weeks 
(Section 5.3). Schedule the next Clinic Visit (Week 2). 
7.2.2 
Titration Phase Phone Contacts 
Visits 3, 4, 5, and 6; Days 3, 6, 9, and 12 (±1) 
• Record all AEs on the AE CRF that occurred since the last visit or phone contact 
(Section 6.12). 
• Record all concomitant medications on the concomitant medications CRF that were 
taken since the last visit or phone contact (Section 5.7). 
• Assess subject’s report of level of daytime sleepiness and tolerability to current dose 
of study drug and provide instructions for dosing (titration up or down, or staying on 
current dose) until the next phone contact or clinic visit (Section 5.3). 
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JP: Protocol 14-004 Amendment 3.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-004 Amendment 3 
 
  
 
 
 
CONFIDENTIAL 
CONFIDENTIAL 
 
• 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 or 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 6.11.7). 
• Remind subject of the next phone contact or clinic visit. 
7.2.3 
Week 2 – End Titration Phase Clinic Visit 
Visit 7, Day 15 (±2) 
• Obtain weight in ordinary indoor clothes (without shoes). 
• Obtain urine sample for urine drug screen (Section 6.9 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 (Section 6.6). 
• Administer the ESS (Section 6.11.2). 
• Administer the C-SSRS Since Last Visit version and record the results (Section 6.8). 
• Record all AEs on the AE CRF that occurred since the last phone contact 
(Section 6.12).  
• Record all concomitant medications on the concomitant medications CRF that were 
taken since the last phone contact (Section 5.7). 
• Collect any remaining study drug from the Titration Phase and assess compliance 
(Section 5.9). 
• 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. 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 6.11.7).  
• Dispense study drug for the Stable Dose Phase and provide instruction for how the 
subject should begin taking study drug on the following morning (Section 5.8.2 and 
Section 6.10). 
• Schedule the next Phone Contact (Week 3) and Clinic Visit (Week 4). 
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Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-004 Amendment 3 
 
  
 
 
 
CONFIDENTIAL 
CONFIDENTIAL 
 
7.3 
Stable Dose Phase 
7.3.1 
Week 3 – Stable Dose Phase Phone Contact 
Visit 8, Day 22 (±3) 
• Record all AEs on the AE CRF that occurred since the last visit (Section 6.12). 
• Record all concomitant medications on the concomitant medications CRF that were 
taken since the last visit (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 or 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 6.11.7). 
• Remind the subject of the next clinic visit. 
7.3.2 
Week 4 – End of Stable Dose Phase Clinic Visit 
Visit 9, Day 28 and 29 (±3) 
On admission to the investigative site in the evening (Day 28), complete the following: 
• Obtain weight in ordinary indoor clothes (without shoes). 
• Obtain urine sample for urine drug screen (Section 6.9 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 6.8). 
• Collect any remaining study drug from the Stable Dose Phase and assess compliance 
(Section 5.9). 
• 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. 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 6.11.7). (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 6.7). 
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Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-004 Amendment 3 
 
  
 
 
 
CONFIDENTIAL 
CONFIDENTIAL 
 
On the morning of the following day (Day 29), 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 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. 
• Administer study drug to the subject 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 (Appendix 2 
and Section 6.11.1). 
• 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 6.6). 
• Administer the following questionnaires to the subject in the order specified below: 
− 
ESS (Section 6.11.2) 
− 
PGIc (Section 6.11.5) Week 4 version (Appendix 12) 
− 
FOSQ-10 (Section 6.11.6) 
• 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. 
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• Record all AEs on the AE CRF that occurred since the last phone contact 
(Section 6.12). 
• Record all concomitant medications on the concomitant medications CRF that were 
taken after the last phone contact (Section 5.7). 
• Complete the CGIc (Section 6.11.4) Week 4 version (Appendix 10). 
• Review PGIc, MWT, and ESS data. If the eligibility criteria for randomization are 
met (Section 4.4), randomize the subject in the Double-blind Withdrawal Phase 
(access the IVRS/IWRS).  
• Dispense double-blind study drug and provide instruction for how the subject should 
begin taking study drug on the following morning (Section 5.8.2 and Section 6.10). 
• Schedule the next Phone Contact (Week 5) and the next clinic visit (Week 6).  
7.4 
Double-blind Withdrawal Phase 
7.4.1 
Week 5 – Double-blind Withdrawal Phase Phone Contact 
Visit 10, Day 36 (±3) 
• Record all AEs on the AE CRF that occurred since the last visit.  
• Record all concomitant medications on the concomitant medications CRF that were 
taken since the last visit. 
•  If the subject uses a primary OSA therapy from which the usage data can be 
extracted, instruct 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 usage data can be extracted or does not use a 
primary OSA therapy, instruct the subject on reporting use as appropriate 
(Section 6.11.7). 
• Remind the subject of the next clinic visit. 
 
7.4.2 
Week 6 – End of Double-Blind Withdrawal Phase Clinic Visit 
Visit 11, Day 42 and 43 (±3) 
On admission to the investigative site in the evening (Day 42), 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 6.9.1, see footnote Table 1 for definitions of childbearing potential). 
• Obtain a urine sample for urinalysis and urine drug screens (Section 6.9.1, 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 6.8). 
• Collect any remaining study drug from the Double-blind Withdrawal Phase and assess 
compliance (Section 5.9). 
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• 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 6.11.7). 
(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 6.7). 
On the morning of the following day (Day 43), 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 
(Section 6.9.1, Table 1).  
• Administer study drug to the subject 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 (Appendix 2 
and Section 6.11.1). 
• 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 6.6). 
• Administer the following questionnaires to the subject in the order specified below: 
− 
ESS (Section 6.11.2) 
− 
PGIc (Section 6.11.5) Week 6 version (Appendix 13) 
− 
FOSQ-10 (Section 6.11.6) 
• 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. 
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• 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 phone contact 
(Section 6.12). 
• Record all concomitant medications on the concomitant medications CRF that were 
taken after the last 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). 
• Complete the CGIc (Section 6.11.4) Week 6 version (Appendix 11). 
• Schedule the (Week 8) Safety Follow-up Visit. 
7.5 
Follow-up Period 
7.5.1 
Week 8 – Safety Follow-up Clinic Visit 
Visit 12, Day 57 (±3) 
• 
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 6.6). 
• Administer the C-SSRS Since Last visit version and record the results (Section 6.8). 
• Record all AEs on the AE CRF that occurred since the last visit or phone contact 
(Section 6.12). 
• 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. 
7.6 
Early Termination Clinic Visit 
If a subject intends to withdraw from the study after completing Visit 9 and before 
completing Visit 11, and the subject is willing and able to safely take additional study drug, 
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schedule a clinic visit and complete all final visit assessments indicated at the Week 6 Visit 
(Section 7.4.2). 
If a subject withdraws prior to completing Visit 9 or 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 6.9.1, see footnote Table 1 for definitions of childbearing potential). 
• Obtain a urine sample for urinalysis and urine drug screens (Section 6.9.1, 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 6.6). 
• Obtain fasting blood samples for serum chemistry and hematology 
(Section 6.9.1, Table 1). 
• Provide a light breakfast after fasting blood samples are obtained. 
• Administer the C-SSRS Since Last visit version and record the results (Section 6.8). 
• 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 6.11.7). 
• Record all AEs on the AE CRF that occurred since the last visit or phone contact 
(Section 6.12). 
• 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, if the subject is willing to continue with follow-
up procedures (Section 7.5). 
7.7 
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. 
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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 this study is to evaluate the efficacy of JZP-110 in the treatment of 
excessive sleepiness in adult subjects with OSA. To address this objective, treatment 
difference between JZP-110 and placebo will be tested. Subjects who were randomized to 
continue JZP-110 in the Double-Blind Withdrawal Phase will be treated as a single group 
regardless of the dose of JZP-110 that they received. Thus, there will be no multiplicity 
issues with respect to multiple doses in the hypotheses testing. A significance level of 0.05 
will be used. A fixed sequential testing strategy will be employed to address the multiplicity 
issues in testing multiple endpoints (co-primary and key secondary endpoints). 
9.3 
Determination of Sample Size 
Approximately 200 subjects are planned for enrollment to ensure that 122 subjects are 
randomized in the Double-blind Withdrawal Phase with 61 subjects per treatment group. 
These sample sizes will provide at least 90% power to detect differences of 6 minutes in the 
mean sleep latency time as determined from the MWT (mean of the first four trials) and 3.5 
points in ESS changes from the beginning to the end of the 2-week Double-blind Withdrawal 
Phase. This calculation assumes common standard deviations of 9.5 minutes for the MWT 
and 5 points for the ESS changes during the Double-blind Withdrawal Phase and a two-sided 
significance level of 0.05 using a t-test. 
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 were randomized 
in the Double-blind Withdrawal Phase, who received at least one dose of study medication in 
the Double-blind Withdrawal Phase, and who have a Week 4 (end of Stable Dose Phase) and 
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at least one post-Week 4 assessment of the MWT or ESS. If a subject in the mITT Population 
does not have an assessment for a particular 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. Subjects who complete the Titration and 
Stable Dose Phases of the study, but who do not meet criteria for randomization in the 
Double-blind Withdrawal Phase will be considered completers of those phases of the trial, 
but will not be included as completers of the Double-blind Withdrawal Phase. Data from 
subjects who complete the Titration and Stable Dose Phases and subjects who complete the 
Double-blind Withdrawal Phase will be summarized separately. 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. 
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. 
9.6 
Handling of Dropouts and Missing Data 
For the analysis of the co-primary efficacy parameter of MWT and ESS, the key secondary 
efficacy parameter of PGIc, and secondary efficacy parameter of CGIc, single 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 the end of the Stable Dose Phase (Week 4) to the 
end of the Double-blind Withdrawal Phase (Week 6) 
• ESS: Change in ESS score from the end of the Stable Dose Phase (Week 4) to the end 
of the Double-blind Withdrawal Phase (Week 6) 
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9.8.2 
Key Secondary Efficacy Endpoint 
• PGIc: Percentage of subjects reported as worse (minimally, much, or very much) on the 
PGIc at the end of the Double-blind Withdrawal Phase (Week 6) 
9.8.3 
Additional Secondary Endpoints 
• CGIc: Percentage of subjects reported as worse (minimally, much, or very much) on the 
CGIc at the end of the Double-blind Withdrawal Phase (Week 6) 
• FOSQ-10: Change in the total score from the beginning of the Titration Phase (Day -1) 
to the end of the Stable Dose Phase (Week 4) and from the end of the Stable Dose 
Phase (Week 4) to the end of the Double-blind Withdrawal Phase (Week 6) 
9.8.4 
Exploratory Endpoints 
• Change in the frequency of use of primary OSA therapy from the beginning of the 
Titration Phase (Day -1) to the end of the Stable Dose Phase (Week 4) and from the end 
of the Stable Dose Phase (Week 4) to the end of the Double-blind Withdrawal Phase 
(Week 6) 
• 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, central apneas, SaO2 
nadir, and SaO2 mean from the end of the Stable Dose Phase (Week 4) to the end of the 
Double-blind Withdrawal Phase (Week 6) 
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 
• 12-lead electrocardiograms (ECGs) 
• Physical examination 
• C-SSRS 
9.10 Efficacy Analyses 
Efficacy analyses will be performed for the mITT Analysis Population. For comparisons 
between JZP-110 and placebo, subjects who were randomized to continue JZP-110 in the 
Double-Blind Withdrawal Phase will be treated as a single group regardless of the dose of 
JZP-110 that they received. Thus, there will be no multiplicity issues with respect to multiple 
doses in the hypotheses testing. A fixed sequential testing strategy will be employed to 
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address the multiplicity issues in testing multiple endpoints (co-primary and key secondary 
endpoints). 
For the analysis of the co-primary efficacy endpoints, an analysis of covariance (ANCOVA) 
model will be used. This model will include treatment group, the measurement at the end of 
the Stable Dose Phase (Week 4), and randomization stratification factor as fixed effects. SAS 
procedure PROC GLM will be used to carry out this analysis. The estimates of treatment 
difference versus placebo and their 95% confidence intervals will be presented. The last-
observation carried forward (LOCF) approach will be used for subjects who discontinued 
early in the Double-Blind Withdrawal Phase. 
The chi-squared test will be used to test the hypotheses associated with the analysis of the 
PGIc endpoint.  
For the FOSQ-10 endpoints, a similar ANCOVA model will be used as the method of 
analysis; the CGIc endpoint will be analyzed using the chi-squared test.  
No sensitivity analyses and no multiplicity adjustments will be employed for these endpoints. 
9.11 Safety Analyses 
Safety analyses will be performed for the Safety Analysis Population. No formal statistical 
testing will be performed for the safety analyses. 
9.11.1 
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. 
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. 
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Clinical Trial Protocol: 14-004 Amendment 3 
 
  
 
 
 
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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). 
9.11.2 
Vital Signs 
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. 
9.11.3 
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. 
9.11.4 
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. 
9.11.5 
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 
adverse change (i.e., worsening) of a physical examination finding after screening will be 
recorded as an AE.  
9.11.6 
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). 
9.12 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. 
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9.13 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. 
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. 
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Clinical Trial Protocol: 14-004 Amendment 3 
 
  
 
 
 
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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 
 
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. 
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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 
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. 
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 
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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.  
11.7 Required Documents 
The investigator must provide Jazz Pharmaceuticals or its designee with the applicable 
regulatory documents before the enrollment of any subject (copies should be kept by the 
investigator in the investigator’s regulatory document binder).  
11.8 Study Monitoring 
Throughout the course of the study, the study monitor will make frequent contacts with the 
investigator.  This will include telephone calls and onsite visits.  During the onsite visits, the 
eCRFs will be reviewed for completeness and adherence to the protocol.  As part of the data 
audit, source documents will be made available for review by the site.  The study monitor 
will also perform drug accountability checks and may periodically request review of the 
investigator study file to assure completeness of documentation in all respects of clinical trial 
conduct. 
Upon completion of the study, the study monitor will arrange for a final review of the study 
files after which the files should be secured for the appropriate time period.  The investigator 
or appointed delegate will receive the study monitor during these onsite visits and will 
cooperate in providing the documents for inspection and respond to inquiries.  In addition, 
the investigator will permit inspection of the study files by authorized representatives of the 
regulatory agencies. 
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11.9 Protocol Violations/Deviations 
All major protocol 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. 
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 
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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, 
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 J, Junghaenel D, Schneider S, et al. Pittsburgh and Epworth Sleep Scale Items: 
Accuracy of Ratings Across Different Reporting Periods. Behavioral sleep Medicine. 2013 
11(3): 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. 
Fietze I, Penzel T, Alonderis A, Barbe F, Bonsignore MR, Calverly P, De Backer W, 
Diefenbach K, Donic V, Eijsvogel MM, Franklin KA, Gislason T, Grote L, Hedner J, 
Jennum P, Lavie L, Lavie P, Levy P, Lombardi C, Mallin W, Marrone O, Montserrat JM, 
Papathanasiou ES, Parati G, Plywaczewski R, Pretl M, Riha RL, Rodenstein D, Saaresranta 
T, Schulz R, Sliwinski P, Steiropoulos P, Svaza J, Tomori Z, Tonnesen P, Varoneckas G, 
Verbraecken J, Vesely J, Vitols A, Zielinski J, McNicholas WT; COST Action B26 Group. 
Management of obstructive sleep apnea in Europe. Sleep Med. 2011; 12:190-7. 
Gasa M, Tamisier R, Launois SH, Sapene M, Martin F, Stach B, Grillet Y, Levy P, Pepin JL; 
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. 
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. 
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, Racineux JL, Sapene M, Lévy P, Dervaux B, Lenne X, 
Mallart A. 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, Bettega G, Boudewyns A, Hamans E, Jalbert F, 
Paoli JR, Sanner B, Smith I, Stuck BA, Lacassagne L, Marklund M, Maurer JT, Pepin JL, 
Valipour A, Verse T, Fietze I. 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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Clinical Trial Protocol: 14-004 Amendment 3 
 
  
 
 
 
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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. 
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. 
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.  
 
 
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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). 
 
 
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Appendix 1 
Schedule of Events  
 
Screening 
Phase 
Titration Phase 
Stable Dose 
Phase 
Double-blind 
Withdrawal 
Phase 
 
Safety 
Follow-
upa 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
 
12 
Day/ End of Week 
Day 
-31 to -3 
Day 
 -2 
&-1 
Day 
3±1 
Day 
6±1 
Day 
9±1 
Day 
12±1 
Day 
15±2 
Wk 2 
Day 
22±3 
Wk 3 
Day 
28&29
±3 
Wk 4 
Day 
36±3 
Wk 
5 
Day 
42&43
±3 
Wk 6 
Early 
Term 
 
Day 57±3 
Wk 8 
Clinic Visit 
X 
X 
 
 
 
 
X 
 
X 
 
X 
X 
X 
Phone Contact 
 
 
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 
Vital signs  
X 
X 
 
 
 
 
X 
 
X 
 
X 
X 
X 
ECG  
X 
X 
 
 
 
 
X 
 
X 
 
X 
X 
X 
Fasting serum chemistry, 
hematology, urinalysis  
X 
Xb 
 
 
 
 
 
 
 
 
X 
X 
 
Serum pregnancy test  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
 
X 
 
 
 
 
 
 
 
 
X 
X 
 
Urine sample for possible 
drug screenc  
X 
X 
 
 
 
 
X 
 
X 
 
X 
X 
 
Light breakfast 
X 
X 
 
 
 
 
 
 
X 
 
X 
X 
 
Light lunch 
 
X 
 
 
 
 
 
 
X 
 
X 
Xd 
 
C-SSRS 
X 
X 
 
 
 
 
X 
 
X 
 
X 
X 
X 
Concomitant medication  
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 
 
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e 78 of 99 
 
 
Screening 
Phase 
Titration Phase 
Stable Dose 
Phase 
Double-blind 
Withdrawal 
Phase 
 
Safety 
Follow-
upa 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
 
12 
Day/ End of Week 
Day 
-31 to -3 
Day 
 -2 
&-1 
Day 
3±1 
Day 
6±1 
Day 
9±1 
Day 
12±1 
Day 
15±2 
Wk 2 
Day 
22±3 
Wk 3 
Day 
28&29
±3 
Wk 4 
Day 
36±3 
Wk 
5 
Day 
42&43
±3 
Wk 6 
Early 
Term 
 
Day 57±3 
Wk 8 
Clinic Visit 
X 
X 
 
 
 
 
X 
 
X 
 
X 
X 
X 
Phone Contact 
 
 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
Provide titration instructions 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Instruct how to discontinue 
excluded medications  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Overnight stay PSG/MWT 
 
Xe 
 
 
 
 
 
 
X 
 
X 
Xd 
 
Study medication 
administration prior to MWT 
 
 
 
 
 
 
 
 
X 
 
X 
Xd 
 
ESS  
 
X 
 
 
 
 
X 
 
X 
 
X 
Xd 
 
CGIs  
 
X 
 
 
 
 
 
 
 
 
 
 
 
PGIc  
 
 
 
 
 
 
 
 
X 
 
X 
Xd 
 
FOSQ-10 
 
X 
 
 
 
 
 
 
X 
 
X 
Xd 
 
Dispense study drug 
 
X 
 
 
 
 
X 
 
X 
 
 
 
 
Collect study drug  
 
 
 
 
 
 
X 
 
X 
 
X 
X 
 
Randomization 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Adverse events  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGIc 
 
 
 
 
 
 
 
 
X 
 
X 
Xd 
 
Schedule next visit and/or 
phone contact 
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 Visit 2 (Day -2) occurs outside of the screening window (i.e., >29 days after the Screening visit) obtain blood samples for serum chemistry and 
hematology and a urine sample for urinalysis. Record if the subject was fasting or nonfasting at the time of the collection. 
c. 
Samples collected at Screening, Visit 2, and Weeks 2, 4, and 6 or Early Termination will be analyzed. Samples collected at other visits may be analyzed at 
the investigator’s discretion. 
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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 will not be 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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Clinical Trial Protocol: 14-004 Amendment 3 
 
  
 
 
 
 
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CONFIDENTIA 
Appendix 2 
Example Schedule of Times for Procedures During 
MWT Visits 
*For subjects who are being rescreened, a repeat PSG and MWT will not be 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. 
Visit 2 – 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 6 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 6 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 
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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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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. 
C. The symptoms cause clinically significant distress or impairment in social, 
occupational, or other important areas of functioning. 
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D. The episode is not attributable to the physiological effects of a substance or another 
medical condition.  
 
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). 
A. The episode is associated with an unequivocal change in functioning that is 
uncharacteristic of the individual when not symptomatic.  
B. The disturbance in mood and the change in functioning are observable by others. 
C. 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. 
D. 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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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. 
 
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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. 
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.” 
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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.  
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. 
o Note: The major depressive episode must include Criterion A1: Depressed mood. 
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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. 
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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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 when 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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CONFIDENTIA 
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 
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CONFIDENTIA 
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? 
! 
! 
! 
! 
!
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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.
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CONFIDENTIA 
Appendix 7 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Baseline/Screening Version 
 
 
 
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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. 
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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
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Signature Date: 20160210
JP: Protocol 14-004 Amendment 3.pdf
Signature Date:
JP: Protocol 14-004 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)   
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CONFIDENTIAL
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Signature Date: 20160210
JP: Protocol 14-004 Amendment 3.pdf
Signature Date:
JP: Protocol 14-004 Amendment 3.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-004 Amendment 3 
 
  
 
 
 
 
CONFIDENTIAL 
CONFIDENTIA 
Appendix 8 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Since Last Visit Version 
 
 
CONFIDENTIAL
Page 98 of 108


Signature Date: 20160210
JP: Protocol 14-004 Amendment 3.pdf
Signature Date:
JP: Protocol 14-004 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 99 of 108


Signature Date: 20160210
JP: Protocol 14-004 Amendment 3.pdf
Signature Date:
JP: Protocol 14-004 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 100 of 108


Signature Date: 20160210
JP: Protocol 14-004 Amendment 3.pdf
Signature Date:
JP: Protocol 14-004 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)    
 
 
                          Page 2 of 2                                     
CONFIDENTIAL
Page 101 of 108


Signature Date: 20160210
JP: Protocol 14-004 Amendment 3.pdf
Signature Date:
JP: Protocol 14-004 Amendment 3.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-004 Amendment 3 
 
  
 
 
 
 
CONFIDENTIAL 
CONFIDENTIA 
Appendix 9 
Clinical Global Impression of Severity (CGIs) 
CGI – SEVERITY 
 
Check if Not Done □ 
 
 
Considering your total clinical experience with this patient population, how ill is the patient at this 
time? (Choose only one) 
 
 
 
 
□ 
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
Page 102 of 108


Signature Date: 20160210
JP: Protocol 14-004 Amendment 3.pdf
Signature Date:
JP: Protocol 14-004 Amendment 3.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-004 Amendment 3 
 
  
 
 
 
 
CONFIDENTIAL 
CONFIDENTIA 
Appendix 10 
Clinical Global Impression of Change (CGIc) - Week 4 
 
CGI – CHANGE FROM THE BEGINNING OF THE TITRATION PHASE TO WEEK 4 
Check if Not Done □ 
 
Compared to the subject’s condition at the START OF THE TITRATION PHASE, 
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 103 of 108


Signature Date: 20160210
JP: Protocol 14-004 Amendment 3.pdf
Signature Date:
JP: Protocol 14-004 Amendment 3.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-004 Amendment 3 
 
  
 
 
 
 
CONFIDENTIAL 
CONFIDENTIA 
Appendix 11 
Clinical Global Impression of Change (CGIc) - Week 6 
 
CGI – CHANGE FROM WEEK 4 TO WEEK 6 
Check if Not Done □ 
 
Compared to the subject’s condition at the END OF THE STABLE DOSE PHASE, 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 104 of 108


Signature Date: 20160210
JP: Protocol 14-004 Amendment 3.pdf
Signature Date:
JP: Protocol 14-004 Amendment 3.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-004 Amendment 3 
 
  
 
 
 
 
CONFIDENTIAL 
CONFIDENTIA 
Appendix 12 
Patient Global Impression of Change (PGIc) – Week 4 
 
PGI – CHANGE SINCE THE START OF THE STUDY 
(Choose only one) 
Check if Not Done □ 
 
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 105 of 108


Signature Date: 20160210
JP: Protocol 14-004 Amendment 3.pdf
Signature Date:
JP: Protocol 14-004 Amendment 3.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-004 Amendment 3 
 
  
 
 
 
 
CONFIDENTIAL 
CONFIDENTIA 
Appendix 13 
Patient Global Impression of Change (PGIc) - Week 6 
 
PGI – CHANGE SINCE LAST VISIT 
(Choose only one) 
Check if Not Done □ 
 
Since your LAST VISIT, 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 106 of 108


Signature Date: 20160210
JP: Protocol 14-004 Amendment 3.pdf
Signature Date:
JP: Protocol 14-004 Amendment 3.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-004 Amendment 3 
 
  
 
 
 
 
CONFIDENTIAL 
CONFIDENTIA 
Appendix 14 
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
Page 107 of 108


Signature Date: 20160210
JP: Protocol 14-004 Amendment 3.pdf
Signature Date:
JP: Protocol 14-004 Amendment 3.pdf
JZP-110 
 
Jazz Pharmaceuticals 
Clinical Trial Protocol: 14-004 Amendment 3 
 
  
 
 
 
 
CONFIDENTIAL 
CONFIDENTIA 
Appendix 15 
Signatures of Agreement for Protocol 
Study Title: 
A Six-Week, Double-Blind, Placebo-Controlled, Randomized-
Withdrawal, 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: 
14-004 
Original Protocol: 
17 December 2014 
Amendment 1: 
18 February 2015 
Amendment 2: 
10 September 2015 
Amendment 3: 
09 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: 
 
 
 
 
 
CONFIDENTIAL
Page 108 of 108


Signature Date: 20160210
JP: Protocol 14-004 Amendment 3.pdf
 
 
 
Signature Manifestation 
 
 

SAP_001.pdf: 
Statistical Analysis Plan 
 
Page 1 of 51 
Sponsor Name:  
Jazz Pharmaceuticals 
Protocol Number: 
14-004 
Protocol Title:  
A Six-Week, Double-Blind, Placebo-Controlled, 
Randomized-Withdrawal, 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) 
 
 
Protocol Version and Date: 
Original protocol, 17 December 2014 
Amendment 1, 18 February 2015 
Amendment 2, 10 September 2015 
Amendment 3, 09 February 2016 
 
 
 
SAP Version: 
 1.0 
SAP Version Date:  
02 Nov 2016 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Jazz Pharmaceuticals. 
Acceptance of this document constitutes agreement by the recipient that no information 
contained herein will be published or disclosed without prior written authorization from an 
official of Jazz Pharmaceuticals.  However, this document may be disclosed to appropriate 
Institutional Review Board and Ethics Committees or duly authorized representatives of a 
national regulatory authority under the condition that they are requested to keep it confidential. 
In the event of an actual or suspected breach of this obligation,
 Research should be notified 
promptly. 
 
 


 
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Version: 
___1.0_______ 
Version Date: 
____02 Nov 2016 
 
I confirm that I have reviewed this document and agree with the content. 
 
APPROVALS 
 
 
 
 
Written by:
                 
                 
 
 
Date  
Approved by: 
                    
                    
 
Date  
Jazz Pharmaceuticals 
 
 
 
Approved by: 
                    
                    
 
Date 
 
 
 
Approved by:
                    
                    
 
Date  
 
 
 
 
 


 
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TABLE OF CONTENTS 
1. 
ABBREVIATION ............................................................................................. 7 
2. 
PURPOSE ....................................................................................................... 9 
3. 
STUDY OBJECTIVES ................................................................................... 10 
3.1. 
Primary Objective .............................................................................................................. 10 
3.2. 
Secondary Objective(s) ..................................................................................................... 10 
3.3. 
Study Design ...................................................................................................................... 10 
3.4. 
Determination of Sample Size .......................................................................................... 13 
3.5. 
Randomization and Stratification ..................................................................................... 13 
3.6. 
Administration of Study Medication ................................................................................ 14 
4. 
ENDPOINTS .................................................................................................. 15 
4.1. 
Co-Primary Efficacy Endpoints ........................................................................................ 15 
4.2. 
Key Secondary Efficacy Endpoint ................................................................................... 15 
4.3. 
Other Secondary Efficacy Endpoints .............................................................................. 15 
4.4. 
Exploratory Endpoints ...................................................................................................... 15 
4.5. 
Pharmacokinetic Endpoints ............................................................................................. 16 
4.6. 
Pharmacodynamic Endpoints .......................................................................................... 16 
4.7. 
Safety Endpoints ................................................................................................................ 16 
5. 
STATISTICAL HYPOTHESES FOR TRIAL OBJECTIVES .......................... 17 
6. 
ANALYSIS POPULATIONS .......................................................................... 18 


 
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6.1. 
Safety Population ............................................................................................................... 18 
6.2. 
Modified Intent-to-Treat Population ................................................................................. 18 
6.3. 
Per Protocol Population .................................................................................................... 18 
7. 
EFFICACY ASSESSMENTS ......................................................................... 19 
7.1. 
Maintenance of Wakefulness Test (MWT) ....................................................................... 19 
7.2. 
Epworth Sleepiness Scale (ESS) ...................................................................................... 19 
7.3. 
Clinician Global Impression of Severity (CGIs) ............................................................... 20 
7.4. 
Clinician Global Impression of Change (CGIc) ................................................................ 20 
7.5. 
Patient Global Impression of Change (PGIc) ................................................................... 20 
7.6. 
Functional Outcomes of Sleep Questionnaire Short Version (FOSQ-10) .................... 20 
7.7. 
Primary OSA Therapy Use ................................................................................................ 20 
8. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS ................................ 22 
8.1. 
General Methods ................................................................................................................ 22 
8.2. 
Key Definitions ................................................................................................................... 23 
8.2.1. 
Baseline ........................................................................................................................... 23 
8.2.2. 
Study Day ........................................................................................................................ 23 
8.2.3. 
JZP-110 Exposure ........................................................................................................... 23 
8.2.4. 
Study Phase .................................................................................................................... 23 
8.3. 
Visit Windows ..................................................................................................................... 24 
8.4. 
Missing Data ....................................................................................................................... 25 
8.5. 
Level of Significance and Multiplicity adjustment ......................................................... 26 
8.6. 
Pooling of Centers and Region ........................................................................................ 26 
8.7. 
Subgroups and Subgroups Analyses .............................................................................. 26 
9. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION ....................................................................................................... 28 
9.1. 
Subject Disposition and Withdrawals .............................................................................. 28 


 
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9.2. 
Demographic and Other Baseline Characteristics ......................................................... 28 
9.3. 
Medical History .................................................................................................................. 29 
9.4. 
Medication/Procedure ....................................................................................................... 29 
9.4.1. 
Prior Medication ............................................................................................................... 29 
9.4.2. 
Concomitant Medication and Procedure ......................................................................... 29 
9.4.3. 
Protocol Deviations .......................................................................................................... 29 
10. 
EFFICACY ................................................................................................. 31 
10.1. 
Co-Primary Efficacy Endpoints and Analyses ................................................................ 31 
10.1.1. 
Primary Analysis ......................................................................................................... 31 
10.1.2. 
Secondary Analysis ..................................................................................................... 32 
10.1.3. 
Sensitivity Analysis ...................................................................................................... 32 
10.1.4. 
Subgroup Analysis ...................................................................................................... 34 
10.2. 
Key Secondary Efficacy Endpoint and Analyses ........................................................... 35 
10.2.1. 
Primary Analysis ......................................................................................................... 35 
10.2.2. 
Secondary Analysis ..................................................................................................... 35 
10.2.3. 
Sensitivity Analyses .................................................................................................... 35 
10.2.4. 
Subgroup Analysis ...................................................................................................... 36 
10.3. 
Other Secondary Efficacy Endpoints and Analyses ...................................................... 36 
10.3.1. 
CGIc: Percentage of Subjects Reported as Worse (Minimally, Much, or Very Much) at 
the End of the Double-Blind Withdrawal Phase (Week 6) ............................................................ 36 
10.3.2. 
FOSQ-10: Change in the Total Score from the End of Stable Dose Phase to the End 
of the Double-Blind Withdrawal Phase (Week 6) ......................................................................... 36 
10.4. 
Exploratory Endpoints ...................................................................................................... 36 
10.4.1. 
FOSQ-10: Change in the FOSQ-10 total score and 5 FOSQ-10 Subscales .............. 36 
10.4.2. 
Use of Primary OSA Therapy ...................................................................................... 37 
10.4.3. 
Change in PSG Parameters ........................................................................................ 38 
10.4.4. 
Categorical Analysis for Maintenance of Wakefulness Test ....................................... 38 
10.5. 
Summary of Efficacy Analysis Methods.......................................................................... 39 
11. 
SAFETY ..................................................................................................... 41 
11.1. 
Extent of Exposure ............................................................................................................ 41 
11.2. 
Treatment Compliance ...................................................................................................... 41 
11.3. 
Adverse Events .................................................................................................................. 41 
11.3.1. 
Subgroup Analyses ..................................................................................................... 43 
11.4. 
Laboratory Evaluations ..................................................................................................... 43 


 
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11.5. 
Vital Signs ........................................................................................................................... 43 
11.5.1. 
Regular Vital Signs ...................................................................................................... 43 
11.5.2. 
Blood Pressure and Pulse on the MWT Day .............................................................. 44 
11.6. 
ECG ..................................................................................................................................... 45 
11.7. 
Columbia-Suicide Severity Rating Scale ......................................................................... 46 
11.7.1. 
C-SSRS Outcomes/Composite Endpoints .................................................................. 46 
11.7.2. 
Analyses ...................................................................................................................... 47 
12. 
INTERIM ANALYSES ................................................................................ 49 
13. 
CHANGE FROM ANALYSIS PLANNED IN THE PROTOCOL ................. 50 
14. 
REFERENCE ............................................................................................. 51 
 


 
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1. 
ABBREVIATION 
Abbreviation 
Description 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
AHI 
Apnea Hypopnea Index 
AI 
Apnea Index  
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
CGIc 
Clinical Global Impression of Change 
CGIs 
Clinical Global Impression of Severity 
CI 
Confidence Interval 
C-SSRS 
Columbia-Suicide Severity Rating Scale  
CRF 
Case Report Form 
CSR 
Clinical Study Report 
ECG 
Electrocardiogram 
ESS 
Epworth Sleepiness Scale  
ET 
Early Termination 
FOSQ-10 
Functional Outcomes of Sleep Questionnaire Short Version  
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System  
LOCF 
Last Observation Carried Forward  
LOE 
Lack of Efficacy 
LS 
Least Squares 
MAR 
Missing at Random 
Max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
Min 
Minimum 


 
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Abbreviation 
Description 
mITT 
Modified Intent-to-Treat 
MNAR 
Missing Not at Random 
MWT 
Maintenance of Wakefulness Test 
OSA 
Obstructive Sleep Apnea  
PAP 
Positive airway pressure 
PGIc 
Patient Global Impression of Change  
PP 
Per Protocol 
PSG 
Polysomnography 
PT 
Preferred Term 
QTcF 
QT Corrected with Fridericia’s Formula  
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SI 
Single Imputation 
TEAE 
Treatment Emergent Adverse Event 
TST 
Total Sleep Time  
WASO 
Wake after Sleep Onset  
WHO 
World Health Organization 
 


 
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2. 
PURPOSE 
This Statistical Analysis Plan (SAP) is created based on Protocol 14-004 Amendment 3 (09 
February 2016) and it describes in detail the statistical methodology and the statistical 
analyses to be conducted for the above mentioned protocol. 
  
Results obtained from the analyses outlined in this document will become the basis of 
the final clinical study report (CSR) for this protocol. The purpose of this plan is to 
provide specific instructions as to how each analysis will be conducted.  Any deviations 
from these guidelines must be substantiated by sound statistical reasoning and 
documented in the final CSR. 
 
 
 


 
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3. 
STUDY OBJECTIVES 
3.1. 
PRIMARY OBJECTIVE 
The primary objective of this study is to evaluate the efficacy of JZP-110 administered 
once daily compared to placebo in the treatment of excessive sleepiness in adult 
subjects with Obstructive Sleep Apnea (OSA). 
 
3.2. 
SECONDARY OBJECTIVE(S) 
The secondary objective of this study is to evaluate the safety and tolerability of JZP-
110 administered once daily for up to 6 weeks in doses of 75, 150, and 300 mg 
compared to placebo in the treatment of excessive sleepiness in adult subjects with 
OSA. 
3.3. 
STUDY DESIGN 
The Schedule of Events is presented in Table 1, and the Study Schema in Figure 1. 
 
This trial is a 6-week, double-blind, placebo-controlled, randomized-withdrawal, 
multicenter study of safety and efficacy of JZP-110 in the treatment of excessive 
sleepiness in adult subjects with OSA. Following the completion of a Screening Phase, 
subjects will enter a 2-week, open-label Titration Phase.  
 
During the 2-week Titration Phase, subjects will be titrated to the maximal dose that is 
tolerated. Subjects will start at a once-daily dose of 75 mg JZP-110 and will be able to 
titrate up one dose level (to 150 mg/day or a maximum dose of 300 mg/day) once every 
3 days following a telephone consultation with investigative site staff. Subjects will also 
be able to titrate down to 75 mg or 150 mg daily at any time following a telephone 
consultation with investigative site staff. Following completion of the Titration Phase, 
subjects who have been titrated to an efficacious and tolerable dose will remain on that 
dose for the subsequent 2 weeks during an open-label Stable Dose Phase. During the 2-
week Stable Dose Phase, subjects will receive a once daily dose of JZP-110 equal to the 
dose that they received at the end of the Titration Phase.  
 
At the end of the Stable Dose Phase (Week 4), subjects who report much or very much 
improvement on the Patient Global Impression of Change (PGIc) scale as compared to 
the beginning of the Titration Phase (after discontinuation of prior medications and 
before receiving JZP-110) will undergo additional assessments, which will include an 
overnight stay at the investigative site for nocturnal polysomnography (PSG) followed by 
a Maintenance of Wakefulness Test (MWT) as well as safety assessments. Subjects who 
complete the Week 4 Visit and who report much or very much improvement on the PGIc 
scale and whose mean sleep latency on the MWT and Epworth Sleepiness Scale (ESS) 
scores also improve will be randomized in the Double-Blind Withdrawal Phase. Stratified 
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OSA therapy will be used to assign subjects in a 1:1 ratio to continue to receive JZP-110 
at the dose that was received in the Stable Dose Phase or to receive placebo for 2 
weeks in the Double-Blind Withdrawal Phase. Subjects who do not report being much or 
very much improved on the PGIc scale or who do not improve on the MWT and ESS from 
the beginning of the Titration Phase to Week 4 will be discontinued from the study. 
 
At the conclusion of the 2-week Double-Blind Withdrawal Phase (end of Week 6), 
subjects will return to the investigative site for a nocturnal PSG and MWT in addition to 
other efficacy and safety assessments. The final dose of study medication will be taken 
prior to the initiation of the Week 6 MWT. 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 ESS score from Week 4 to Week 6 as co-primary endpoints, percentage of patients 
who report a worsening of their condition on the PGIc from Week 4 to Week 6 as a key 
secondary endpoint, and Clinical Global Impression of Change (CGIc) and Functional 
Outcomes of Sleep Questionnaire Short Version (FOSQ-10) from Week 4 to Week 6 as 
additional secondary endpoints. 
 
Subjects will return at the end of Week 8, 2 weeks after the final dose of study 
medication, 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 8 visit. 
 
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 sign measurements, and the Columbia-Suicide Severity Rating 
Scale (C-SSRS). Safety will be assessed throughout the study. 
 
Figure 1 Study Schema 
 
 
 
   
 


 
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Table 1 Schedule of events 
 
 
 
 


 
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3.4. 
DETERMINATION OF SAMPLE SIZE 
Approximately 200 subjects are planned for enrollment to ensure that 122 subjects are 
randomized in the Double-Blind Withdrawal Phase with 61 subjects per treatment 
group. These sample sizes will provide at least 90% power to detect differences of 6 
minutes in the mean sleep latency time as determined from the MWT (mean of the first 
four trials) and 3.5 points in ESS changes from the beginning to the end of the 2-week 
Double-Blind Withdrawal Phase. This calculation assumes common standard deviations 
(SD) of 9.5 minutes for the MWT and 5 points for the ESS changes during the Double-
Blind Withdrawal Phase and a two-sided significance level of 0.05 using a t-test. 
 
3.5. 
RANDOMIZATION AND STRATIFICATION 
Subjects who complete the Week 4 Visit at the end of the Stable Dose Phase, who 
report much or very much improvement on the PGIc scale, and who also show a 
numerical improvement in mean sleep latency on the MWT and ESS score from the 
beginning of the Titration Phase (Day -1) to Week 4 will be randomized in the Double-
Blind Withdrawal Phase. Stratified randomization on the basis of subjects’ compliant or 
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be used to assign subjects in a 1:1 ratio to continue to receive JZP-110 at the dose that 
was received in the Stable Dose Phase or to receive placebo for 2 weeks in the Double-
Blind Withdrawal Phase. 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. 
 
3.6. 
ADMINISTRATION OF STUDY MEDICATION 
Subjects will receive JZP-110 75, 150, or 300 mg once daily as a single oral dose during 
the Titration and Stable Dose Phases of the study. Subjects will receive one of the doses 
of JZP-110 listed above or placebo once daily as a single oral dose during the Double-
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4. 
ENDPOINTS 
4.1. 
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 the end of the Stable Dose 
Phase (Week 4) to the end of the Double-Blind Withdrawal Phase (Week 6) 
• 
ESS: Change in ESS score from the end of the Stable Dose Phase (Week 4) to 
the end of the Double-Blind Withdrawal Phase (Week 6) 
4.2. 
KEY SECONDARY EFFICACY ENDPOINT 
• 
Patient Global Impression of Change (PGIc): Percentage of subjects reported 
as worse (minimally, much, or very much) on the PGIc at the end of the 
Double-Blind Withdrawal Phase (Week 6) 
 
4.3. 
OTHER SECONDARY EFFICACY ENDPOINTS 
• 
Clinical Global Impression of Change (CGIc): Percentage of subjects reported 
as worse (minimally, much, or very much) on the CGIc at the end of the 
Double-Blind Withdrawal Phase (Week 6) 
• 
Functional Outcomes of Sleep Questionnaire Short Version (FOSQ-10): Change 
in the total score from the beginning of the Titration Phase (Day -1) to the 
end of the Stable Dose Phase (Week 4) and from the end of the Stable Dose 
Phase (Week 4) to the end of the Double-Blind Withdrawal Phase (Week 6) 
4.4. 
EXPLORATORY ENDPOINTS  
• 
Changes in the 5 FOSQ-10 subscales from the beginning of the Titration Phase 
(Day -1) to the end of the Stable Dose Phase (Week 4) and from the end of 
the Stable Dose Phase (Week 4) to the end of the Double-Blind Withdrawal 
Phase (Week 6) 
• 
Change in the percentage of nights that the primary OSA therapy is used in 
the Screening Phase to each subsequent phase (Titration and Stable Dose) in 
the study 
• 
Change in the percentage of nights that the primary OSA therapy is used in 
the Stable Dose Phase to the Double-Blind Withdrawal Phase 


 
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• 
Change in PSG parameters including total sleep time (TST), time in Stages 
N1, N2, N3, wake after sleep onset (WASO), number of awakenings, apnea 
index (AI), AHI, central apneas, SaO2 nadir, and SaO2 mean from the end of 
the Stable Dose Phase (Week 4) to the end of the Double-Blind Withdrawal 
Phase (Week 6) 
4.5. 
PHARMACOKINETIC ENDPOINTS 
Not applicable 
4.6. 
PHARMACODYNAMIC ENDPOINTS  
Not applicable 
4.7. 
SAFETY ENDPOINTS  
To evaluate the safety and tolerability evaluations as determined by the occurrence of 
and/or changes in: 
• 
Treatment-emergent adverse events (TEAEs) 
• 
Change in clinical laboratory tests (chemistry, hematology, and urinalysis) 
• 
Vital signs 
• 
12-lead electrocardiograms (ECGs) 
• 
C-SSRS 
 


 
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5. 
STATISTICAL HYPOTHESES FOR TRIAL OBJECTIVES 
The 2 co-primary hypotheses, corresponding to the 2 co-primary efficacy variables 
(MWT and ESS), are the following:  
• 
JZP-110 is superior to placebo as measured by change in the mean sleep latency 
time (in minutes) as determined from the first four trials of a 40-minute MWT 
from the end of the Stable Dose Phase (Week 4) to the end of the Double-Blind 
Withdrawal Phase (Week 6) 
 
The statistical null hypothesis is that for the MWT mean sleep latency time, the 
mean change in the mean sleep latency time (in minutes) from the end of the 
Stable Dose Phase (Week 4) to the end of the Double-Blind Withdrawal Phase 
(Week 6) for the JZP-110 group is the same as  the mean change in the mean 
sleep latency time (in minutes) from the end of the Stable Dose Phase (Week 4) 
to the end of the Double-Blind Withdrawal Phase (Week 6) for the placebo 
group.  
 
• 
JZP-110 is superior to placebo as measured by change in ESS score from the end 
of the Stable Dose Phase (Week 4) to the end of the Double-Blind Withdrawal 
Phase (Week 6) 
 
The statistical null hypothesis is that for the ESS score, the mean change from 
the end of the Stable Dose Phase (Week 4) to the end of the Double-Blind 
Withdrawal Phase (Week 6) for the JZP-110 group is the same as  the mean 
change from the end of the Stable Dose Phase (Week 4) to the end of the 
Double-Blind Withdrawal Phase (Week 6) for the placebo group. 
In addition to the 2 co-primary hypotheses, the key secondary hypothesis is: 
 
• 
JZP-110 is superior to placebo as measured by Patient Global Impression of 
Change (PGIc) at the end of the Double-Blind Withdrawal Phase (Week 6). 
 
The statistical null hypothesis is that for the PGIc, the proportion of subjects 
reported as worse (minimally, much, or very much) at the end of the Double-
Blind Withdrawal Phase (Week 6) for JZP-110 group is the same as  the 
proportion of subjects reported as worse (minimally, much, or very much) at the 
end of the Double-Blind Withdrawal Phase (Week 6) for the placebo group.   
                                                                                                                                                  


 
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6. 
ANALYSIS POPULATIONS 
6.1. 
SAFETY POPULATION 
The Safety Population will include 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. 
 
In addition, the subjects who received at least one dose of study medication at the 
study Phase (e.g., Titration, Stable Dose, and Double-Blind Withdrawal) will be 
presented by the study phase. 
 
6.2. 
MODIFIED INTENT-TO-TREAT POPULATION  
The Modified Intent-to-Treat (mITT) population will include subjects who were 
randomized in the Double-Blind Withdrawal Phase, who received at least one dose of 
study medication in the Double-Blind Withdrawal Phase, and who have a Week 4 (end of 
Stable Dose Phase) and at least one post-Week 4 assessment of the MWT or ESS.  If a 
subject in the mITT Population does not have an assessment for a particular efficacy 
endpoint, that subject will be excluded in the analysis of that endpoint. 
The mITT population will be used for efficacy,functional outcomes, and quality of life 
analyses.  
6.3. 
  PER PROTOCOL POPULATION  
The Per-Protocol (PP) population will include subjects who completed the trial 
according to protocol specifications without a major violation. Based on the protocol 
deviation management plan, a major violation will be identified by an  exclusion from 
Per-Protocol population flag in the study protocol deviation report. The reasons for 
exclusion will also be detailed in the study protocol deviation report. Subjects who 
complete the Titration and Stable Dose Phases of the study, but who do not meet 
criteria for randomization into the Double-Blind Withdrawal Phase will be considered 
completers of the Titration and Stable Dose Phases of the trial, but will not be included 
as completers of the Double-Blind Withdrawal Phase.  
 
The categories of major protocol deviations will be defined in the protocol deviation 
management plan, and the plan will be approved before unblinding the study.  
The Per-Protocol population will be used in a secondary analysis of the co-primary 
endpoints and the key secondary endpoint. 
 


 
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7. 
EFFICACY ASSESSMENTS 
7.1. 
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. A five-trial, 40-minute MWT will be performed at the beginning 
of the Titration Phase (Day -1) and at the Week 4 and 6 visits (or Early 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. 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 beginning of the Titration Phase (Day -1) 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. 
 
7.2. 
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 (Protocol 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 beginning of the Titration Phase (Day -1) and at 
Weeks 2, 4, and 6 (or Early Termination). The ESS provides a measure of a person’s 
general level of daytime sleepiness, or their average sleep propensity in daily life. It is a 
validated measure with high specificity and sensitivity for assessing subjective 
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7.3. 
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 (Protocol Appendix 9). 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 condition at the beginning of the Titration 
Phase relative to his/her experience with this patient population. 
 
7.4. 
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 on a 7-point scale ranging from 1 = very much improved to 7 = 
very much worse at Week 4 (Protocol Appendix 10) and at Week 6 (or Early Termination) 
(Protocol Appendix 11). 
 
7.5. 
PATIENT GLOBAL IMPRESSION OF CHANGE (PGIC) 
The PGIc is a 7-point Likert-type rating scale and a widely used assessment to assess 
efficacy in clinical drug trials. Subjects will rate the change in their condition on a 7-
point scale ranging from 1 = very much improved to 7 = very much worse at Week 4 
(Protocol Appendix 12) and Week 6 (or Early Termination) (Protocol Appendix 13). 
 
7.6. 
FUNCTIONAL OUTCOMES OF SLEEP QUESTIONNAIRE SHORT 
VERSION (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 abilities are improved by effective treatment. The FOSQ-10 is a short version of 
the original 30-item FOSQ that has been shown to perform similarly to the longer 
version. 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. Subjects will complete the FOSQ-10 at the beginning of the Titration Phase 
(Day -1) and at Week 4 and 6 (or Early Termination) (Protocol Appendix 6). 
 
7.7. 
PRIMARY OSA THERAPY USE 
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 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 Double-Blind 


 
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Withdrawal Phase (Week 6). 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 Double-Blind Withdrawal Phase (Week 
6). 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 phase.  
 
Subjects will be encouraged to stay on their current primary OSA therapy at the same 
level of use throughout the study. 
 


 
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8. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
8.1. 
GENERAL METHODS 
Unless otherwise specified, for numeric data, descriptive statistics will include the 
number of subjects with data to be summarized (n), mean, standard deviation (SD), 
median, minimum (min) and maximum (max). The same number of decimal places as in 
the raw data will be presented when reporting min and max, 1 more decimal place than 
in the raw data will be presented when reporting mean and median, and 2 more 
decimal places than in the raw data will be presented when reporting SD. If the raw 
data have 3 decimals or more, 3 decimals will be presented for mean, median, min and 
max, and SD.  
All categorical/qualitative data will be presented using absolute and relative frequency 
counts and percentages. All percentages will be presented with one decimal point. 
Percentages equal to 100 will be presented as 100% and percentages will not be 
presented for zero frequencies, but the categories whose counts are zero will be 
displayed for the sake of completeness. 
P-value > 0.9999 will be present as ‘>0.9999’ and p-value < 0.0001 will be presented as 
‘< 0.0001’. 
All subject data will be summarized by study Phase (e.g., Titration, Stable Dose, and 
Double-Blind Withdrawal) separately. All data will be summarized in the following 
manner, unless specified otherwise. 
• 
In the Titration and Stable Dose Phases, the analyses will be summarized overall 
and by Stable Dose level (e.g., JZP-110 75 mg, 150 mg, or 300 mg). If a subject 
terminates early before reaching the Stable Dose Phase, then the last dose level 
that subject is taking in the study will be used.   
• 
For randomized subjects, the analyses will be summarized by treatment group 
(Placebo or Combined JZP-110) for the Double-Blind Phase.    
• 
For randomized subjects who received JZP-110, the analyses will  also be 
summarized overall and by Stable Dose level of JZP-110.  
All analyses and summary outputs will be generated using SAS® version 9.3 (or higher). 
All data collected in this study will be presented in by-subject listings.    


 
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8.2. 
KEY DEFINITIONS 
8.2.1. 
Baseline  
The Baseline measurement for a variable is defined as the last non-missing value from 
the baseline visit measured prior to the first dose of the study drug. If a subject has 
repeated measurements from the baseline visit, then the last repeated non-missing 
value will be used. If there is not a value from the scheduled baseline visit, the last 
non-missing value from other screening visits measured or unscheduled visits measured 
prior to the first dose of study drug will be used.  
The baseline will be used for efficacy evaluations during the Titration and Stable Dose 
Phases.   
For the subjects who were randomized in the Double-Blind Withdrawal Phase, the last 
non-missing value from the visit measured at the end of the Stable Dose Phase (Week 4) 
will be used as ‘efficacy baseline’ for primary efficacy evaluation.  
8.2.2. 
Study Day 
A study day will be assigned as follows: 
• 
The first dose of study drug is designated as Day 1. 
• 
For visit days after Day 1, study day = visit date - Day 1 date + 1. 
• 
For visit days prior to Day 1, study day = visit date - Day 1 date.  Thus, study 
days for screening visit are negative numbers.  There is no “Day 0”. 
• 
A subject’s treatment end date is defined by the subject’s last dose date in the 
study. 
• 
A subject’s study end date is defined by the date of the subject’s last 
assessment including the safety follow up in the study.  
 
8.2.3. 
JZP-110 Exposure 
JZP-110 exposure is defined as the days  that a dose of JZP-110 is taken , for each JZP-
110 dose level and all JZP-110 dose levels combined.  
 
8.2.4. 
Study Phase 
The following study phases are defined for analyses: 
 
• 
The Titration Phase is the period from the first dose of study drug up to Week 2 
(Visit 7) for subjects who enter the Stable Dose Phase, or to the Early 
Termination visit for subjects who discontinue without reaching the Stable Dose 
Phase. 
 


 
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• 
The Stable Dose Phase is the period from the first dose of study drug after the 
Week 2 (Visit 7) visit to the last day of the Week 4 (Visit 9)  for subjects who did 
not enter the Double-Blind Withdrawal Phase or to the Early Termination visit for 
subjects who discontinue prior to Double-Blind Withdrawal Phase. For the 
subjects who enter the Double-Blind Withdrawal Phase, the stable dose phase is 
the period from the first dose of study drug after the Week 2 (Visit 7) to the day 
of the randomization date.  
 
• 
The Double-Blind Withdrawal Phase is the period from the day after the 
randomization date through the Week 6 (Visit 11) visit, or to the Early 
Termination visit for subjects who discontinue prior to the Week 6 (Visit 11) 
visit. 
 
8.3. 
VISIT WINDOWS 
The unscheduled or early termination (ET) visit will be mapped to a scheduled visit for 
analysis using the date of collection/assessment as a basis to determine study day and 
then study day will be mapped to the intended visit. The table below contains the 
analysis visit windows.  
 
Once analysis visit windows are assigned, all visits, including scheduled visits, 
unscheduled visits, and ET visits will be eligible for being flagged as the “analyzed 
record” within the analysis visit window, a subject’s individual analysis visit window 
could potentially contain more than one visit.  In the event of multiple visits falling 
within an analysis visit window or in case of a tie, the following rules will be used in 
sequence to determine the “analyzed record” for the analysis visit window: 
 
• 
If there is a scheduled visit/week for the analysis visit window, then the 
scheduled visit/week data will be used. 
• 
If there is no scheduled visit/week for the analysis visit window, the data closest 
to the scheduled day will be used.   
• 
If there is no scheduled visit/week for the analysis visit window and there is a tie 
between the data in the number of days before and after the scheduled day, the 
later data will be used.   
 
The unscheduled or early termination visit will be mapped to a scheduled visit before 
the imputation methods are used for handling dropouts and missing data for efficacy 
endpoints.  
 
The data not flagged as the “analyzed record” will also be listed in subject listings.   
 
 


 
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Study Day Window 
Scheduled day   
Scheduled Visit/Day or 
Week 
Days (-31) to (-3) 
Day -3 
Visit 1/Screening  
Day (-2) to (-1)  
Day -2 & -1 
Visit 
2/ 
”Beginning 
of 
Titration Phase” 
Day  1 - 4 
Day 3 
Visit 3/Day 3 
Day 5 - 7 
Day 6 
Visit 4/Day 6 
Day 8 - 10 
Day 9 
Visit 5/Day 9 
Day 11 - 13 
Day 12 
Visit 6/Day 12 
Day 14 - 17 
Day 15 
Visit 7/Week 2 
Day 18 – 25 
Day 22 
Visit 8/Week 3 
Day 26 – 32  for the non-
randomized subjects; Day 
26 to the day of the 
randomization date for the 
randomized subjects 
Day 28 & 29 
Visit 9/Week 4 
Day 1 to Day 10 after the  
randomization date for the 
randomized subjects 
Day 36 
Visit 10/Week 5”Beginning 
of Double-Blind Withdrawal 
Phase” 
Day 11 to 20 after the day 
of the randomization date 
for the randomized subjects 
Day 42 & 43 
Visit 11/Week 6 
Day > Date of Visit 9/Week 
4   for non-randomized 
subjects, Day >20 after the 
day of the randomization 
date for the randomized 
subjects 
Date of Visit 9/Week 4 + 2 
weeks for non-randomized 
subjects; Day 57 for 
randomized subjects 
Visit 12/Week 8 
 
8.4. 
MISSING DATA 
For the analysis of the co-primary efficacy parameters of MWT mean sleep latency time 
and the total ESS score, missing data will be imputed using a single imputation approach 
(SI) - the last observation carried forward (LOCF, i.e. the last-observation during the 
Double-Blind Withdrawal Phase) for the primary analysis. Another SI approach (mean 
imputation) will be used for imputation to assess the potential impact of missing data as 
a sensitivity analysis described in section 10.1.3.1.  Additional sensitivity analyses will 
be conducted to investigate robustness of primary analysis method; the details are 
described in section 10.1.3.2. 
 
The algorithm of calculation of the MWT mean sleep latency time and the total ESS 
score is described in Section 10.1.   
  


 
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For the key secondary efficacy parameter of PGIc and the other efficacy endpoint CGIc, 
missing data will be imputed using a single imputation approach (SI) - the last 
observation carried forward (LOCF, i.e. the last-observation during the Double-Blind 
Withdrawal Phase) for primary analyses. Two SI approaches (worst case and varies by 
early termination reason) will be used to impute the missing data to assess the potential 
impact of missing data as sensitivity analyses.  
 
8.5. 
LEVEL OF SIGNIFICANCE AND MULTIPLICITY ADJUSTMENT 
Subjects who were randomized to continue on JZP-110 in the Double-Blind Withdrawal 
Phase will be treated as a single group regardless of the dose of JZP-110 that they 
received. Thus, there will be no multiplicity issues with respect to multiple doses in the 
hypotheses testing. A significance level of 0.05 will be used. A fixed sequential testing 
strategy will be employed to address the multiplicity issues in testing multiple 
endpoints (co-primary and key secondary endpoints). 
 
To address the multiplicity in the analyses of co-primary and key secondary efficacy 
endpoints, a fixed hierarchical testing sequence will be used. Testing will begin with 
the comparison of combined JZP-110 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 from the primary analysis before the test can proceed to 
the comparison of combined JZP-110 versus placebo for the key secondary efficacy 
endpoint PGIc. Testing will stop when a significance level exceeds 0.05. This 
gatekeeping approach will control the family-wise error rate at 0.05.  
 
8.6. 
POOLING OF CENTERS AND REGION 
Because of the large number of centers and the fact that many centers have a small 
number of subjects, analyses will not be performed by center and will not include an 
adjustment for center. Data from all investigative sites will be pooled for the primary 
analyses.  
Data will be summarized by region (North America and Europe) for specified analyses. 
 
8.7. 
SUBGROUPS AND SUBGROUPS ANALYSES 
Exploratory analyses of the key efficacy and safety endpoints will be conducted in the 
following subgroups of subjects: 
• 
Subgroups of subjects with compliant or non-compliant use of a primary OSA 
therapy at randomization 
• 
Subgroups of subjects by region (North America and Europe) 
• 
Subgroups of subjects by country (US, Canada, France, Germany, Finland, and 
Sweden) 
 


 
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The following endpoints will be included in the subgroup analyses: 
• 
MWT: Change in the mean sleep latency time (in minutes) as determined from 
the first four trials of a 40-minute MWT from end of the Stable Dose Phase (Week 
4) to the end of the Double-Blind Withdrawal Phase (Week 6)  
• 
ESS: Change in total ESS score from end of the Stable Dose Phase (Week 4) to the 
end of the Double-Blind Withdrawal Phase (Week 6) 
• 
PGIc: Percentage of subjects reported as worse from end of the Stable Dose 
Phase (Week 4) to the end of the Double-Blind Withdrawal Phase (Week 6)  
• 
CGIc: Percentage of subjects reported as worse from end of the Stable Dose 
Phase (Week 4) to the end of the Double-Blind Withdrawal Phase (Week 6) 
• 
FOSQ-10: Change in the total score from the end of the Stable Dose Phase (Week 
4) to the end of the Double-Blind Withdrawal Phase (Week 6) 
• 
TEAEs  
 
For the subgroup of subjects by country, only descriptive statistics will be performed. 


 
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9. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION 
9.1. 
SUBJECT DISPOSITION AND WITHDRAWALS 
Number of all enrolled  subjects and number and percentage of subjects in each 
analysis population will be presented.  In addition, the number of subjects who 
completed/prematurely discontinued and reason for discontinuation will be presented 
by phase for each analysis population and subgroup of subjects by region. 
The summary of disposition over time will show the number of subjects terminating the 
study in each week. 
For the screen failure subjects, reasons for screen failure will be summarized 
separately.  
 
9.2. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographics and baseline characteristics will be summarized based on the safety, 
mITT,  Per-protocol populations, and subgroups of subjects by region.  
  
Demographics and baseline characteristics include: age, gender, race, ethnicity, 
country, height, weight, and Body Mass index (BMI). 
 
• 
Height (in cm) = height (in inches) * 2.54 
• 
Weight (in kg) = weight (in lbs) * 0.4536 
 
For the screen failure subjects, demographics will be summarized separately.  
 
In addition, the following variables will be summarized: 
• 
Baseline disease severity (at the beginning of the Titration Phase): MWT mean 
sleep latency time, total ESS score, and clinical global impression of severity 
(CGIs) 
• 
Randomization stratification factor (compliant and non-compliant use of a 
primary OSA therapy)at randomization as collected on the CRF 
• 
Efficacy endpoints  at the end of Stable Dose Phase (Week 4): MWT mean sleep 
latency , total ESS score, CGIc, and PGIc. 


 
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9.3. 
MEDICAL HISTORY 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA), Version 18.0. 
Medical history data will be summarized by system organ class (SOC) and preferred term 
(PT) for the safety population.  
9.4. 
MEDICATION/PROCEDURE 
Medications will be coded using WHO DRUG dictionary, Version: March, 2015. 
Procedures will be coded using MedDRA, Version 18.0. 
9.4.1. 
Prior Medication 
Prior medications will be defined as medications with a start date prior to first dose of 
the study drug. The stop date of the medication may be before or after the first dose of 
study drug or the medication may be ongoing. If a start date is completely missing, then 
the medication will be considered a prior medication.   
Prior medications will be summarized by anatomical therapeutic chemical (ATC) level 3 
term and PT based on the safety population.  
9.4.2. 
Concomitant Medication and Procedure 
Concomitant medications will be defined as medications with a stop date on or after the 
first dose of study drug or any medication that is ongoing.  The start date of the 
medication may be before or after the first dose of study drug. A medication with 
completely missing use dates or partially missing use dates without evidence that the 
medication was stopped prior to the first dose of study drug will be considered a 
concomitant medication. Concomitant procedures will be defined as procedures with a 
procedure date on or after first dose of study drug. A procedure with a completely or 
partially missing use date without evidence that the procedure was conducted prior to 
the first dose of study drug will be considered a concomitant procedure. 
Concomitant medications during each phase will be summarized by ATC level 3 term 
and PT. Procedures will be summarized by MedDRA SOC and PT. The summaries will be 
based on the safety population.  
9.4.3. 
Protocol Deviations 
Before database lock, the cumulative protocol deviation report will be generated by the 
 clinical team and reviewed by the Jazz Medical Monitor and Lead Statistician per 
the protocol deviation management plan. Source data will include both deviations 


 
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reported directly from the sites and deviations identified from CRF data through 
programmatic edit checks. A flag of exclusion from Per-Protocol population due to 
major violation(s) will be identified and the reasons for exclusion from Per-Protocol 
population will be documented based on discussion by the Jazz Medical Monitor, Lead 
Statistician, and Clinical Operations Lead. The flag of exclusion from the Per-Protocol 
population and the reason for exclusion from the Per-Protocol population will be 
included in the cumulative protocol deviation report and the final protocol deviation 
report.  After database lock, the final protocol deviations report will be filed in the TMF 
and will be used as source data for the clinical study database. 
Major protocol deviations will be summarized  for each treatment phase based on the 
safety population. Major protocol deviations will also be summarized by randomized 
treatment group for the Double-Blind Withdrawal Period based on the mITT population.  
   


 
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10. 
EFFICACY 
Observed data at each time point and change from the beginning of the Titration Phase 
(baseline) or the end of the Stable Dose Phase (efficacy baseline) to each subsequent 
time point during each phase will be summarized as described below. For categorical 
data, frequency counts and percentages will be presented in a similar manner. 
10.1. 
CO-PRIMARY EFFICACY ENDPOINTS AND ANALYSES 
The co-primary efficacy endpoints are: 
• 
MWT: Change in the mean sleep latency time (in minutes) as determined from 
the first four trials of a 40-minute MWT from the end of the Stable Dose Phase 
(Week 4) to the end of the Double-Blind Withdrawal Phase (Week 6) 
• 
ESS: Change in ESS score from the end of the Stable Dose Phase (Week 4) to the 
end of the Double-Blind Withdrawal Phase (Week 6) 
The mean sleep latency time at each time point is the average of sleep latency time (in 
minutes) from the first four trials of a 40-minute MWT at the specific time point. If two 
or more of the first four individual trial MWT sleep latencies  are  missing at a given 
time point, the mean sleep latency  on the MWT will be set to missing  at the specific 
time point. If one of the first four individual trial MWT sleep latencies  is missing, the 
mean of the remaining three of the first four MWT trials will be used for calculating the 
mean sleep latency  on the MWT at that specific time point. 
The MWT sleep latency  can range from 0 to 40 minutes, with higher latencies indicating 
greater ability to stay awake. Thus, an increase in mean sleep latency  on the MWT 
represents an improvement in the ability to stay awake.  
The ESS total score is the sum of eight item scores. If three or more item scores are 
missing at a specific time point, the ESS total score will be set to missing. If one or two 
ESS items are missing at a specific time point, the mean of the remaining seven or six 
non-missing ESS items at that time point will be used to impute the missing ESS items. 
The ESS total score will be calculated as the sum of the observed and the imputed item 
scores.  
 
The ESS score can range from 0 to 24 points, with higher scores indicating a greater 
chance of dozing. Thus, a decrease in ESS score represents an improvement in excessive 
sleepiness.  
 
10.1.1. 
Primary Analysis 
For the analysis of the co-primary efficacy endpoints, an analysis of covariance 
(ANCOVA) model will be used. The response variable will be the change from the end of 


 
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the Stable Dose Phase (Week 4) to the end of the Double-Blind Withdrawal Phase (Week 
6). This model will include the following fixed effects:  
• 
Treatment (with 2 levels: Combined JZP-110 and Placebo), 
• 
‘Efficacy Baseline’, defined as the MWT or ESS measurement at the end of the 
Stable Dose Phase (Week 4) 
• 
Randomization stratification factor (with 2 levels: compliant and non-compliant 
use of a primary OSA therapy) 
 
Missing data will be imputed using the LOCF approach.  
SAS PROC GLM will be used to carry out this analysis. Estimates of the least squares (LS) 
mean treatment difference versus placebo and their 95% confidence intervals will be 
presented. The primary analysis will be based on the mITT population. 
10.1.2. 
Secondary Analysis 
For both co-primary efficacy endpoints, the analysis will be performed using the same 
statistical model as the primary analysis based the PP population, instead of the mITT 
population. 
 
10.1.3. 
Sensitivity Analysis 
This section describes analyses to explore the potential impact of missing data.  
Importantly, the analyses described in Section 10.1.1 are anticipated to be the most 
appropriate methods; the methods described in this section will be used to qualitatively 
evaluate the robustness of the primary analysis method. Sensitivity analyses will be 
based on the mITT population.  
10.1.3.1. Sensitivity Analyses using Single Imputation (SI) Approach 
The ANCOVA model described in Section 10.1.1 will be used to evaluate the change in 
co-primary endpoints from the end of the Stable Dose Phase (Week 4) to the end of the 
Double-Blind Withdrawal Phase (Week 6) using the SI approach described below.   
Mean imputation approach assumes missing completely at random, meaning that the 
probability of an observed data being missing does not depend on observed data or on 
unobserved data. For each subject, missing data at the end of the Stable Dose Phase 
(Week 4) to the end of the Double-Blind Withdrawal Phase (Week 6) will be replaced 
with the corresponding treatment group mean. 
 
10.1.3.2. Sensitivity Analyses using Multiple Imputation (MI) Approach 
Pattern-Mixture Model using dropout pattern imputation is planned to explore the 
possibility of non-ignorable missing data.  


 
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For the missing data due to dropout, pattern-mixture imputation will be considered 
based on the dropout patterns below.  
Scenario 1: 
MNAR (missing not at random):  
• 
dropout due to lack of efficacy (LOE) in JZP-110 treatment group 
MAR (missing at random): 
• 
dropout due to other reason (not LOE) in JZP-110 treatment group 
• 
dropout due to any reason in the placebo group 
Scenario 2: 
MNAR (missing not at random):  
• 
dropout due to AE in JZP-110 treatment group 
MAR (missing at random): 
• 
dropout due to other reason (not AE) in JZP-110 treatment group 
• 
dropout due to any reason in the placebo group 
Scenario 3: 
MNAR (missing not at random):  
• 
dropout due to AE or LOE in JZP-110 treatment group 
MAR (missing at random): 
• 
dropout due to other reason (not AE or LOE) in the treatment group 
• 
dropout due to any reason in the placebo group 
A tipping point approach will be used to stress test the robustness of the primary 
analysis method; imputed values for subjects in the JZP-110 treatment group that fall 
into a MNAR pattern will be adjusted under the different scenarios above (Carpenter 
and Kenward 2013, pp. 237–239; van Buuren 2012, pp. 88–89) using the delta 
adjustment imputation method.    
 


 
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If the missing data in the combined JZP-110 treatment group falls into a MNAR pattern, 
the analysis will assume that treatment differences over the missing visit (e.g., Week 6) 
progressively decrease from 0%, 10%, 20%, .., and up to 100% (i.e., equivalent to 
placebo). Otherwise, the regression method for monotone missing data on the basis of 
the predicted future pattern for the same treatment group will be applied.  
The tipping point analysis will be performed for each co-primary endpoint separately if 
the primary analysis results are statistically significant (p-value < 0.05). The procedure 
will be implemented using the steps delineated below: 
Step 1:  For the JZP-110 treatment group that falls into an MNAR pattern, delta = k (0%, 
10%, 20%, ..,100%) * LS mean treatment difference obtained from the primary ANCOVA 
analysis will be subtracted from the imputed values. The delta adjustment will be 
performed for the three drop out pattern scenarios above separately: dropout due to 
LOE in the JZP-110 treatment group, dropout due to AE in the JZP-110 treatment group, 
and drop out due to LOE or AE in JZP-110 treatment group. 
Step 2: For other missingness, the regression method for monotone missing data on the 
basis of the predicted future pattern for the same treatment group will be applied.  
Step 3: One hundred (100) imputed datasets will be generated for each MI analysis. 
Each imputed dataset will be analyzed separately using the ANCOVA model specified in 
Section 10.1.1. The final estimate of treatment difference will be the average of the 
estimates based on the 100 individual imputed datasets. The pooling of the individual 
estimates and inferences based on the combined estimate will be handled by SAS 
procedure MIANALYZE.  
Step 1 will be repeated iteratively while increasing the penalty (e.g., 10%, 20%, …, 
100%) for the JZP-110 treatment group that falls into an MNAR pattern  until the tipping 
point value (i.e., where p-value > 0.05) is identified.  
 
10.1.4. 
Subgroup Analysis 
The primary analysis in Section 10.1.1 will be used for the subgroup analyses, however 
the randomization stratification factor (with 2 levels, compliant and non-compliant use 
of a primary OSA therapy based on the CRF data) will be removed from the model for 
analysis by the subgroup of subjects with complaint or non-compliant use of a primary 
OSA therapy at randomization. The analysis will be based on the mITT population. 
 


 
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10.2. 
KEY SECONDARY EFFICACY ENDPOINT AND ANALYSES 
The key secondary efficacy endpoint is percentage of subjects reported as worse 
(minimally, much, or very much) on PGIc at the end of the Double-Blind Withdrawal 
Phase (Week 6).  
10.2.1. 
Primary Analysis 
The percentage of subjects reported as worse  on the PGIc at Week 6 will be calculated 
and summarized by treatment group. Comparison between combined JZP-110 and 
placebo will be performed using a chi-square test. 95% confidence intervals for the 
difference in proportions will be calculated.  Missing data at Week 6 will be imputed 
using LOCF. The analysis will be based on the mITT population. 
10.2.2. 
Secondary Analysis 
The analysis of the key secondary endpoint will be performed using the same statistical 
method as the primary analysis based on the PP population instead of the mITT 
population  
10.2.3. 
Sensitivity Analyses 
Missing data at the end of the Double-Blind Withdrawal Phase (Week 6) will be imputed 
using the following single imputation approaches:  
Approach 1 – SI Varies by Early Termination Reason 
Subjects with missing data the end of the Double-Blind Withdrawal Phase (Week 6) due 
to lack of efficacy or adverse events will be considered worsened (minimally, much, or 
very much) at Week 6. Subjects with missing data at the end of the Double-Blind 
Withdrawal Phase (Week 6) for other reasons will be imputed using LOCF.  
Approach 2 – SI by the Worst-Case  
All subjects with missing data the end of the Double-Blind Withdrawal Phase (Week 6) 
will be considered worsened (minimally, much, or very much).   
The chi-square test will be used to test the treatment difference between combined 
JZP-110 and placebo. 95% confidence intervals for the difference in percentages 
between treatment groups will be calculated. These analyses will be based on the mITT 
population.  


 
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10.2.4. 
Subgroup Analysis 
The primary analysis in Section 10.2.1 will be used for the subgroup analyses. Analyses 
will be based on the mITT population. 
 
    
10.3. 
OTHER SECONDARY EFFICACY ENDPOINTS AND ANALYSES 
Other secondary efficacy endpoints will be analyzed based on the mITT population. 
10.3.1. 
CGIc: Percentage of Subjects Reported as Worse (Minimally, Much, or 
Very Much) at the End of the Double-Blind Withdrawal Phase (Week 6) 
Primary analysis of this efficacy endpoint will be the same as the primary analysis of the 
key secondary efficacy endpoint. See Section 10.2. 
Missing data will be imputed using the LOCF approach. 
Similar analyses will be conducted for the subgroups listed in Section 8.7.  
10.3.2. FOSQ-10: Change in the Total Score from the End of Stable Dose 
Phase to the End of the Double-Blind Withdrawal Phase (Week 6) 
FOSQ-10 total score is the mean of non-missing 5 subscales (General Productivity, 
Activity Level, Vigilance,  Social Outcomes, Intimacy and Sexual Relationship) multiplied 
by 5.    
Change in the FOSQ-10 total score and the 5 FOSQ-10 subscales  from the end of the 
Stable Dose Phase (Week 4) to the end of the Double-Blind Withdrawal Phase (Week 6) 
will be summarized.  Change in the FOSQ-10 total score will be analyzed using a similar 
ANCOVA model as the primary analysis of co-primary efficacy endpoints (Section 
10.1.1). 
 
10.4. 
EXPLORATORY ENDPOINTS 
10.4.1. 
FOSQ-10: Change in the FOSQ-10 total score and 5 FOSQ-10 
Subscales  
Changes in the FOSQ-10 total score and the 5 FOSQ-10 subscales from the 
beginning of the Titration Phase (Day -1) to the end of the Stable Dose Phase 
(Week 4) will be summarized.  


 
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10.4.2. Use of Primary OSA Therapy 
For summaries and analyses of use of primary OSA therapy, if a subject’s primary OSA 
therapy use was missing during the Screening, Titration, Stable Dose, and Double-Blind 
Withdrawal Phases, the missing daily data will be imputed using LOCF method at that 
phase up to the early termination date or the date of the end of that phase, whichever 
is earlier. Otherwise, the missing data will not be imputed.   
The variables below will be summarized for each phase: 
• 
Percentage of nights that subjects use primary OSA therapy in the Screening 
phase (e.g., all available data prior to the first dose date of study drug) and 
subsequent phases (Titration, Stable Dose, and Double-Blind Withdrawal) 
• 
Change in the percentage of nights that the primary OSA therapy is used in the 
Screening Phase to each subsequent phase (Titration and Stable Dose) in the 
study 
 
• 
Change in the percentage of nights that the primary OSA therapy is used in the 
Stable Dose Phase to the Double-Blind Withdrawal Phase 
 
The change in the percentage of nights that the primary OSA therapy is used from the 
Stable Dose Phase to the Double-Blind Withdrawal Phase will be analyzed using a 
Wilcoxon-Mann-Whitney test to compare the treatment difference between combined 
JZP-110 with placebo. 
 
In addition, the following exploratory summary analyses will be conducted:  
 
For subjects who have electronically retrievable data : 
• 
Average number of hours  that a subject used OSA device per night in each 
phase, will be calculated as: 
o Total number of hours that a subject used OSA device in a phase/ total 
number of nights that the subject used OSA device at the phase. The 
nights that the subject did not use OSA device will not be included in the 
calculation.   
 
 
For subjects who don’t have electronically retrievable data, the followings will be 
calculated for each phase : 
o Percentage  of nights  that subjects used an OSA device more than half of 
the night  
o Percentage  of nights that subjects used an OSA device less than half of 
the night  
o Percentage of nights  that subjects used an OSA device with unknown 
duration 


 
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10.4.3. Change in PSG Parameters  
PSG parameters include the following:  
• 
Total sleep time (TST, in minutes) 
• 
Stage N1 time (in minutes) 
• 
Stage N2 time (in minutes) 
• 
Stage N3 time (in minutes)  
• 
Wake time after sleep onset (WASO, in minutes), total minutes of wakefulness 
recorded after sleep onset, as scored by epochs. 
o WASO = Wake epochs/2 - (Sleep Latency {+ Final Wake Time}) 
• 
Number of awakenings 
• 
APNEA Index (AI), the average number of apneas (obstructive, central and 
mixed) in an hour of sleep 
o Calculated as:  60 x total # of apneas / total sleep time in minutes 
• 
AHI, the average number of apneas and hypopneas in an hour of sleep. 
o Calculated as: 60 x total # of (apneas + hypopneas) / total sleep time in 
minutes 
• 
Number of central apneas 
• 
Post-baseline minimum SaO2 value 
• 
SaO2 
 
Change in each PSG parameter, except for number of awakenings and number of central 
apneas, from the end of the Stable Dose Phase (Week 4) to the end of the Double-Blind 
Withdrawal Phase (Week 6) will be analyzed using a similar ANCOVA model as the 
primary analysis of co-primary efficacy endpoints (Section 10.1.1). 
 
Change in number of awakenings and number of central apneas from the end of the 
Stable Dose Phase (Week 4) to the end of the Double-Blind Withdrawal Phase (Week 6) 
will be analyzed using Wilcoxon-Mann-Whitney test to compare the treatment 
difference between combined JZP-110 with placebo.  
 
10.4.4. 
Categorical Analysis for Maintenance of Wakefulness Test 
Categorical summaries will be provided as follows:  
• 
Number and percentage of subjects with an increase in mean sleep latency time 
on the MWT from the Beginning of the Titration Phase to the end of the Stable 
Dose Phase will be summarized by increase every 5 minutes (e.g.,  >=5 min, >=10 
min, >=15 min , >=20 min, >=25 min, and >=30 min)  
 
• 
Number and percentage of subjects with a decrease in mean sleep latency time 
on the MWT from the end of the Stable Dose Phase to the end of Double-Blind 


 
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Withdrawal Phase (Week 6) will be summarized by decrease every 5 minutes 
(e.g., >=5 min, >=10 min, …,>=30 min), respectively.  
 
 
10.5. 
SUMMARY OF EFFICACY ANALYSIS METHODS 
Endpoint 
Time 
Point 
Analysis/ 
Population 
Method 
Missing Data 
Imputation 
Co-primary 
Change from Week 4 in 
MWT, ESS   
Week 6 
Primary/ 
mITT  
ANCOVA 
SI: LOCF 
 
 
Secondary/ 
PP 
ANCOVA 
 
 
 
Sensitivity/ 
mITT 
ANCOVA 
SI: Mean Imputation 
MI: Pattern-mixture 
model using a dropout 
pattern imputation.  
 
 
Subgroup/ 
mITT  
ANCOVA 
SI: LOCF 
Key Secondary 
Worsening in PGIc 
Week 6 
Primary/ 
mITT 
Chi-
square 
SI: LOCF 
 
 
Secondary/ 
PP 
Chi-
square 
 
 
 
Sensitivity/ 
mITT 
Chi-
square 
SI: Varies by early 
termination reason;  
SI: Worst-case 
 
 
Subgroup/ 
mITT 
Chi-
square 
SI: LOCF 
Other Secondary 
Worsening in CGIc 
Week 6 
Primary/ 
mITT 
Chi-
square 
SI: LOCF 
 
 
Subgroup/ 
mITT 
Chi-
square 
SI: LOCF 
Change from Week 4 in 
FOSQ-10 
Week 6 
Primary / 
mITT 
ANCOVA 
 
 
 
Subgroup/ 
mITT 
ANCOVA 
 
Exploratory 
Change in the 
percentage of nights 
that the primary OSA 
therapy is used from 
Week 6 
Primary/ 
mITT 
Wilcoxon 
rank sum  
 


 
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Endpoint 
Time 
Point 
Analysis/ 
Population 
Method 
Missing Data 
Imputation 
the Stable Dose Phase 
to the Double-Blind 
Withdrawal Phase 
 
 
 
 
 
Change from Week 4 in 
number of awakenings  
Week 6 
Primary/ 
mITT 
Wilcoxon 
rank sum  
 
Change from Week 4 in 
number of central 
apneas 
Week 6 
Primary/ 
mITT 
Wilcoxon 
rank sum  
 
Change from Week 4 in 
PSG Parameters, 
except for number of 
awakening and number 
of apneas 
Week 6 
Primary/ 
mITT 
ANCOVA 
 


 
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11. 
SAFETY 
Safety analyses will be based on the safety population. No inferential statistics will be 
provided. Only summary statistics will be provided unless otherwise noted.  Missing 
safety data will not be imputed. 
11.1. 
EXTENT OF EXPOSURE 
Exposure to study drug (in days) will be summarized for each study phase (Titration, 
Stable Dose, and Double-Blind Withdrawal). Exposure to study drug during each phase 
(in days) is calculated as last dose date of study drug – first dose date of study drug + 1.  
Extent of exposure to study drug (in days) will also be summarized by JZP-110 dose level 
(placebo will be considered as dose of 0). Extent of exposure to study drug for a specific 
dose level will be calculated as total number of days during the study that the subject 
was exposed to the specific dose level of the study drug. 
11.2. 
TREATMENT COMPLIANCE  
Compliance with study drug (%) during a specific phase is calculated as: 100 x (total 
number of tablets dispensed – total number of tablets returned)/total number of tablets 
expected to be taken during the specific period (once daily). 
In addition, the number and percentage of subjects in pre-specified compliance 
categories (< 80%, 80-100%, >100%, and  >120%) will be summarized similarly. 
Overall Compliance will also be summarized across Titration, Stable Dose, and Double-
Blind Withdrawal Phases, regardless of dose level. 
 
11.3. 
ADVERSE EVENTS 
AEs will be coded using MedDRA 18 to classify events under primary SOC and PT. 
 
A TEAE is defined as an AE that either begins after the first dose of study drug or 
worsens after the first dose of study drug.  
 
An overview AE, incidence TEAE, and incidence serious TEAE will be summarized by the 
study phase (e.g., Titration Phase, Stable Dose Phase, and Double-Blind Withdrawal 
Phase) and across the study phases, respectively.  
TEAEs will be summarized by SOC and PT, the sorting is based on alphabetical order for 
the SOC and frequency count (descending order) for the PT.  In addition, incidence of 


 
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all TEAEs and serious TEAEs will be summarized by PT, the sorting is based on the 
frequency count (descending order).  
 
For the Titration and Stable Dose Phases, the TEAE will be summarized by Overall, JZP-
110 dose level (75 mg, 150 mg, and 300 mg).   
In the Double-Blind Withdrawal Phase, the TEAE will be presented by randomization 
treatment (placebo, combined JZP-110) and JZP-110 dose level (75 mg, 150 mg, and 
300 mg).  
 Across the Titration, Stable Dose, and Double-Blind Withdrawal Phases, TEAE overview, 
all TEAEs and serious TEAEs will be summarized  by JZP-110 dose level (placebo is 
considered as JZP-110 dose of 0) at the time of onset in the study.   
An overview of adverse events  will include the number and percent of subjects who 
had at least one TEAE, Serious TEAE, TEAE related/suspected related to study drug, 
TEAE related/suspected related to study procedure, study drug withdrawn due to TEAE, 
TEAE of maximum severity, and AE with fatal outcome.  Multiple occurrences of an AE 
are counted only once per subject per SOC and PT for summary tables. 
 
 The following TEAEs will be summarized: 
 
• 
Incidence of all TEAEs 
• 
Incidence of all TEAEs by maximum severity (severe, moderate and mild) 
specified by investigators  
• 
Incidence of TEAEs related/suspected to be related to study drug specified by 
investigators 
• 
Incidence of TEAEs related/suspected to be related to study procedure specified 
by investigators 
• 
Incidence of serious TEAEs 
• 
Incidence of serious TEAEs related/suspected to be related to study drug 
specified by investigators 
• 
Incidence of TEAEs leading to study drug dose reduction   
• 
Incidence of TEAEs leading to study drug dose increase 
• 
Incidence of TEAEs leading to study drug interruption 
• 
Incidence of TEAEs leading to study drug withdrawn and withdrawn from study 
• 
Incidence of TEAEs in which the outcome is fatal 
 
 
 
Incidence of TEAEs occurring in ≥ 5% and ≥ 10% of subjects at the any treatment group 
will be tabulated in a similar manner.   
 
All data collected in the AE case report form (CRF) will be listed in by-subject listings.   


 
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11.3.1. 
Subgroup Analyses 
The following analyses  will be repeated for the subgroups listed in Section 8.7. 
• 
Overview of AEs 
• 
Incidence of all TEAEs  
• 
Incidence of TEAEs related/suspected to be related to study drug specified by 
investigators 
• 
Incidence of TEAEs leading to study drug withdrawn and withdrawn from study  
• 
Incidence of serious TEAEs  
• 
Incidence of TEAEs in which the outcome is fatal 
 
 
11.4. 
LABORATORY EVALUATIONS 
 
If a continuous laboratory value is reported as either below or above the limits of 
quantification, the qualifiers should be dropped and the numeric value used in the 
analysis (e.g., “< 3” should be “3” and “> 200” should be “200”). 
Observed values and the change from baseline to Week 6  in hematology, serum 
chemistry and quantitative urinalysis test results will be summarized.  
 
For hematology and serum chemistry including calculated creatinine clearance, normal 
ranges for each parameter will be used to categorize the test result as low (value lower 
than the lower limit), normal (value within the normal range), or high (value higher 
than the upper limit). For urinalysis, test results will be categorized as normal or  
abnormal. The number and percentage of subjects will be summarized by each 
category.  
 
Additional information on clinical significance will also be included in the listing of lab 
values. 
 
 
11.5. 
VITAL SIGNS 
11.5.1. 
Regular Vital Signs 
For the vital signs obtained on the admission to the site the evenings before the PSG 
nights at Day -1 and the end of Weeks 4 and 6; at Week 2; and at the Follow-up visit or 
at Early Termination, the observed values and the change from baseline in each vital 
sign parameters from the baseline to the end of the Titration and the end of the Stable 
Dose Phases, and from the end of Stable Dose Phase to the end of Double-Blind 
Withdrawal Phase will be summarized.  


 
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The number and percentage of subjects with changes from baseline in blood pressure 
and heart rate from the baseline to the end of the Titration and the end of the Stable 
Dose Phases, and from the end of Stable Dose Phase to the end of Double-Blind 
Withdrawal Phase in the following categories will be summarized:  
 
• 
% of subjects with an increase in HR of ≥15 and ≥30   
• 
% of subjects with a decrease in HR of ≥15 and ≥30   
• 
% of subjects with an increase in SBP of ≥10, ≥20, and ≥30 
• 
% of subjects with a decrease in SBP of ≥10, ≥20, and ≥30 
• 
% of subjects with an increase in DBP of ≥10, ≥20, and ≥30 
• 
% of subjects with a decrease in DBP of ≥10, ≥20, and ≥30 
 
Reference ranges for each vital sign parameter will be used to categorize the results as 
low (lower than the lower limit), within the reference range, or high (higher than the 
upper limit). Shifts in categories from the baseline to the end of the Titration Phase, 
from the baseline to the end of the Stable Dose Phase, and from the end of Stable Dose 
Phase to the end of Double-Blind Withdrawal Phase will be summarized.  
 
Reference ranges: 
Parameter 
Lower Limit of Reference 
Range 
Upper Limit of 
Reference Range 
Systolic Blood Pressure (mmHg) 
90 
155 
Diastolic Blood Pressure (mmHg) 
60 
95 
Heart Rate (beats/min) 
Female: 55, Male 50 
Female: 95, Male 90 
Respiration Rate (breaths/min) 
12 
30 
 
 
11.5.2. 
Blood Pressure and Pulse on the MWT Day 
On the MWT day at the start of the Titration Period (Day -1), blood pressure and pulse 
will be taken approximately 30 minutes after awakening. 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 6 (or Early Termination if PSG/MWT is 
performed), blood pressure and pulse will be taken approximately 30 minutes  before 
dosing. Blood pressure and pulse will be taken at approximately 1, 2, 4, 6, 8, and 10 
hours after dosing. 
 
The blood pressure and pulse parameters obtained on the MWT day will be summarized 
as follows: 
 


 
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• 
Observed values and changes from Day -1 (~0.5 hr relative to “Light on”)  to 
Week 4 and 6 (~(-0.5 hr) relative to dosing) visit 
• 
Observed value and changes from the pre-dose (~(-0.5 hr)) to post-dose (~ 1 hr, 
~2 hrs, ~4 hrs, ~6 hrs, ~8 hrs, and ~10 hrs) at Week 4 and Week 6 visit and 
observed value and change from the (~(0.5 hr)) after awakening to the 2, 3, 5, 7, 
9 and 11 hours after awakening at baseline (Day -1) visit 
 
In addition, mean of blood pressure and pulse based on the seven measurements taken 
during the MWT day (e.g., Day -1 at ~0.5 hr, 2 hrs, 3 hrs, 5 hrs, 7 hr, 9 hrs, and 11 hrs 
after awakening, Week 4 and 6 at ~(-0.5 hr), ~ 1 hr, ~2 hrs, ~4 hrs, ~6 hrs, ~8 hrs, and 
~10 hrs relative to dosing) will be calculated and the mean and mean changes from the 
Day –1 to the Week 4 and 6 visit will be summarized.  
 
The number and percentage of the subjects with maximum change in blood pressure 
and pulse from pre-dose to the any post-dose time points at Week 4 and Week 6 visit, 
and the mean change from Day -1 to Week 4 and Week 6 visit will be summarized by 
following categories:  
 
• 
% of subjects with an increase in HR of ≥15 and ≥30   
• 
% of subjects with a decrease in HR of ≥15 and ≥30   
• 
% of subjects with an increase in SBP of ≥10, ≥20, and ≥30 
• 
% of subjects with a decrease in SBP of ≥10, ≥20, and ≥30 
• 
% of subjects with an increase in DBP of ≥10, ≥20, and ≥30 
• 
% of subjects with a decrease in DBP of ≥10, ≥20, and ≥30 
 
Additional information on clinical significance will also be included in the listing of 
regular/MWT day vital signs. 
 
 
11.6. 
ECG  
Observed data and the change in each ECG parameter [HR, RR, PR, QRS, QT and QT 
corrected with Fridericia’s formula (QTcF)] from baseline to end of Titration Phase, 
from baseline to end of Stable Dose phase and from end of Stable Dose to end of Double 
Blind Withdrawal phase will be summarized. 
The number and percentage of subjects with QT and QTcF values falling into the below 
categories  will be summarized by each study phase.  
Titration Phase and Stable Dose Phase: 
• 
Change from baseline of 30 – 60 msec in QT and QTcF 
• 
Change from baseline of > 60 msec in QT and QTcF 


 
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• 
Post-baseline value > 480 msec and baseline value <= 480 msec in QT and QTcF  
• 
Post-baseline value > 500 msec and baseline value <= 500 msec in QT and QTcF  
 
Double-Blind Withdrawal Phase:  
• 
Change from the end of Stable Dose Phase of 30 – 60 msec in QT and QTcF 
• 
Change from the end of Stable Dose Phase  of > 60 msec in QT and QTcF 
• 
End of Double Blind Withdrawal value > 480 msec and end of Stable Dose value 
<= 480 msec in QT and QTcF  
• 
End of Double Blind Withdrawal value > 500 msec and end of Stable Dose value 
<= 500 msec in QT and QTcF  
 
 
Additional information on clinical significance will also be included in the listing of ECG 
measurements. 
 
11.7. 
COLUMBIA-SUICIDE SEVERITY RATING SCALE 
Suicidal Ideation, Suicidal Behavior, and Self- Injurious Behavior without Suicidal Intent 
at each time point will be classified by C-SSRS outcomes and composite score.  
 
11.7.1. 
C-SSRS Outcomes/Composite Endpoints 
The following C-SSRS outcomes/composite endpoints have binary responses (yes/no).  
   
• 
Suicidal Ideation (Categories 1 – 5) 
1. Wish to be dead 
2. Non-specific active suicidal thoughts 
3. Active suicidal ideation with any methods (not plan) without intent to act 
4. Active suicidal ideation with some intent to act, without specific plan 
5. Active suicidal ideation with specific plan and intent 
• 
Suicidal Behavior (Categories 6 – 10) 
6. Preparatory acts or behavior 
7. Aborted attempt 
8. Interrupted attempt 
9. Non-fatal suicide attempt 
10. Completed suicide 
• 
Suicidal Ideation or Behavior (1-10) 
• 
Self-injurious behavior without suicidal intent 
Composite endpoints based on the above categories are defined below: 
• 
Suicidal ideation:  A “yes” answer during treatment to any one of the five 
suicidal ideation questions (Categories 1-5) on the C-SSRS. 


 
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• 
Suicidal behavior:  A “yes” answer during treatment to any one of the five 
suicidal behavior questions (Categories 6-10) on the C-SSRS. 
• 
Suicidal ideation or behavior: A “yes” answer during treatment to any one 
of the ten suicidal ideation and behavior questions (Categories 1-10) on 
the C-SSRS. 
 
Composite scores based on the above categories are defined below:  
 
Suicidal Ideation score (0 to 5) is based on answers (Yes) to five suicidal ideation 
questions (Categories 1-5) on the C-SSRS. 
0 = no suicidal ideation 
1 = wish to be dead 
2 = Non-specific active suicidal thoughts 
3 = Activity suicidal ideation with any methods (not plan) without intent 
to act 
4 = Activity suicidal ideation with some intent to act, without specific 
plan 
5 = Activity suicidal ideation with specific plan and intent 
 
Suicidal Behavior score (6 to 10) is based on answers (Yes) to the five suicidal behavior 
questions (Categories 6-10) on the C-SSRS.  
0 = no suicidal behavior 
6 = Preparatory acts or behavior 
7 = Aborted attempt 
8 = Interrupted attempt 
9 = Non-fatal suicide attempt  
10 = Completed suicide 
 
Suicidal ideation or behavior score (0 to 10) is based on answers (Yes) to the ten suicidal 
ideation and behavior questions (Categories 1-10) on the C-SSRS. 
 
 
11.7.2. 
Analyses 
The number and percentage of subjects having a response of ‘Yes’ to the above 
outcomes/composite endpoints during each phase will be summarized by category. 
 
In addition, to evaluate potential  treatment emergent findings on the  C-SSRS, the 
following variables will be summarized: 
• 
Shift to the most serious outcome in the C-SSRS outcomes (No suicidal ideation 
or behavior, Suicidal Ideation, and Suicidal Behavior) from baseline to end of 
the Titration Phase, from baseline to end of the Stable Dose phase, from end of 
the Stable Dose phase to end of Double Blind Withdrawal Phase.  


 
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• 
Shift to the maximum score in C-SSRS composite scores (Suicidal Ideation score, 
Suicidal Behavior score, Suicidal Ideation or Behavior score) from baseline to 
end of the Titration Phase, from baseline to end of the Stable Dose Phase, from 
end of the Stable Dose phase to end of Double Blind Withdrawal Phase.  
 
A listing of subjects with suicidal Ideation, suicidal behavior, or self-Injurious behavior 
without suicidal intent based on the C-SSRS  will be provided.      
 


 
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12. 
INTERIM ANALYSES 
No interim analysis is planned. 


 
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13. 
CHANGE FROM ANALYSIS PLANNED IN THE PROTOCOL 
• 
Original text in the protocol Section 9.8.4 
 
Change in the frequency of use of primary OSA therapy from the beginning of the 
Titration Phase (Day -1) to the end of the Stable Dose Phase (Week 4) and from 
the end of the Stable Dose Phase (Week 4) to the end of the Double-blind 
Withdrawal Phase(Week 6) 
 
• 
Has been changed to read in SAP Section 4.4 
 
 
Changes in the 5 FOSQ-10 subscales from the beginning of the Titration Phase 
(Day -1) to the end of the Stable Dose Phase (Week 4) and from the end of the 
Stable Dose Phase (Week 4) to the end of the Double-Blind Withdrawal Phase 
(Week 6) 
Change in the percentage of nights that the primary OSA therapy is used in the 
Screening Phase  to each subsequent phase (Titration and Stable Dose) in the 
study 
 
Change in the percentage of nights that the primary OSA therapy is used in the 
Stable Dose Phase to the Double-Blind Withdrawal Phase 
 
 
 
 
 


 
Jazz Pharmaceuticals 
Protocol: 14-004 
Version 1.0 
Statistical Analysis Plan 
 
 
Page 51 of 51 
14. 
REFERENCE 
1. Carpenter, J. R. and Kenward, M. G. (2013), Multiple Imputation and Its Application, 
New York: John Wiley & Sons. 
2. van Buuren, S. (2012), Flexible Imputation of Missing Data, Boca Raton, FL: Chapman 
& Hall/CRC.